Canad. M. A . J .

WENEP
A NDHOFF: PEPT I C ULCER 1 1 5
A u g . 1 9 4 8 , v o l .' 5 9 j
c r u de c l i ni c al m e t h o ds m i g h t w e l l b e i nap p r o -
p r i at e t o e l i c i t a t e ndo n r e f l e x t h at m i g h t b e
b r o u g h t o u t w i t h a f i ne r t e c h ni q u e . Ei s m ay e r
and Mu l l e r 5 h av e de m o ns t r at e d t h at c l i ni c al l y
ab o l i s h e d r e f l e x e s c o u l d b e e l i c i t e d b y e l e c t r o -
m y o g r ap h i c m e t h o ds .
A s e ar l y as 1 9 1 2 , B ab i ns k i .s t u di e d c o ndi t i o ns
w h e r e i n c au s e s o f h y p e r ac t i v e and ab s e nt r e -
f l e x e s w e r e as s o c i at e d. He m ade h i s f i r s t
s t u di e s 6 w i t h c as e s o f t ab e s c o m p l i c at e d w i t h
an o r g ani c h e m i p l e g i a. A m o ng t h e t y p e s u s u -
al l y de al t w i t h h e c h o s e o ne w h e r e t h e r e f l e x e s
o f al l f o u r l i m b s w e r e c o m p l e t e l y ab o l i s h e d
b e f o r e t h e o ns e t o f h e m i p l e g i a and h e c o m -
m e nt e d as f o l l o w s :
" l I n s u c h c as e s , t h e p y r am i dal l e s i o n w i l l no t i nf l u -
e nc e t h e r e t u r n o f t h e r e f l e x e s . A s a m at t e r o f f ac t ,
o ne c an c o nc e i v e t h at ab s e nt r e f l e x e s c au s e d b y a de e p
al t e r at i o n o f t h e ar c ar e i r r e v e r s i b l e . Ho w e v e r , c as e s
h av e b e e n r e p o r t e d w h e r e i n ab s e nt r e f l e x e s h av e c h ang e d
t o h y p e r ac t i v e o ne s i n t h e p ar al y z e d l i m b s . I n s u c h
i ns t anc e s , t h e r adi c u l ar l e s i o ns m u s t h av e b e e n m o r e
s u p e r f i c i al and l e s s e x t e ns i v e . One m u s t adm i t t h at
ab s e nt t e ndo n r e f l e x e s do no t ne c e s s ar i l y m e an a c o m -
p l e t e p h y s i o l o g i c al i nt e r r u p t i o n o f r e f l e x p at h w ay s . T o
b e c o nv i nc e d o f t h i s f ac t o ne s h o u l d o nl y r e c al l h o w
l o ng , at t i m e s , t e ndo n r e f l e x e s m ay r e m ai n ab o l i s h e d i n
c o nv al e s c e nt s o f p o l y ne u r i t i s .' '
S u c h r e as o ni ng and s u c h e x am p l e s h e l p o ne
t o u nde r s t and t h at an i m p o r t ant p y r am i dal
l e s i o n m ay , i n c e r t ai n c o ndi t i o ns , m ani f e s t
i t s e l f b y s i g ns t h at s p e ak l o u de r t h an a m e r e
- s o l i t ar y p l ant ar e x t e ns i o n.
A f t e r t h i s s h o r t i nc u r s i o n i nt o ne w p at h -
w ay s , i t b e c o m e s p l au s i b l e t o adm i t w i de r
' f r am e s f o r Fr i e dr e i c h ' s at ax i a and f o r h e r e di -
t ar y de g e ne r at i o ns at l ar g e . T h e m o r e o ne s e e s
s u c h c as e s , t h e m o r e o ne i s i nc l i ne d t o b e l i e v e
i n a v as t g r o u p o f s p i no - c e r e b e l l ar de g e ne r a-
t i o ns w i t h o r w i t h o u t al l c o m p o ne nt s b e i ng
ne c e s s ar i l y p ar t o f t h e p i c t u r e .
REFERENCES
1 . REc HT MA N, A . M. A ND A LPERS , B . J .: A r c h . Ne u r o l .
& Ps y c h ., 3 2 : 2 4 8 , 1 9 3 4 .
2 . GUI LLA I N, G. A ND MOLLA RET , P.: Pr e s s e Me di c al e , 7 3 :
1 4 1 7 , 1 9 3 3 .
3 . S HERMA N, I .: A r c h . Ne u r o l . & Ps y c h ., 3 2 : 1 2 8 2 , 1 9 3 4 .
4 . KREB S , E. A ND MOLLA RET , P.: Re v . Ne u r o l ., 2 : 8 2 , 1 9 3 1 .
5 . EI s MA YER, J . A ND MULLER, K.: De u t s . Z e i t s f u r
Ne r v e nh ., 4 3 : 2 0 1 ( q u o t e d b y Kr e b s and Mo l l ar e t ) .
6 . B A B I NS KI , J ., VI NCENT , C. A ND J A RKOWS KI , J .: Re v .
Ne u r o l ., 1 : 4 6 3 , 1 9 1 2 .
1 4 1 4 Dr u m m o nd S t .
RES UME
Pr s e nt at i o n de h u i t c as d ' at ax i e de Fr i e dr e i c h
dans c i nq g e n6 r at i o ns de de u x f am i l l e s al l i e e s . Le
s y ndr 6 m e c o m p r e nd l e de b u t e nt r e 7 e t 1 3 ans e t 1 ' ag -
g r av at i o n p r o g r e s s i v e de s s i g ne s c l as s i q u e s : at ax i e ,
ny s t ag m u s , r i g i di t e , p ar o l e s c ande e , s c o l i o s e e t p i e ds
c r e u x v ar u s - 6 q u i ns . La m al adi e s e m b l e s ' 8 t r e t r ans -
m i s e , dans c e t t e f am i l l e , s e l o n u n f ac t e u r r e c e s s i f no n
l i e au s e x e . Un m ar i ag e e nt r e c o u s i ns g e r m ai ns , h
l a t r o i s i e m e g &n6 r at i o n, e u t p e r m i s l ' ap p ar i t i o n d ' u n
m o de do m i nant , c e q u i n ' a p as ' t e l e c as . Par ai l l e u r s ,
] a m al adi e s ' e s t m ani f e s t e e c h e z de u x f r e r e s do nt l e s
as c e ndant s n ' e n o nt p as e t 6 t o u c h e s du r ant q u at r e
g e n6 r at i o ns . Ce t t e o b s e r v at i o n p e r m e t de r e ndr e
c o m p t e de 1 ' ap p ar i t i o n s o u dai ne de c as s o i - di s ant
s p o r adi q u e s . L ' at ax i e de Fr i e dr e i c h p ar al t c o ns t i t u e r ,
av e e l a p ar ap 1 e g i e s p as t i q u e h 6 r 6 di t ai r e e t l ' at ax i e
h e r 6 do - e 6 r 6 b e l l e u s e , u I i g r o u p e de
"
d6 g e n6 r e s e e nc e s
e c r 6 b e l l o - r ac h i di e nne s ' do nt l e s e 1 6 ni e nt s p e u v e nt
n' 8 t r e p as t o u s p r e s e nt s dans t o u s l e s c as .
PA UL DE B ELLEFEUI LLE
T HE NEURO- HUMORA L A S PECT S OF
PEPT I C ULCER FORMA T I ON*
J . We ne r , B .S c ., M.S c ., M.D.C.M.t
and
H. E. Ho f f , B .S ., B .A ., D.Ph i l ., M.D.t
Mo nt r e al , Q u e .
I NT RODUCT I ON
I N
s p i t e
o f t h e e ar l y and
b r i l l i ant
o b s e r v at i o ns
o f c l i ni c al p at h o l o g i s t s , no t ab l y Ro k i t ans k y ,
w h o f i r s t c al l e d at t e nt i o n t o t h e as s o c i at i o n o f
b r ai n dam ag e and p at h o l o g i c al c h ang e s i n t h e
s t o m ac h , s u g g e s t i ng a ne u r o g e ni c b as i s f o r u l c e r
f o r m at i o n, t h i s c o nc e p t w as f o r m any de c ade s
o v e r s h ado w e d b y t h e v i e w s o f Vi r c h o w and h i s
f o l l o w e r s w h o h e l d t h at p e p t i c u l c e r w as e s s e n-
t i al l y a l o c al di s e as e .
A l t h o u g h t h e ne u r o g e ni c c o nc e p t w as l at e r
s u p p o r t e d b y b o t h e x p e r i m e nt al and c l i ni c al
s t u di e s , i t w as no t u nt i l t h e p u b l i c at i o n
o f
Cu s h i ng ' s B al f o u r Le c t u r e , r e l at i ng p e p t i c
u l c e r t o di s t u r b anc e s i n t h e i nt e r b r ai n, t h at
t h e i nt e r e s t i n t h i s as p e c t o f u l c e r f o r m at i o n
w as r e v i v e d. I n t h e y e ar s t h at f o l l o w e d, t h e r e
h as b e e n an i nc r e as e i n b o t h c l i ni c al and e x -
p e r i m e nt al r e p o r t s i ndi c at i ng t h at t h e i ni t i a-
t i o n and t h e m ai nt e nanc e o f c h r o ni c p e p t i c
u l c e r i n m an m ay b e m e di at e d t h r o u g h a s u b -
s t r at u m o f ne r v o u s ac t i v i t y .
T h e e m o t i o nal and p s y c h i c as p e c t s o f t h e
u l c e r p r o b l e m h av e b e e n s t r e s s e d i n t h e p as t ,
b u t i t i s o nl y i n r e c e nt y e ar s t h at p s y c h i at r i s t s
i n t h e i r e x ac t i ng anal y s i s o f t h e f e at u r e s o f
t h e p e r s o nal i t y w h i c h p r e do m i nat e i n p at i e nt s
w i t h p e p t i c u l c e r , h av e r e - e nf o r c e d t h e c o nc e p t
t h at p e p t i c u l c e r m ay b e a p s y c h o s o m at i c di s -
e as e , i ndu c e d b y an i m b al anc e o f t h e au t o no m i c
ne r v o u s s y s t e m r e s u l t i ng f r o m s u s t ai ne d e m o -
t i o nal c o ni f l i c t s . T h e b e ne f i t t h u s f ar de r i v e d
f r o m v ag o t o m y i n t h e t r e at m e nt o f p e p t i c u l c e r
*
Fr o m t h e De p ar t m e nt o f Ph y s i o l o g y , Mc Gi l l Uni -
v e r s i t y , Mo nt r e al .
t G. Ru t h e r f u r d Cav e r h i l l Fe l l o w i n Me di c i ne , Me Gi l l
Uni v e r s i t y , Fac u l t y o f Me di c i ne , Mo nt r e al .
t S u p p o r t e d b y a g r ant f r o m t h e B l anc h e E. Hu t c h i n-
s o n Re s e ar c h Fu nd, Fac u l t y o f Me di c i ne , Me Gi l l Uni v e r -
s i t y , Mo nt r e al .
WENER A ND HOFF: PEPT I C ULCER
Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
t e nds t o s u p p o r t t h i s v i e w . I t t h u s ap p e ar s
ap p r o p r i at e t o r e v i e w t h e e v i de nc e f o r t h e
ne u r o g e ni c c o nc e p t o f u l c e r f o r m at i o n.
EA RLY HI S T ORY OF T HE NEUROGENI C DOCT RI NE
Ov e r a c e nt u r y ag o , Kam m e r e r ' i n 1 8 2 3 and
Ro k i t ans k y 2 i n 1 8 4 1 f i r s t c al l e d at t e nt i o n t o t h e
as s o c i at i o n o f b r ai n dam ag e and c h ang e s i n
t h e s t o m ac h . Ro k i t ans k y de s c r i b e d t w o t y p e s
o f l e s i o ns i n t h e s t o m ac h , t h e f i r s t , a g e l at i no u s
s o f t e ni ng u s u al l y s e e n i n i nf anc y as s o c i at e d
w i t h de m o ns t r ab l e p at h o l o g i c al c h ang e s o f t h e
b r ai n. He t h o u g h t t h at , " t h e p r o x i m at e c au s e
m ay b e l o o k e d f o r i n t h e di s e as e d i nne r v at i o n
o f t h e s t o m ac h o w i ng t o a m o r b i d c o ndi t i o n o f
t h e v ag u s , and t o t h e e x t r e m e ac i di f i c at i o n o f
t h e g as t r i c j u i c e " . T h e s e c o nd f o r m , w h i c h
o c c u r r e d b o t h i n c h i l dr e n and adu l t s as a r e -
s u l t o f m e ni ng i t i s , e s p e c i al l y w h e n i t i nv o l v e d
t h e b as e o f t h e b r ai n, w as as c r i b e d t o a r e f l e x
ac t i o n o f t h e c e s o p h ag e al and g as t r i c b r anc h e s
o f t h e v ag i .
S e v e r al y e ar s l at e r , S c h i f f 3 r e p o r t e d t h e
i nt e r e s t i ng o b s e r v at i o n t h at e x p e r i m e nt al l y
p r o du c e d i nt r ac r ani al l e s i o ns i n do g s and
r ab b i t s w h i c h i nv o l v e d t h e o p t i c t h al am u s o r
t h e c e r e b r al p e du nc l e s r e g u l ar l y l e d t o h y p e r -
ae m i a w i t h b l o o d s t as i s , e r o s i o ns , o r s o f t e ni ng
and o c c as i o nal l y t o ac t u al p e r f o r at i o ns o f t h e
s t o m ac h . Dam ag e t o o t h e r p ar t s o f t h e b r ai n
i n f r o nt o f o r ab o v e t h e c e r e b r al p e du nc l e s and
t h e o p t i c t h al am u s h ad no e f f e c t o n t h e g as t r i c
m u c o s a. Le s i o ns i n t h e p o ns o r t h e m e du l l a
al s o g av e r i s e t o s i m i l ar p at h o l o g i c al c h ang e s
i n t h e s t o m ac h , b u t no t as c o ns i s t e nt l y . Fr o m
t h e s e o b s e r v at i o ns , S c h i f f c o nc l u de d t h at t h e
p at c h y e r o s i o ns and s o f t e ni ng o f t h e s t o m ac h
w e r e du e t o a ne u r o p ar al y t i c h y p e r ae m i a p r o -
du c e d b y i nj u r y o f t h e c e nt r al p at h w ay o f t h e
v as o m o t o r ne r v e s t o t h e s t o m ac h . S c h i f f ' s o b -
s e r v at i o ns w e r e r e p e at e d and c o nf i r m e d b y
B r o w n- S e q u ar d, 4 Eb s t e i n5 and Po m o r s k i .6
I n s p i t e o f t h e s e e ar l y and b r i l l i ant o b s e r v a-
t i o ns , t h i s c o nc e p t o f a ne u r o g e ni c b as i s f o r
g as t r i c l e s i o ns w as f o r m any y e ar s o v e r -
s h ado w e d b y t h e v i e w s o f Vi r c h o w , 7 w h o h e l d
t h at a g as t r i c u l c e r w as e s s e nt i al l y a l o c al di s -
e as e r e s u l t i ng f r o m a l o c al v as c u l ar di s t u r b anc e ,
s u c h as an e m b o l u s , e t c ., l e adi ng t o l o c al
i s c h aw m i a and de s t r u c t i o n o f t h e g as t r i c m u c o u s
m e m b r ane b y t h e ac i d g as t r i c j u i c e . I n 1 8 8 5 ,
We l c h 8 l e c t u r i ng o n t h e g e ne s i s o f g as t r i c u l c e r
s t at e d, " t h at t h e ne u r o g e ni c t h e o r y o f t h e
o r i g i n o f g as t r i c u l c e r i s al t o g e t h e r s p e c u l at i v e
and h as ne v e r g ai ne d w i de ac c e p t anc e " .
Vi r c h o w ' s p o s t u l at e t h at g as t r i c u l c e r i s e s -
s e nt i al l y a l o c al di s e as e c o nt i nu e d t o i nf l u e nc e
i nv e s t i g at o r s f o r m any g e ne r at i o ns . T h e y
m ade u s e o f v ar i e d t e c h ni q u e s , s u c h as i nt e r -
f e r e nc e w i t h t h e l o c al b l o o d s u p p l y t o t h e
s t o m ac h , o r l o c al ap p l i c at i o n o f c h e m i c al ,
m e c h ani c al , t o x i c , and b ac t e r i al i r r i t ant s . T h e y
s o o n f o u nd h o w e v e r , t h at al t h o u g h t h e y c o u l d
o c c as i o nal l y p r o du c e ac u t e l e s i o ns and e v e n
ac u t e g as t r i c u l c e r s , s u c h l e s i o ns h e al e d r ap i dl y
and ne v e r b e c am e c h r o ni c . A c c o u nt s o f t h i s
e ar l i e r w o r k m ay b e f o u nd i n t h e r e v i e w s b y
Gr e g g i o 9 and Mc Cann.1 0 I n 1 9 3 2 , Cu s h i ng 1 "
w r o t e , " Ou t o f t h i s w o r k h as c o m e t h e h i g h l y
u np r o f i t ab l e s e ar c h f o r a p r i m ar y c au s e i n t h e
w al l s o f t h e s t o m ac h i t s e l f , a s e ar c h b e s e t b y
m any p i t f al l s and c o nt r adi c t i o ns " . A l t h o u g h
m o s t e x p e r i m e nt al i s t s o f t h i s e p o c h p ai d l i t t l e
o r no at t e nt i o n t o t h e ne u r o g e ni c as p e c t s o f
t h e u l c e r p r o b l e m , f r o m t i m e t o t i m e t h e ne u r o -
g e ni e t h e o r y w as r e v i e w e d, and i s o l at e d i n-
v e s t i g at o r s at t e m p t e d t o e x t e nd t h e w o r k o f
Kam m e r e r , Ro k i t ans k y , S c h i f f and o t h e r s .
A ne w ap p r o ac h t o t h e u nde r s t andi ng o f c e r -
t ai n t y p e s o f c l i ni c al f u nc t i o nal di s o r de r s w as
o p e ne d b y Ep p i ng e r and He s s 1 2 i n t h e i r m o no -
g r ap h o n " Vag o t o ni a" . Hi t h e r t o p at i e nt s
p r e s e nt i ng t h e m s e l v e s w i t h l o ng - s t andi ng c o m -
p l ai nt s , e s p e c i al l y r e f e r ab l e t o t h e h e ar t o r
g as t r o - i nt e s t i nal t r ac t , i n w h o m no anat o m i c al
o r p at h o l o g i c al b as i s f o r t h e c o m p l ai nt s c o u l d
b e e s t ab l i s h e d, w e r e l ab e l l e d as ne u r o t i c s . A c -
c o r di ng t o Ep p i ng e r and He s s , s u c h i ndi v i du al s
s h o u l d b e c l as s i f i e d as " Vag o t o ni c " . T h e y r e -
ac t w i t h s w e at i ng and s al i v at i o n t o s m al l do s e s
o f p i l o c ar p i ne ; t h e y ar e ap t t o b e as t h e ni c , t o
h av e c ar di ac i r r e g u l ar i t i e s , b r ady e ar di a, and t o
s h o w i nc r e as e d g as t r i c m o t i l i t y and ac i di t y . A l l
t h e s e s y m p t o m s i ndi c at e a s t at e o f i nc r e as e d
t o ni c i t y o f t h e au t o no m i c ne r v o u s s y s t e m .
Fu r t h e r m o r e , s u c h c o ndi t i o ns as t r o u b l e s o m e
s al i v at i o n, p y l o r o s p as m , t h e di s c o m f o r t o f h y p e r -
ac i di t y , b r o nc h i al as t h m a, c ar di o s p as m and
h u ng e r p ai ns , t o w h i c h v ag o t o ni c p e r s o ns ar e
p r o ne , ar e f r e q u e nt l y m ade w o r s e b y i nj e c t i o n
o f p i l o c ar p i ne and r e l i e v e d b y at r o p i ne . S u c h
v ag o t o ni c i ndi v i du al s w e r e b e l i e v e d t o b e c o n-
s t i t u t i o nal l y di s p o s e d t o r e ac t di f f e r e nt l y and
w i t h g r e at e r i nt e ns i t y t o v ar i o u s s t i m u l i t h an
no r m al p e r s o ns .' 2
1 1 6
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 j
WENER A ND HOFF: PEPT I C ULCER
A l t h o u g h Ep p i ng e r and He s s ' 2 di s c u s s e d
b r i e f l y t h e r e l at i o n o f v ag o t o ni a t o g as t r i c u l c e r ,
t h e y di d no t s t at e de f i ni t e l y t h at v ag o t o ni a p r e -
di s p o s e s t o u l c e r , b u t t h e i r c o nc e p t o f au t o no m i c
i m nb al anc e , p ar t i c u l ar l y r e g ar di ng t h e v ag u s w as
e nl ar g e d u p o n b y Vo n B e r g m ann1 3 w h o b e l i e v e d
t h at h y p e r ac t i v i t y o f t h e v ag u s e v o k e d a s p as t i c
c o nt r ac t i o n o f t h e s t o m ac h , l e adi ng t o s t r ang u l a-
t i o n o f t h e i nc o m i ng v e s s e l s and p r o du c i ng
t h e r e b y l o c al i s c h w m i a and ne c r o s i s . T h e i s c h -
s e m i c ar e as b e i ng di g e s t e d b y t h e g as t r i c j u i c e ,
e r o s i o ns and u l c e r s r e s u l t . S u c h p at i e nt s , Vo n
B e r g m ann b e l i e v e d, w e r e b e ne f i t e d b y at r o p i ne .
Ph ar m ac o l o g i c al s u p p o r t o f t h i s v i e w w as
s u p p l i e d b y t h e o b s e r v at i o n o f We s t p h al , ' 4 t h at
s u b c u t ane o u s adm i ni s t r at i o n o f p i l o c ar p i ne f r e -
q u e nt l y l e d t o m u c o s al h ae m o r r h ag e s and e r o -
s i o ns i n t h e r ab b i t . T h i s w o r k w as c o nf i r m e d b y
Fr i e dm an1 5 and Unde r h i l l and Fr e i h e i t .1 6 Cu s h -
i ng ( 1 9 3 1 ) i nj e c t e d p i l o c ar p i ne and p o s t e r i o r
p i t u i t ar y e x t r ac t ( p i t u i t r i n) i nt o t h e c e r e b r al
v e nt r i c l e s o f p at i e nt s and f o u nd t h at i n s u s -
c e p t i b l e ( o r v ag o t o ni c ) i ndi v i du al s i t p r o du c e d
p ar as y m p at h e t i c e f f e c t s , s u c h as s w e at i ng , f l u s h -
i ng , l ac h r y m at i o n and e x c e s s i v e v o m i t i ng w h i c h
w as o c c as i o nal l y b l o o d- t i ng e d. T h e s e e f f e c t s
c o u l d b e c h e c k e d b y at r o p i ne o r b y b ar b i t u r at e s ,
( w h i c h ar e k no w n t o de p r e s s t h e h y p o t h al am i c
c e nt r e s ) . T h e s e o b s e r v at i o ns l e d t o t h e as s u m p -
t i o n t h at t h e p ar as y m p at h e t i c as w e l l as t h e
s y m p at h e t i c s y s t e m i i s h ad a p r i m ar y nu c l e ar
r e p r e s e nt at i o n i n t h e i nt e r b r ai n. T h e e f f e c t o f
p i l o c ar p i ne i nj e c t e d i nt o t h e v e nt r i c l e s w as s o o n
c o nf i r m e d b y B i s h o p , Ke ndal l and Li g h t .1 8 A t
t h i s t i m e B e at t i e ' 9 r e p o r t e d t h e o b s e r v at i o n t h at
e l e c t r i c al s t i m u l at i o n o f , t h e t u b e r al nu c l e i i n t h e
h y p o t h al am u s c au s e d i nc r e as e d p e r i s t al s i s and
g as t r i c s e c r e t i o n and l e d t o g as t r i c
m u c o s al
h ae m o r r h ag e s and e r o s i o ns . T h e s e e f f e c t s w e r e
ab o l i s h e d w i t h s e c t i o n o f t h e v ag i .
I n 1 9 3 2 , Cu s h i ng 1 " r e v i e w e d t h e e v i de nc e o n
h and i n s u p p o r t o f t h e ne u r o g e ni c b as i s o f u l c e r
f o r m at i o n and c o nc l u de d t h at
" Di r e c t s t i m u l at i o n o f t h e t u b e r nu c l e i i n t h e
h y p o - .
t h al am u s o r i t s de s c e ndi ng t r ac t s , o r w h at t h e o r e t i c al l y
am o u nt s t o t h e s am e t h i ng , a f u nc t i o nal r e l e as e o f t h e
v ag u s f r o m p ar al y s i s o f t h e ant ag o ni s t i c s y m p at h e t i c
f i b r e s l e ads t o h y p e r s e c r e t i o n, h y p e r c h l o r h y dr i a
and
h y p e r m o t i l i t y , e s p e c i al l y m ar k e d i n t h e p y l o r i c s e g m e nt .
B y t h e s p as m o di c c o nt r ac t i o ns o f t h e m u s c u l at u r e , p o s -
s i b l y s u p p l e m e nt e d b y ac c o m p any i ng l o c al s p as m s o f
t h e t e r m i nal b l o o d v e s s e l s , s m al l ar e as o f i s c h ae m i a o r
h e m o r r h ag i c e r o s i o ns ar e p r o du c e d, l e av i ng t h e o v e r l y i ng
m u c o s a e x p o s e d t o t h e di g e s t i v e e f f e c t s o f i t s o w n h y p e r -
ac i d j u i c e s " .
T h i s r e - af f i r m e d and s t at e d m o r e c o nc i s e l y t h e
e ar l i e r v i e w s o f Ro k i t ans k y , 2 S c h i f f , 3 Vo n B e r g -
m ann' 3 and o t h e r s . Cu s h i ng ' s w o r k c r e at e d a
ne w i nt e r e s t i n t h e s u b j e c t , and i n t h e y e ar s
f o l l o w i ng h i s p ap e r t h e r e h as b e e n an i nc r e as e
i n b o t h c l i ni c al and e x p e r i m e nt al r e p o r t s w h i c h
t e nds t o s u p p o r t t h e ne u r o g e ni c b as i s f o r u l c e r
f o r m at i o n.
PA T HOLOGI CA L CRI T ERI A FOR T HE DI A GNOS I S
OF ULCER
I n r e v i e w i ng t h e l i t e r at u r e , i t h as b e e n no t e d
t h at m any au t h o r s h av e m ade no at t e m p t t o
di f f e r e nt i at e c l e ar l y b e t w e e n e r o s i o ns and t r u e
u l c e r s , and i n t h e i r di s c u s s i o n h av e f r e q u e nt l y
r e f e r r e d t o u l c e r s , w h e n o nl y e r o s i o ns w e r e
p r e s e nt . T h i s h as o nl y adde d t o t h e c o nf u s i o n
t h at al r e ady e x i s t e d. I n o r de r t o p r o v i de a
b as i s f o r c o m p ar i s o n, t h e t e r m s e r o s i o n and
u l c e r s as r e f e r r e d t o i n t h i s p ap e r m ay b e de -
f i ne d as f o l l o w s . A n e r o s i o n i s a b r e ak i n t h e
c o nt i nu i t y o f m u c o u s m e m b r ane . I t m ay b e
as s o c i at e d w i t h h e m o r r h ag e . I t m ay b e s u p e r -
f i c i al o r de e p ; i f i t i s de e p , t h e n i t m ay b e r e -
f e r r e d t o as a c r at e r . A n u l c e r i s al s o an
i nt e r r u p t i o n i n t h e c o nt i nu i t y o f t h e m u c o u s
m e m b r ane , b u t i s i n addi t i o n, al w ay s ac c o m -
p ani e d b y an i nf l am m at o r y r e ac t i o n ( Kar s ne r , 2 0
B o y d2 1 ) . T h i s k i nd o f u l c e r m ay b e ap p r o -
p r i at e l y t e r m e d an ac u t e u l c e r ; i t m ay o c c u r
any w h e r e i n t h e s t o m ac h o r du o de nu m and
m ay b e m u l t i p l e . A c h r o ni c u l c e r , o f t h e t y p e
u s u al l y s e e n i n m an, i s m o r e l o c al i z e d, and i s
m o s t o f t e n l i m i t e d t o t h e f i r s t p ar t o f t h e du o -
de nu m , o r t o t h e l e s s e r c u r v at u r e o f t h e s t o m -
ac h , and p o s t e r i o r w al l , p ar t i c u l ar l y i n t h e
p y l o r i c r e g i o n. Gr o s s l y a c h r o ni c u l c e r r e v e al s
a s h ar p l y de f i ne d c r at e r w i t h o v e r h ang i ng
e dg e s o f m u c o u s m e m b r ane and a ne c r o t i c and
i ndu r at e d b as e . Mi c r o s c o p i c al l y , f o u r z o ne s
c an b e di s t i ng u i s h e d i n t h e f l o o r o f t h e u l c e r
( B o y d2 1 ) ; ( 1 ) an i nf l am m at o r y z o ne c o ns i s t i ng
o f f i b r i n and p o l y m o r p h o nu c l e ar l e u c o c y t e s ;
( 2 ) a z o ne o f ne c r o t i c g r anu l at i o n t i s s u e ; ( 3 )
a z o ne o f l i v i ng g r anu l at i o n t i s s u e ; and ( 4 ) a
z o ne o f de ns e s c ar t i s s u e , w h i c h f o r m s o ne o f
t h e m o s t i m p o r t ant f e at u r e s o f t h e c h r o ni c
u l c e r .
A c u t e u l c e r s m ay e i t h e r h e al c o m p l e t e l y and
l e av e no s c ar s , o r m ay h e al and s h o w e v i de nc e
o f c i c at r i z at i o n o r s c ar r i ng . T h e p r e s e nc e o f a
h e al e d u l c e r w i t h c i c at r i z at i o n h as o f t e n b e e n
i nc o r r e c t l y r e f e r r e d t o as e v i de nc e o f c h r o ni c i t y .
1 1 7
WENER A ND HOFF: PEPT I C ULCER
[ Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
CLI NI CA L- PA T HOLOGI CA L EVI DENCE FOR T HE
A S S OCI A T I ON OF GA S T RI C A ND DUODENA L LES I ONS
WI T H I NT RA CRA NI A L DI S ORDERS
Re p o r t s b y A r ndt , 2 2 Vo n Ei s e l b e r g , 2 3 B e ne k e , 2 4
Har t , 2 5 Mo g i l i ni t s k y 2 6 and Ko r s t , ' 7 h av e de m o n-
s t r at e d c l e ar l y t h e as s o c i at i o n o f g as t r i c and
du o de nal l e s i o ns w i t h l e s i o ns o f t h e b r ai n. Cu s h -
i ng " 1 r e p o r t e d 1 1 c as e s o f i nt r ac r ani al l e s i o ns
ac c o m p ani e d b y g as t r i c and du o de nal l e s i o ns
w h i c h v ar i e d f r o m h ae m o r r h ag i c e r o s i o ns t o
ac t u al p e r f o r at i o ns . I n 6 o f t h e 1 1 p at i e nt s , t h e
l e s i o ns i nv o l v e d t h e p o s t e r i o r c r ani al f o s s a. One
c as e , a c h i l d i n w h o m a m i d- l i ne c e r e b e l l ar t u -
m o u r w as v e r i f i e d, l i v e d f o r t w o y e ar s and at
au t o p s y a c h r o ni c du o de nal u l c e r w as f o u nd.
Fo l l o w i ng Cu s h i ng ' s p ap e r , t h e r e h as b e e n an
i nc r e as e d nu m b e r o f r e p o r t s i l l u s t r at i ng t h e
c l i ni c al - p at h o l o g i c al c o r r e l at i o n o f g as t r i c and
du o de nal l e s i o ns w i t h af f e c t i o ns o f t h e b r ai n and
s p i nal c o r d. CGas t r i c and du o de nal l e s i o ns h av e
b e e n as s o c i at e d w i t h a l ar g e v ar i e t y o f i nt r a-
c r ani al di s o r de r s , i nc l u di ng s u c h c o ndi t i o ns as
ac u t e m e ni ng i t i s , ( Mas t e n and B ant s 2 9 ) ; Har -
t u ng and Wo r k ang ; 3 0 1 e nc e p h al i t i s , Mas t e n and
B ant s ; 2 9 b r ai n t u m t o u r s , Gr ant , 3 1 Mas t e n and
B ant s , 2 9 B o l e s and Ri g g s ; 4 2 p i t u i t ar y t u m o u r s ,
Co m r o e ; 3 2 S w an and S t e p h e ns o n ; 3 3 Fo l e y , S ne l l
and Cr ai g ; 3 4 v as c u l ar l e s i o ns o f t h e b r ai n,
Dav i e s , 3 5 A s k - Up m ar k ; 3 6 Mas t e n and B ant s ; 2 9
Do t t ; 3 7 and b r ai n t r au m a, Vanz ant and
B r o w n ; 3 8 A s k - Up m ar k .3 6
I t h as b e e n s h o w n t h at m e l aw na i n i nf ane y 6
i s f r e q u e nt l y du e t o i nt r ac r ani al l e s i o ns o c -
c u r r i ng at b i r t h , and i s e s p e c i al l y no t e d af t e r
p r o l o ng e d and di f f i c u l t l ab o u r s .2 8 A c u t e g as t r i c
and du o de nal e r o s i o ns h av e al s o b e e n as s o c i at e d
w i t h l e s i o ns o f t h e u p p e r s p i nal c o r d, Ri ddo c k 3 9
and Mo o l t o n.4 ' Par s o ns , Pl u m m e r e t al ., 4 0
s t u di e d t h e o c c u r r e nc e o f p e p t i c u l c e r i n s y p h i l i s
o f t h e c e nt r al ne r v o u s s y s t e m . T h e y f o u nd t h at
p e p t i c u l c e r o c c u r r e d i n 1 0 .5 % o f 2 0 0 c as e s o f
ne u r o s y p h i l i s , w h i l e am o ng 4 0 0 c o nt r o l s , t h e
i nc i de nc e o f u l c e r w as o nl y 3 % .
S UMMA RY
Ne ar l y al l o f t h e g as t r o - i nt e s t i nal l e s i o ns di s -
c o v e r e d t o b e as s o c i at e d w i t h t h e i nt r ac r ani al
and s p i nal c o r d l e s i o ns w e r e o f t h e ac u t e t y p e ,
u s u al l y m u l t i p l e and w i t h no s p e c i al p r e f e r e nc e
f o r l o c al i z at i o n. T h e p at h o l o g i c al c h ang e s o b -
s e r v e d w e r e ne ar l y al l o f t h e h ae m o r r h ag i c t y p e
o f e r o s i o n w i t h c e de m a o f t h e m u c o u s m e m -
b r ane . Cr at e r s w e r e o nl y o c c as i o nal l y no t e d
and t r u e ac u t e u l c e r s w i t h o r w i t h o u t p e r f o r a-
t i o n w e r e r ar e . Onl y i n t h e s i ng l e c as e r e -
p o r t e d b y Cu s h i ng , " 1 w as t h e r e any e v i de nc e
o f t h e as s o c i at i o n o f a b r ai n l e s i o n w i t h a
c h r o ni c p e p t i c u l c e r .
I n al m o s t al l t h e c as e s r e v i e w e d, g as t r i c
b l e e di ng o r p e r f o r at i o n i ndi c at i ng a g as t r i c
o r du o de nal l e s i o n, w as no t e d v e r y s h o r t l y
af t e r t h e b r ai n i ni j u r y o r s o o n af t e r t h e o p e r a-
t i v e i nt e r f e r e nc e , u s u al l y w i t h i n 2 4 t o 7 2 h o u r s .
I n m o s t i ns t anc e s , t h e p at i e nt s w e r e no t f e d
f o r at l e as t 2 4 h o u r s o r l o ng e r p r i o r t o o p e r a-
t i o n, and f o r 2 4 h o u r s o r l o ng e r af t e r o p e r at i o n.
T h e s e p at i e nt s al l h ad s t o r m y p o s t o p e r at i v e
c o u r s e s , as s o c i at e d w i t h s h o c k - l i k e c o ndi t i o ns .
Many p at i e nt s w e r e c o m at o s e f o r 2 4 h o u r s o r
l o ng e r p r i o r t o t h e de at h , and l e s i o ns w e r e di s -
c o v e r e d o nl y at au t o p s y . A s k - Up m ar k , 3 6 ana-
l y z e d t h e f as t i ng g as t r i c s e c r e t i o ns i n 1 0 c as e s
o f i nt r ac r ani al t u m o u r s p r e o p e r at i v e l y , and
f o u nd t h e ac i di t y o f t h e g as t r i c j u i c e m ay b e
u naf f e c t e d, r e du c e d, o r e nh anc e d. Dr ag s t e dt , 1 5 4
r e p o r t e d t h at i m m e di at e l y f o l l o w i ng b r ai n
o p e r at i o ns , p at i e nt s e x h i b i t e d a l ar g e i ne r e as e
i n t h e v o l u m e and ac i di t y o f t h e t o t al ni g h t
g as t r i c s e c r e t i o n.
T h e m aj o r i t y o f i nt r ac r ani al l e s i o ns ac c o m -
p ani e d b y g as t r i c o r du o de nal c h ang e s r e p o r t e d
i n t h e l i t e r at u r e r e v i e w e d ab o v e , w e r e l o c at e d
i n t h e ne i g h b o u r h o o d o f t h e t h i r d and f o u r t h
v e nt r i c l e s , w h i l e t u m o u r s i nv o l v i ng t h e b as al
g ang l i a, m i d- b r ai n, o r u p p e r p o r t i o ns o f t h e
c o r d w e r e l e s s f r e q u e nt l y as s o c i at e d w i t h
g as t r o - i nt e s t i nal p at h o l o g y .
A l t h o u g h t h e as s o c i at i o n o f b r ai n l e s i o ns and
g as t r i c o r du o de nal p at h o l o g i c al c h ang e s s e e m s
w e l l e s t ab l i s h e d, i t i s s i g ni f i c ant t h at s u c h a
l o w i nc i de nc e o f g as t r o - i nt e s t i nal l e s i o ns w e r e
r e p o r t e d f o l l o w i ng b r ai n di s o r de r s . S i nc e i t
w as o nl y t h o s e c as e s w i t h c l i ni c al e v i de nc e o f
h e e m at e m e s i s , m e l e na o r t ar r y s t o o l s and t h o s e
ac c i de nt al l y di s c o v e r e d at au t o p s y w h i c h h av e
b e e n r e p o r t e d, i t i s v e r y p o s s i b l e t h at m any
m o r e c as e s w i t h p o s t o p e r at i v e g as t r i c m u c o s al
h am o r r h ag e s o r e r o s i o ns h av e r e m ai ne d u ndi ag -
no s e d b e c au s e t h e y di d no t s h o w any o f t h e
o u t w ar d s i g ns o f b l e e di ng . Wi t h i m p r o v e m e nt
i n c l i ni c al c o ndi t i o ns , t h e r e s u m p t i o n o f a
p r o p e r di e t , and ai de d b y t h e r ap i d r e g e ne r a-
t i v e p o w e r s o f t h e g as t r o - i nt e s t i nal m u c o s a,
m any o f t h e s e ac u t e l e s i o ns m ay h e al c o m -
p l e t e l y , l e av i ng no t r ac e at t h e s i t e o f t h e
l e s i o n. I t w o u l d b e i nt e r e s t i ng t o o b s e r v e t h e
1 1 8
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ' ULCER
nu m b e r o f p at i e nt s w i t h i nt r ac r ani al l e s i o ns
w h o s h o w no o u t w ar d c l i ni c al s i g ns o f g as t r o -
i nt e s t i nal p at h o l o g y , b u t i n w h o m o c c u l t b l o o d
m ay b e f o u nd i n t h e s t o o l s .
EX PERI MENT A L DA T A RELA T I NG T HE
HYPOT HA LA MUS T O T HE FUNCT I ON OF T HE
CI A S T RO- I NT ES T I NA L T RA CT A ND T O
PEPT I C ULCER
Ef f e c t s o f s t i m u l at i o n o f t h e h y p o t h al am u s .-
T h e e x i s t e nc e o f a c e r e b r al di e nc e p h al i c c e nt r e
f o r t h e s y m p at h e t i c ne r v o u s s y s t e m w as i ndi -
c at e d w h e n, i n 1 9 0 9 , Kar p l u s and Kr e i dl 4 3 f i r s t
s h o w e d e x p e r i m e nt al l y t h at e l e c t r i c al s t i m u l a-
t i o n o f t h e h y p o t h al am u s c au s e d a s y m p at h e t i c -
l i k e r e s p o ns e , e .g ., p u p i l l ar y di l at i o n, s w e at i ng ,
l ac h r y m at i o n and s al i v at i o n. S i nc e t h e n e x -
p e r i m e nt al r e p o r t s h av e c o nf i r m e d Kar p l u s and
Kr e i dl ' s w o r k and h av e l i nk e d t h e h y p o t h al a-
m u s w i t h t h e c o nt r o l o f s u c h c o m m o n au t o -
no m i c f u nc t i o ns as c ar b o h y dr at e m e t ab o l i s m ,
w at e r m e t ab o l i s m , h e at r e g u l at i o n, s l e e p and
c ar di o - v as c u l ar r e g u l at i o n.4 7 T h e r e s e ar c h e s o f
Canno n and B r i t t o n, 4 4 B ar d, 4 5 and Fu l t o n and
I ng r ah am , 4 6 h av e i ndi c at e d t h at w h e n t h e
h y p o t h al am u s i s r e l e as e d f r o m c o r t i c al c o nt r o l ,
p r i m i t i v e b e h av i o u r r e ac t i o ns i n ani m al s m ay
b e e l i c i t e d. T h i s q u as i - e m o t i o nal s t at e i s o f t e n
c al l e d " s h am - r ag e " , and i s ac c o m p ani e d b y a
m as s di s c h ar g e o f t h e s y m p at h i c o - adr e nal
s y s t e m . S i m i l ar r e ac t i o ns h av e b e e n no t e d i n
m an i n as s o c i at i o n w i t h h y p o t h al am i c l e s i o ns .4 8
T h e f i r s t de s c r i p t i o n o f t h e c h ang e i n t h e
g as t r o - i nt e s t i nal t r ac t f o l l o w i ng s t i m u l at i o n o f
t h e h y p o t h al am u s w as g i v e n b y B e at t i e l 9 i n
1 9 3 2 . S t i m u l at i ng t h e l at e r al m ar g i ns o f t h e
i nf u ndi b u l u m u nde r di r e c t v i s i o n, h e no t e d i n-
c r e as e d p e r i s t al s i s and s e c r e t i o n i n t h e s t o m -
ac h . ( B i p o l ar e l e c t r o de s w e r e u s e d w i t h a c u r -
r e nt j u s t s u b m i ni m al f o r c o nt r ac t i o n o f t h e
f i b r e s o f t h e t e m p o r al m u s c l e .) T h e s e c r e t i o n
w as w at e r y , c o nt ai ne d s o m e f r e e h y dr o c h l o r i c
ac i d, p e p s i n, e t c ., and i n g e ne r al , r e s e m b l e d
r h at o b t ai ne d b y s t i m u l at i o n o f t h e v ag u s
ne r v e s . Wh e n t h e s t i m u l at i o n w as c o nt i nu e d
f o r o ne - h al f h o u r , s m al l p at c h e s o f h y p e r am i c
m u c o u s m e m b r ane w e r e s e e n ne ar t h e l e s s e r
c u r v at u r e o f t h e s t o m ac h . S e c t i o n o f t h e v ag i
ab o l i s h e d t h e r e s p o ns e .
I n an addr e s s o n h y p o t h al am i c m e c h ani s m s ,
B e at t i e 5 1 ' p r e s e nt e d t h e f o l l o w i ng h y p o t h e s i s o f
h y p o t h al am i c f u nc t i o n w h i c h s e e m e d t o f i t al l
t h e e x p e r i m e nt al dat a. He s u g g e s t e d t h at an
ant e r i o r h y p o t h al am i c c o m p l e x c o ns i s t i ng o f
t h e s u p r a- o p t i c and t u b e r al r e g i o ns ac t e d as a
p ar as y m p at h e t i c c e nt r e , w h i l e a p o s t e r i o r
h y p o t h al am i c c o m p l e x s i t u at e d i n t h e m am m i l -
l ar y r e g i o n o f t h e h y p o t h al am u s s e r v e d as a
s y m p at h e t i c c e nt r e . He b e l i e v e d t h at al l t h e
e v i de nc e w as ag ai ns t t h e e x i s t e nc e o f a s e r i e s
o f di s c r e t e " c e nt r e s " i n t h e ant e r i o r o r p o s -
t e r i o r c o m p l e x e s , ' b u t f av o u r e d t h e v i e w t h at
o ne o r o t h e r c o m p l e x g av e r i s e t o m o r e g e ne r al -
i z e d " m as s r e ac t i o ns " .
T h i s h y p o t h e s i s r e c e i v e d s o m e di r e c t e x p e r i -
m e nt al s u p p o r t f r o m t h e w o r k o f B e at t i e and
S h e e h an, 5 2 w h o f o u nd t h at s t i m u l at i o n o f t h e
t u b e r r e g i o n r e s u l t e d i n a r i s e o f t h e i nt r a-
g as t r i c p r e s s u r e v ar y i ng f r o m 1 0 t o 5 0 m i l .
H2 0 , af t e r a l at e nt p e r i o d o f ap p r o x i m at e l y
3 0 s e c o nds . I n no c as e w as i t as m ar k e d as
t h at p r o du c e d b y s t i m u l at i o n o f t h e p e r i p h e r al
e nd o f t h e c u t v ag u s . T h e r i s e o f t h e i nt r a-
g as t r i c p r e s s u r e w as ac c o m p ani e d b y a f al l i n
b l o o d p r e s s u r e and b y a s u b s e q u e nt i nc r e as e i n
t h e p e r i s t al t i c m o v e m e nt s o f t h e s t o m ac h .
S e c t i o n o f t h e v ag i ab o l i s h e d t h e s e e f f e c t s .
S t i m u l at i o n o f t h e p o s t e r i o r h y p o t h al am u s
c au s e d a s l i g h t f al l i n t h e i nt r ag as t r i c p r e s s u r e ,
ac c o m p ani e d b y a r i s e i n t h e b l o o d p r e s s u i r e
and b y c o m p l e t e o b l i t e r at i o n o f al l g as t r i c
m o t i l i t y . S e c t i o n o f t h e v ag i di d no t af f e c t
t h e s e r e s u l t s .
He s l o p , 5 3 u s i ng m o r e ac c u r at e m e t h o ds o f
s t i m u l at i ng t h e h y p o t h al am u s and r e c o r di ng
g as t r i c m o t i l i t y r e p e at e d and c o nf i r m e d t h e
w o r k o f B e at t i e and S h e e h an.5 2 He f o u nd t h at
s t i m u l at i o n o f t h e ant e r i o r h y p o t h al am u s p r o -
du c e d a m ar k e d i nc r e as e i n g as t r i c t o ne and
m o t i l i t y ; p o s t e r i o r h y p o t h al am i c s t i m u l at i o n
o nl y c au s e d a t r ans i e nt r e l ax at i o n o f t h e
p y l o r i c e nd o f t h e s t o m ac h . He s l o p s 4 f o u nd
al s o t h at s t i m u l at i o n o f t h e ant e r i o r ' h y p o -
t h al am i c r e g i o n p r o du c e d an i nc r e as e i n g as t r i c
s e c r e t i o n and a m ar k e d r i s e i n t h e f r e e and
t o t al ac i d. S t i m u l at i o n o f t h e p o s t e r i o r r e g i o n
r e s u l t e d i n t h e p r o du c t i o n o f a m ar k e d i nc r e as e
i n t h e am o u nt o f m u c u s and a t e nde nc y t o
di m i ni s h t h e r at e o f f l o w and ac i di t y .
Kab at , A ns o n, Mag o u n and Rans o n5 5 ( u s i ng
c at s at l e as t t w o and o ne - h al f h o u r s af t e r e t h e r
anae s t h e t i c w as di s c o nt i nu e d) , f o u nd t h at s t i m u -
l at i o n o f t h e h y p o t h al am u s w i t h t h e Ho r s l e y -
Cl ar k e s t e r e o t ax i c i ns t r u m e nt al w ay s c au s e d c e s -
s at i o n o f p e r i s t al s i s and l o s s o f t o ne o f t h e
s t o m ac h and s m al l i nt e s t i ne ,
af t e r a s h o r t l at e nt
1 1 9
WENER A ND HOFF: PEPT I C ULCER
ECanad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
p e r i o d o f o ne s e c o nd. Gas t r o - i nt e s t i nal m o t i l i t y
w as ne v e r i nc r e as e d. A c c o m p any i ng t h e di m i n-
i s h e d ac t i v i t y o f t h e g u t w e r e m ar k e d di l at i o n
o f t h e p u p i l s , i nc r e as e d r at e and am p l i t u de o f
r e s p i r at i o n, e r e c t i o n o f h ai r , e t c ., w h i c h h as b e e n
r e f e r r e d t o as a " s y m p at h e t i c di s c h ar g e " . T h e s e
o b s e r v e r s t h u s f o u nd no e v i de nc e o f a " p ar a-
s y m p at h e t i c c e nt r e " f o r g as t r o - i nt e s t i nal ac t i v i t y
as de s c r i b e d b y B e at t i e , b u t t h e i r r e s u l t s i n-
di c at e d t h at t h e r e i s a h y p o t h al am i c c e nt r e
w h i c h i nh i b i t s g as t r o - i nt e s t i nal ac t i v i t y . A l -
t h o u g h t h e e x ac t l o c al i z at i o n w as no t c e r t ai n, t h e
l at e r al h v p o t h al am u s w as c h i e f l y i nv o l v e d s i nc e
s t i m u l at i o n o f t h i s r e g i o n al w ay s r e s u l t e d i n
g as t r o - i nt e s t i nal i nh i b i t i o n. S i nc e i nh i b i t i o n w as
al w ay s ac c o m p ani e d b y a " s y m p at h e t i c di s -
c h ar g e " , t h e y b e l i e v e d t h at o ne c e nt r e i s c o n-
c e r ne d i n al l r e s p o ns e s , t h o u g h t h e i r r e s p e c t i v e
t h r e s h o l ds di f f e r , t h at f o r g as t r o - i nt e s t i nal i n-
h i b i t i o n b e i ng t h e h i g h e s t o f al l . S t i m u l at i o n o f
t h e t h al am u s , i nt e r nal c ap s u l e , ant e r i o r c o m -
m i s s u r e , s e p t u m p e l l u c i du m and i nf u ndi b u l ar
s t al k w i t h t h e s am e s t r e ng t h o f c u r r e nt p r o du c e d
no c h a.ng e i n g as t r o - i nt e s t i nal m o t i l i t y .
T h e r e s u l t s o f Mas s e r m an and Hae r t i g , 5 6 o f f e r
a p o s s i b l e e x p l anat i o n f o r t h e di f f e r e nc e s i n
r e s u l t s o b t ai ne d b y B e at t i e and Rans o n e t al .
T h e s e au t h o r s f o u nd t h at w h e n t h e ant e r i o r
h y p o t h al am u s w as s t i m u l at e d w i t h a w e ak
c u r r e nt ( t o o w e ak t o i ndu c e t y p i c al m ar k e d
e m o t i o nal m i m e t i c r e s p o ns e ) i nc r e as e d g as t r o -
i nt e s t i nal ac t i v i t y r e s u l t e d. Ent e r o m o t o r e f f e c t s
w e r e al s o o b t ai ne d w h e n t h e do r s al p o r t i o n o f
t h e s u p r am am m i l l ar y de c u s s at i o n and t h e m am -
m i l l ar y b o di e s w e r e s t i m u l at e d. Wh e n any
p o r t i o n o f t h e h y p o t h al am u s w as s t i m u l at e d w i t h
c u r r e nt s i nt e ns e e no u g h t o e l i c i t di f f u s e s y m -
p at h e t i c di s c h ar g e s , i nt e s t i nal ac t i v i t y w as de f i -
ni t e l y r e du c e d o r s t o p p e d. T h u s i t m ay b e t h at
m o t o r r e s p o ns e s o f t h e g as t r o - i nt e s t i nal t r ac t ar e
o nl y e l i c i t e d b y w e ak e r s t i m u l i .
S h e e h an4 9 i n h i s e x c e l l e nt r e v i e w o f t h i s s u b -
j e c t c al l e d at t e nt i o n t o t h r e e o t h e r f ac t s , ( a)
t h at Rans o n e t al . ne v e r s t i m u l at e d t h e s u p r a-
o p t i c ar e a f r o m w h i c h B e at t i e c l ai m e d t o o b t ai n
i nc r e as e d e nt e r o m o t o r e f f e c t s ; ( ( b ) t h at v ar i -
ab i l i t y i n r e s u l t s m ay b e du e t o di f f e r e nc e s i n
f r e q u e nc y as w e l l as i n s t r e ng t h o f s t i m u l at i o n.
B e c au s e o f t h e l ac k o f u ni f o r m i t y i n m e t h o ds o f
s t i m u l at i o n, i t w as i m p o s s i b l e t o c o m p ar e t h e
s t r e ng t h o r t h e nat u r e o f t h e s t i m u l at i o n u s e d
b y v ar i o u s w o r k e r s ; ( c ) t h at t h e s i g ni f i c ant di f -
f e r e nc e s w h i c h e x i s t e d i n t h e l at e nt p e r i o d b e -
t w e e n t h e m o t o r r e s p o ns e s w h i c h f o l l o w e d
ant e r i o r ( 3 0 s e c .) and p o s t e r i o r ( ap p r o x . 1 s e c .)
h y p o t h al am i c s t i m u l at i o n i ndi c at e d t h at t h e r e
m ay b e s o m e f u ndam e nt al di f f e r e nc e b e t w e e n
t h e m e c h ani s m s o f t h e t w o r e s p o ns e s .
Mo r e r e c e nt l y Wang , Cl ar k , De y and Rans o n5 7
f o u nd t h at w h e n t h e ant e r i o r h y p o t h al am u s
w as
s t i m u l at e d, t h e r e w as o c c as i o nal l y a s l i g h t
i n-
h i b i t i o n, b u t u s u al l y a m ar k e d de l ay e d e x c i t at o r y
r e s p o ns e o f t h e i nt e s t i ne , c o l o n, and s t o m ac h
o c c u r r e d af t e r a l at e nt p e r i o d o f 4 0 t o 6 0 s e c -
o nds ( av e r ag e 5 2 s e c o nds ) . T h e r e s p o ns e w as
al w ay s g r adu al i n o ns e t , r e ac h i ng a m ax i m u m i n
o ne o r t w o m i nu t e s and s l o w l y di m i ni s h i ng ,
m ak i ng a t o t al du r at i o n o f 2 t o 7 m i nu t e s . B i -
l at e r al v ag o t o m y di d no t ab o l i s h t h e de l ay e d
e x c i t at o r y r e s p o ns e . Vag al e f f e c t s o n t h e g u t
w e r e al s o o b t ai ne d w h e n t h e h y p o t h al am u s
at o r
b e h i nd t h e i nf u ndi b u l ar l e v e l w as s t i m u l at e d.
S u c h r e s p o ns e s w e r e e l i c i t e d i n c h r o ni c s p i naI
c at s and w e r e ab o l i s h e d af t e r b i l at e r al v ag o t o m y .
T h e s e r e s p o ns e s w e r e p r o m p t ; t h e l at e nt p e r i o d
ne v e r e x c e e de d 7 s e c o nds and c l o s e l y r e s e m b l e d
t h e r e s p o ns e s o b t ai ne d b y B e at t i e l 9 and Mas s e r -
m an and Hae r t i g .5 6 T h e de l ay e d t y p e o f r e -
s p o ns e s w e r e s i m i l ar t o t h e r e s p o ns e s
o f t h e
s t o m ac h o b t ai ne d b y B e at t i e and S h e e h an, 5 2 and
He s l o p 5 3 w h e r e t h e l at e nt p e r i o d
w as at l e as t 3 0
s e c o nds . Wang e t al .5 7 w e r e u nab l e t o o b t ai n
t h i s de l ay e d r e s p o ns e i n s p i nal b u t v ag u s - i nt ac t
c at s , and b e l i e v e d t h at i t w as no t a s i m p l e v ag al
e f f e c t .
A l t h o u g h t h e e x p e r i m e e nt al f i ndi ng s ar e c o n-
t r adi c t o r y and i nc o m p l e t e , S h e e h an4 9 b e l i e v e d
t h e r e ar e ade q u at e g r o u nds f o r ac c e p t i ng a
s y m p at h e t i c c e nt r e r e g u l at i ng g as t r o - i nt e s t i nal
ac t i v i t y , l o c at e d i n t h e h y p o t h al am u s , m o r e
p ar t i c u l ar l y i n t h e l at e r al h y p o t h al am i c ar e a.
T h e p o s t e r i o r o r t h e m nam m i l l ar y r e g i o n ap -
p e ar e d t o b e p ar t i c u l ar l y r e s p o ns i v e . T h e e v i -
de nc e f o r t h e e x i s t e nc e o f a p ar as y m p at h e t i c
c e nt r e i n t h e ant e r i o r h y p o t h al am u s as p o s t u -
l at e d b y B e at t i e , i s s t i l l v e r y m u c h i n di s p u t e .
S h e e h an, 4 9 h as c o ns i de r e d t h e p o s s i b i l i t y t h at
s t i m u l at i o n o f t h e ant e r i o r h y p o t h al am i c ar e a
m ay ac t i v at e t h e c o r t i c al i nh i b i t o r y f i b r e s t o
t h e s y m p at h e t i c c e nt r e and t h u s t h e e nt e r o -
m o t o r r e s u l t s m ay b e du e t o i nh i b i t i o n o f t h e
m o r e p o s t e r i o r l y s i t u at e d s y m p at h e t i c c e nt r e .
Mo r e r e c e nt l y Har e and Ge o h e g an5 8 and
B r o nk , Pi t t s and Lar r ab e e 5 9 h av e c al l e d at t e n-
t i o n t o t h e i nf l u e nc e o f t h e f r e q u e nc y o f h y p o -
t h al am i c s t i m u l at i o n u p o n t h e r e s p o ns e . Har e
1 2 0
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ULCER
and Ge o h e g an5 8 f o u nd t h at i n c at s , s t i m u l at i o n
o f t h e h y p o t h al am u s w i t h l o w f r e q u e nc i e s p r o -
du c e d a p ar as y nm p at h e t i c r e s p o ns e c h ar ac t e r -
i z e d b y f al l o f b l o o d p r e s s u r e , c o ns t r i c t i o n o f
p u p i l s , e t c ., w h i l e s t i m u l at i o n o f t h e s am e ar e a
at a h i g h e r f r e q u e nc y c au s e d a r i s e i n b l o o d
p r e s s u r e , di l at i o n o f t h e p u p i l s , e t c ., i .e ., a
s y m p at h e t i c r e s p o ns e . B r o nk e t al , 5 9 f o u nd t h at
s t i m u l at i o n o f a p o i nt i n t h e t u b e r al r e g i o n at
a f r e q u e nc y o f 2 0 p e r s e c . p r o du c e d an i n-
c r e as e d di s c h ar g e o f i m p u l s e s i n t h e i nf e r i o r
c ar di ac ne r v e and a r i s e o f b l o o d p r e s s u r e . T h e n
s t i m u l at i o n at e x ac t l y t h e s am e p o i nt w i t h a
f r e q u e nc y o f 2 p e r s e c o nd, i nh i b i t e d t h e e x i s t -
i ng s y m p at h e t i c ac t i v i t y w i t h a r e s u l t ant f al l
o f b l o o d p r e s s u r e .
Du e t o t h e l ac k o f u ni f o r m i t y i n m e t h o ds o f
h y p o t h al am i c s t i m u l at i o n u s e d b y t h e di f f e r e nt
w o r k e r s , i t i s no t p o s s i b l e t o c o m p ar e t h e
s t r e ng t h o r f r e q u e nc y o f s t i nf u l at i o n u t i l i z e d,
b u t i t m ay w e l l b e t h at t h e c o nf l i c t i ng r e s u l t s
o b t ai ne d b y B e at t i e 1 9 and Rans o n e t al .5 5 m ay b e
du e t o t h e di f f e r e nc e i n f r e q u e nc y as w e l l as i n
t h e s t r e ng t h o f t h e h y p o t h al am i c s t i m u l at i o n.5 6
I n 1 9 4 1 Car l s o n, Ge l l h o r n and Dar r o w 2 7 4
e x p e r i m e nt i ng o n c at s , c o nc l u de d t h at h y p o -
t h al am i c s t i m u l at i o n l e d t o an e x c i t at i o n o f t h e
s y m p at h e t i c and p ar as y m p at h e t i c s y s t e m s , o c c a-
s i o nal l y t o an i nh i b i t i o n o f t h e p ar as y m p at h e t i c
and t h at e x c i t at i o n o f b o t h s y s t e m s m ay r e s u l t
f r o m s t i m u l at i o n o f t h e s am e p ar t o f t h e h y p o -
t h al am u s . T h e s e r e s u l t s w e r e f u r t h e r s u p -
p o r t e d b y t h e o b s e r v at i o n o f Fe l dm an, Co r t e l l
and Ge l l h o r n, 2 7 5 and Ge l l h o r n, Co r t e l l and
Fe l dm an2 7 2 w h o s h o w e d t h at c e nt r al e x c i t at i o n
o f t h e au t o no m i c c e nt r e s b y ano x i a, m e t r az o l ,
r ag e and " s h am - r ag e " p r o du c e d b y s t i m u l a-
t i o n o f t h e h y p o t h al am u s , ac t i v at e d t h e p ar a-
s y m p at h e t i c and s y m p at h e t i c c e nt r e s at t h e
s am e t i m e , r e s u l t i ng i n a s i m u l t ane o u s s y m p a-
t h i c o - adr e nal and v ag o - i ns u l i n di s c h ar g e ; w i t h
a s l i g h t p r e do m i nanc e o f t h e f o r m e r . Fr o m
t h e s e o b s e r v at i o ns t h e y c o nc l u de d t h at i t i s
no t j u s t i f i e d t o ap p l y t h e c o nc e p t o f r e c i p r o c al
i nne r v at i o n t o c e nt r al au t o no m i c p r o c e s s e s .2 7 5
S UMMA RY
I n v i e w o f t h e m o r e r e c e nt f i ndi ng s , al l at -
t e m p t s .t o l o c al i z e s y m p at h e t i c and p ar as y m p a-
t h e t i c c e nt r e s i n t h e h y p o t h al am u s m ay p r o v e
f u t i l e , f o r t h e di v i s i o n b e t w e e n t h e s y m p at h e t i c
and p ar as y m p at h e t i c s y s t e m s m ay
no
l o ng e r
b e
c o n.s i de r e d anat o m i c al l y o r f u nc t i o nal l y
c o m -
p l e t e . Wh e n t h e h y p o t h al am u s i s s t i m u l at e d
e l e c t r i c al l y , t h e s t at e o f s t r i c t r e c i p r o c i t y o f
t h e t w o au t o no m i c c e nt r e s i s s u s p e nde d and
b o t h c e nt r e s di s c h ar g e s i m u l t ane o u s l y w i t h t h e
s y m p at h e t i c r e s p o ns e p r e do m i nat i ng .
Ef f e c t s o f h y p o t h al am i c l e s i o ns .- T h e f i r s t e x -
p e r i m e nt s de s i g ne d t o di s c l o s e t h e e f f e c t s o f
h y p o t h al am i c l e s i o ns o n t h e g as t r o - i nt e s t i nal
t r ac t w e r e p e r f o r m e d b y B u r de nk o and Mo g i l -
ni t z k i 6 0 i n 1 9 2 6 . Pl ac i ng l e s i o ns b e h i nd t h e
i nf u ndi b u l ar s t al k , t h e y no t i c e d g as t r i c m u c o s al
h w e m o r r h ag e s , e r o s i o ns , o c c as i o nal l y p e r f o r at i o ns
w i t h p e r i t o ni t i s , and c i c at r i z at i o n o f s o m e u l c e r s
i n a f e w o f t h e i r ani m al s w h i c h s u r v i v e d t h e
o p e r at i o n f o r s e v e r al m o nt h s . Po s t - m o r t e m s t u dy
o f t h e b r ai ns o f s u c h ani m al s s h o w e d t h at t h e
t u b e r al r e g i o n w as e x t e ns i v e l y de s t r o y e d i n m o s t
o f t h e c as e s . A s a c o nt r o l , l e s i o ns w e r e m ade i n
o t h e r p ar t s o f t h e b r ai n, b u t t h e s e w e r e w i t h o u t
e f f e c t . B u r de nk o and Mo g i l ni t z k i t h e n c o n-
c l u de d t h at t h e de s t r u c t i o n o f a s y m p at h e t i c
v as o c o ns t r i c t o r c e nt r e i n t h e m am m i l l ar y and
t u b e r al r e g i o ns o f t h e h y p o t h al am u s r e s u l t e d i n
di l at i o n o f b l o o d v e s s e l s , m u c o s al h w m o r r h ag e s
and ne c r o s i s , t h e ne c r o t i c ar e as u nde r g o i ng
di g e s t i o n b y t h e ac i d g as t r i c j u i c e .
I n 1 9 3 3 , Ke l l e r , Har e and D' A m o u r , 6 1 m ade
a p r e l i m i nar y r e p o r t o n a s e r i e s o f 5 0 c at s and
4 0 do g s i n w h i c h e x p e r i m e nt al l e s i o ns i n t h e
u p p e r b r ai n s t e m r e s u l t e d i n ac u t e g as t r o -
i nt e s t i nal c h ang e s i n a r e l at i v e l y s m al l nu m b e r
o f ani m al s . I n 1 2 do g s , m u c o s al h e e m o r r h ag e s
and h y p e r am i a w e r e no t e d i n t h e b o dy o f t h e
s t o m ac h at de at h w h i c h o c c u r r e d 7 t o 2 4 h o u r s
af t e r o p e r at i o n. T h e s e w e r e o f t e n as s o c i at e d
w i t h h y p e r ae m i a o f du o de nal and j e j u nal m u c o s a,
b e c o m i ng l e s s p r o no u nc e d as t h e di s t al i l e u m w as
ap p r o ac h e d. I n t h e 8 day s i n w h i c h e r o s i o ns
w e r e no t e d, h o w e v e r , l e s i o ns e x i s t e d i n t h e
ant e r i o r h y p o t h al am u s at t h e l e v e l o f t h e c h i as m a.
Wat t s and Fu l t o n6 2 p r o du c e d e x t e ns i v e l e s i o ns
i n t h e h y p o t h al am u s o f m o nk e y s and w e r e u n-
ab l e t o f i nd a de f i ni t e r e l at i o ns h i p b e t w e e n
de s t r u c t i o n o f any s i ng l e g r o u p o f h y p o t h al am i c
nu c l e i ( s u p r a- o p t i c , t u b e r o r p ar av e nt r i c u l ar )
and p at h o l o g i c al c h ang e s i n t h e g as t r o - i nt e s t i nal
t r ac t . Ou t o f t h e 1 7 ani m al s i n w h i c h t h e l e s i o ns
i nv o l v e d t h e t u b e r al , s u p r a- o p t i c and p ar a-
v e nt r i c u l ar nu c l e i , o nl y 7 r e v e al e d any g as t r o -
i nt e s t i nal di s e as e . Er o s i o ns o f t h e s t o m ac h w e r e
f o u nd i n 4 ani m al s , f r e e b l o o d i n t h e l u m e n i n
2 c as e s and a du o de nal p e r f o r at i o n
i n 1 c as e .
S e v e r al ani m al s w i t h s i m i l ar h y p o t h al am i c
1 2 1
WENER A ND HOFF: PEPT I C ULCER
r
Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
l e s i o ns s h o w e d no e v i de nc e o f g as t r o - i nt e s t i nal
di s e as e . Po s t e r i o r h y p o t h al am i c l e s i o ns di d no t
r e s u l t i n g as t r i c o r du o de nal c h ang e s .
I n a c o nt r o l s e r i e s o f 6 3 m o nk e y s w h i c h h ad
u nde r g o ne o p e r at i o ns u p o n s o m e o t h e r p ar t o f
t h e b r ai n o r s p i nal c o r d, 1 9 %
s h o w e d m u l t i p l e
p u nc t at e m u c o s al h e m o r r h ag e s , u nac c o m p ani e d
b y e r o s i o ns i n t h e s t o m ac h o r s m al l and l ar g e
i nt e s t i ne s . I n o nl y 3 ani m al s w as f r e e b l o o d
no t e d i n t h e l u m e n o f t h e g u t , t w i c e i n m o nk e y s
w i t h m i d- t h o r ac i c t r ans e c t i o n o f t h e c o r d, and
o nc e i n an ani m al i n w h i c h b o t h p r e m o t o r ar e as
h ad b e e n de s t r o y e d. I t w as c o nc l u de d t h at
t h e s e l e s i o ns w e r e du e t o h y p e r ac t i v i t y o f t h e
s y m p at h e t i c c e nt r e , e i t h e r b y a r e l e as e o r an
i r r i t at i o n, w h i c h l e d t o v as o c o ns t r i c t i o n o f t h e
b l o o d v e s s e l s o f t h e g u t , l o c al i s c h ne m i a and
ne c r o s i s .
A s t h e o b s e r v at i o ns o f Wat t s and Fu l t o n
w e r e b as e d o n r e l at i v e l y l o ng t e r m e x p e r i -
ni e nt s , t h i s w o r k w as c o nt i nu e d b y Ho f f and
S h e e h an6 3 and s t u di e s w e r e m ade o n ani m al s
w h i c h w e r e s ac r i f i c e d e ar l i e r , i n o r de r t o de -
t e r m i ne w h e t h e r any e ar l i e r l e s i o ns h ad b e e n
m i s s e d. I n t h e i r s t u dy o f 1 9 m o nk e y s , 3 o f
w h i c h di e d du r i ng t h e o p e r at i o n, 5 o f t h e r e -
m ai ni ng 1 6 s h o w e d ac u t e m u c o s al e r o s i o ns .
T h e s e w e r e c o nf i ne d m ai nl y t o t h e b o dy o f t h e
s t o m ac h and s h o w e d no p r e di l e c t i o n f o r t h e
p y l o r u s o r l e s s e r c u r v at u r e o f t h e s t o m ac h .
T h e e r o s i o ns w e r e al w ay s m u l t i p l e , m any h ad
a p u nc h e d o u t ap p e ar anc e and w e r e h al f a
c e nt i m e t r e s q u ar e . T h e y w e r e s t i p e r f i c i al and
ne v e r i nv o l v e d t h e m u s c u l ar i s .
Hi s t o l o g i c al e x am i nat i o n o f t h e h y p o t h al am i c
i nj u r i e s r e v e al e d t h at i n al l 5 ani m al s s h o w i ng
g as t r i c l e s i o ns at au t o p s y , t h e l e s i o ns w e r e
s m al l and c o nf i ne d t o t h e t u b e r al nu c l e i .
Le s i o ns i n t h e p o s t e r i o r h y p o t h al am u s w e r e
ne v e r f o l l o w e d b y c h ang e s i n t h e g u t . I n o nl y
1 o u t o f 5 m o nk e y s w as t h e t r ac k o f t h e l e s i o n
h ae m o r r h ag i c , and i n al l 5 c as e s t h e b as e o f t h e
t h i r d v e nt r i c l e h ad b e e n o p e ne d, b u t o t h e r
h y p o t h al am i c nu c l e i w e r e no t i nj u r e d. T h u s
i t w as f o u nd t h at l e s i o ns r e s t r i c t e d t o t h e
t u b e r al nu c l e i l e d t o h ae m at e m e s i s and m u l t i p l e
e r o s i o ns i n t h e b o dy o f t h e s t o m ac h , al t h o u g h
' s i m i l ar l y p l ac e d l e s i o ns w e r e as o f t e n u nas s o c i -
at e d w i t h g as t r o - i nt e s t i nal c h ang e s . I t i s o f
s p e c i al i nt e r e s t t h at o f t h o s e 5 ani m al s w h i c h
s h o w e d e r o s i o ns , 2 di e d o n t h e f i r s t day af t e r a
s t o r m y p o s t o p e r at i v e c o u r s e , and ano t h e r o n t h e
s e c o nd day , w h i l e t h e o t h e r 2 , w h i c h w e r e
s ac r i f i c e d o n t h e t h i r d day , s h o w e d a m ar k e d
di s i nc l i nat i o n t o e at du r i ng t h e t h r e e - day
s u r v i v al p e r i o d. I n a c o nt r o l s e r i e s o f 5 0
ani m al s s u b j e c t e d t o v ar i o u s no n- h y p o t h al am i c
c e r e b r al l e s i o ns , au t o p s y e x am i nat i o ns r e v e al e d
o nl y 1 c as e o f g as t r o - i nt e s t i nal l e s i o n, i n an
ani m al i n w h i c h b o t h t h e r i g h t and l e f t m o t o r
and p r e m o t o r ar e as h ad b e e n e x t i r p at e d 5
m o nt h s p r i o r t o 2 t r ans e c t i o ns o f t h e s p i nal
c o r d.
A l t h o u g h t h e nu m b e r o f p o s i t i v e f i ndi ng s
w as s m al l , Ho f f and S h e e h an c o nc l u de d t h at
t h e c o ns i s t e nt l y ne g at i v e f i ndi ng s i n t h e c o nt r o l
e x p e r i m e nt s as w e l l as t h o s e o f Wat t s and
Fu l t o n ap p e ar e d t o l e nd s o m e s i g ni f i c anc e t o
t h e as s o c i at i o n o f g as t r o - i nt e s t i nal l e s i o ns w i t h
i nj u r y t o t h e h y p o t h al am u s o r i nt e r r u p t i o ns o f
t h e de s c e ndi ng au t o no m i c p at h w ay s , e s p e c i al l y
t h o s e l e s i o ns i n t h e t u b e r al r e g i o n.
A l ar g e s e r i e s o f 2 0 0 do g s
w i t h a v ar i e d
di s t r i b u t i o n o f b r ai n s t e i n l e s i o ns , ap p r o x i -
m at e l y o ne - h al f o f w h i c h w e r e l o c at e d i n o r
ne ar t h e h y p o t h al am u s w as r e v i e w e d b y
Ke l l e r 6 4 i n 1 9 3 6 . I nc l u de d i n t h i s s e r i e s w e r e
6 do g s w i t h m as s i v e p r e c h i as m al l e s i o ns , 3 w i t h
e x t e ns i v e t r ans v e r s e c h i as m al dam ag e , 2 0 w i t h
l e s s e x t e ns i v e u ni l at e r al h y p o t h al am i c l e s i o ns
and 3 3 do g s i n w h i c h t h e r e w as al m o s t c o m -
p l e t e de s t r u c t i o n o f t h e h y p o t h al am u s .
Of t h e
w h o l e s e r i e s o f 2 0 0 do g s , 1 9 s h o w e d h e e m o r -
r h ag i c s t at e s and 1 1 r e v e al e d c r at e r s o r
e r o s i o ns at au t o p s y . Of t h o s e w i t h h x e m o r -
r h ag i c s t at e s t h e f u ndi c p o r t i o n o f t h e s t o m ac h
w as m o s t f r e q u e nt l y i nv o l v e d, o f t e n w i t h a
s h ar p l i ne o f de m ar c at i o n f r o m t h e b l anc h e d
p y l o r i c o r c ar di ac e nd. Oc c as i o nal l y t h e s e
l e s i o ns o f s t o m ac h and du o de nu m r e v e al e d e n-
g o r g e m e nt o f c ap i l l ar i e s and l o c al i z e d ar e as o f
m u c o s al h am o r r h ag e s , and i n no i ns t anc e w as
any c e l l u l ar i nf l am m at o r y r e ac t i o n no t e d i n
t h e s e l e s i o ns .
I t i s o f s p e c i al i nt e r e s t t o no t e t h at o f t h e s e
2 0 ani m al s w h i c h s h o w e d l e s i o ns , 1 2 di e d i n
2 4 h o u r s o r l e s s ; 4 di e d i n l e s s t h an 4 8 h o u r s ;
and 4 w i t h i n 7 2 h o u r s o f t h e o p e r at i o n. I n
s e v e r al i ns t anc e s , b l o o dy v o m i t i ng and b l o o dy
di ar r h e e a w e r e no t e d s o o n af t e r o p e r at i o n and
b l o o d w as f o u nd i n t h e l u m e n at au t o p s y 8 t o
1 2 h o u r s af t e r o p e r at i o n. Of t h e 1 9 do g s w i t h
g as t r o - i nt e s t i nal di s e as e , 1 4 h ad l e s i o ns i n t h e
ant e r i o r h y p o t h al am u s at t h e l e v e l o f t h e o p t i c
c h i as m a. I n 3 ani m al s t h e l e s i o n e nc r o ac h e d
u p o n t h e t u b e r al nu c l e i ; i n no i ns t anc e w as
1 2 2
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 i
WENER A ND HOFF: PEPT I C ULCER
t h e p o s t e r i o r h y p o t h al am u s i nv o l v e d, and i n al l
b u t o ne , t h e l e s i o ns e x t e nde d i nt o t h e t h i r d
v e nt r i c l e .
I n 1 1 do g s w i t h g as t r i c c r at e r s o r e r o s i o ns ,
8 h ad t r ans v e r s e c h i as m al l e s i o ns , i nv o l v i ni g
m ai nl y t h e r o s t r al p o r t i o n o f t h e ant e r i o r
h y p o t h al am u s ( s u p r a- o p t i c r e g i o n) , and t h e r e -
m ai ni ng 3 h ad p o nt i ne l e s i o ns . A g ai n, 5 o f
t h e s e ani m al s di e d w i t h i n 8 4 h o u r s af t e r o p e r a-
t i o n; o ne di e d o n t h e 1 5 t h day , and t h e r e m ai n-
i ng 2 w e r e s ac r i f i c e d o n t h e 2 6 t h day . T h e s e
e r o s i o ns w e r e no t as s o c i at e d w i t h h e e m o r r h ag i c
s t at e s and m ai nl y i nv o l v e d t h e s u r f ac e m u c o s a,
b u t i n s e v e r al i ns t anc e s e x t e nde d do w n t o t h e
m u s c u l ar i s . I n no i ns t anc e w as t h e r e any
r e s e m b l anc e t o a c h r o ni c u l c e r as s e e n i n m an.
Ke l l ar no t e d p ar t i c u l ar l y t h at h e am o r r h ag i c
s t at e s u s u al l y o c c u r r e d af t e r c o m p l e t e de s t r u c -
t i o n o f t h e ant e r i o r h y p o t h al am u s and w e r e
as s o c i at e d w i t h ab s e nc e o f f r e e ac i d i n t h e
g as t r i c c o nt e nt at au t o p s y , w h e r e as t h e c r at e r s
w e r e no t e d o nl y w h e n p ar t o f t h e ant e r i o r p ar t
o f t h e h y p o t h al am u s w as i nt ac t , and at au t o p s y
t h e p r e s e nc e o f c r at e r s w as as s o c i at e d w i t h
f r e e ac i d i n g as t r i c c o nt e nt s . Ke l l e r 6 5 t h e n s u b -
m i t t e d 2 4 do g s t o b i l at e r al v ag o t o m y p r i o r t o
p r o du c i ng a c h i as m al l e s i o n, and t y p i c al
h ae m o r r h ag i c s t at e s b u t no e r o s i o ns w e r e p r e -
c i p i t at e d i n 9 o f t h e s e ani m al s . On t h e o t h e r
h and, b i l at e r al r e m o v al o f t h e t h o r ac i c and
l u m b ar s y m p at h e t i c c h ai ns p r i o r t o m ak i ng t h e
h y p o t h al am i c l e s i o ns r e s u l t e d i n e r o s i o ns w i t h -
o u t h ae m o r r h ag e i n 1 4 o u t o f 2 9 do g s .
Ke l l e r and D ' A m o u r 6 6 ne x t r e p o r t e d t h e
p r o du c t i o n o f h ae m o r r h ag i c l e s i o ns and e r o s i o ns
i n 5 o u t o f 2 3 ani m al s f o l l o w i ng r e m o v al o f t h e
h y p o p h y s i s . T h e y f e l t t h at t h e l e s i o ns w e r e p r e -
c i p i t at e d b e c au s e o f a ne i g h b o u r i ng ne u r al
de r ang e m e nt , p o s s i b l y i nt r av e nt r i c u l ar s t i m u -
l at i o n as a r e s u l t o f o p e ni ng i nt o t h e t h i r d
v e nt r i c l e o r i nc i de nt al dam ag e t o t h e h y p o -
t h al am u s . Mar t i n and S c h ne do r f , 6 7 o n t h e
o t h e r h and, f o u nd no c h ang e s i n g as t r o - i nt e s t i nal
m o t i l i t y o r s e c r e t i o n f o l l o w i ng h y p o t h al am i c
l e s i o ns i n c at s and m o nk e y s . I n no i ns t anc e
w as t h e r e any g as t r i c o r du o de nal l e s i o n f o u nd,
i n any o f t h e ani m al s w h i c h w e r e s ac r i f i c e d
af t e r 4 2 t o 1 9 0 day s , e v e n t h o u g h i n al l t h e
m o nk e y s and i n 1 0 c at s t h e l e s i o ns w e r e m ade
i n t h e t u b e r r e g i o n i n an e f f o r t t o p ar al l e l
t h e
r e s u l t s o f Ho f f and S h e e h an. I ng r am 4 7
al s o r e -
p o r t e d t h at h e f o u nd no s i g ni f i c ant e v i de nc e o f
g as t r o - i nt e s t i nal l e s i o ns i n s o m e h u ndr e ds o f
ani m al s w i t h h y p o t h al am i c l e s i o ns .
Di s c u s s i o n. A l t h o u g h t h e e x p e r i m e nt al l e -
s i o ns o f t h e h y p o t h al am u s p r o du c e d g as t r o -
i nt e s t i nal l e s i o ns m o r e f r e q u e nt l y t h an di d
l e s i o ns p l ac e d e l s e w h e r e i n t h e c e nt r al ne r v o u s
s y s t e m , i t di d no t f o l l o w t h at al l h y p o t h al am i c
l e s i o ns r e s u l t e d i n s u c h c h ang e s i n t h e g u t .
I nde e d as S h e e h an4 9 h as p o i nt e d o u t i n a s t u dy
o f t h e c o l l e c t e d dat a o f Wat t s and Fu l t o n,
Ho f f and S h e e h an, Ke l l e r and Mar t i n and
S c h ne do r f , c h ang e s i n t h e g as t r o - i nt e s t i nal
t r ac t o c c u r r e d i n l e s s t h an o ne - t h i r d o f al l t h e
e x p e r i m e nt al h y p o t h al am i c l e s i o ns . T h e p o s i -
t i v e f i ndi ng s i ndi c at e t h at t h e g u t l e s i o ns w e r e
as s o c i at e d m ai nl y w i t h i nj u r i e s o f t h e ant e r i o r
h y p o t h al am u s , t h e s u p r a- o p t i c and t u b e r al
r e g i o ns , e s p e c i al l y t h e l at t e r . A s h as al r e ady
b e e n no t e d ab o v e , t h e t u b e r r e g i o n w as b e l i e v e d
t o b e p ar t o f a g e ne r al i z e d s y m p at h e t i c c e nt r e
i nf l u e nc i ng , am o ng t h e o t h e r v i s c e r al f u nc t i o ns ,
t h e m o t i l i t y and s e c r e t o r y ac t i v i t y o f t h e g u t .
I n g e ne r al , l e s i o ns s u c h as w e r e f o u nd w e r e
o f an ac u t e v ar i e t y , v ar y i ng f r o m m u c o s al
h s e m o r r h ag e s t o e r o s i o ns and c r at e r s , b u t ne v e r
w e r e c h r o ni c u l c e r s p r o du c e d o f t h e t y p e s e e n
i n m an. T h e l e s i o ns p r o du c e d o c c u r r e d i n t h e
f u ndi c p o r t i o n o f t h e s t o m ac h , w e r e m u l t i p l e
and s h o w e d no p r e di l e c t i o n f o r t h e p y l o r u s ,
l e s s e r c u r v at u r e o f t h e s t o m ac h o r du o de nu m ,
as i n m an.
I t i s o f i nt e r e s t t h at s i m i l ar l y p l ac e d l e s i o ns
f r e q u e nt l y g av e ne g at i v e f i ndi ng s , and t h at
s m al l , c ar e f u l l y l o c al i z e d l e s i o ns p l ac e d i n al l
p ar t s o f t h e h y p o t h al am u s , e s p e c i al l y i n t h e
t u b e r al r e g i o ns b y Mar t i n and S c h ne do r f , 6 7
c o m p l e t e l y f ai l e d t o p r o du c e p at h o l o g i c al
c h ang e s i n t h e g u t . T h e l e s i o n o f t h e g u t ap -
p e ar e d t o b e m ai nl y as s o c i at e d w i t h t h e l ar g e
e x t r e m e h y p o t h al am i c l e s i o ns as p r o du c e d b y
Wat t s and Fu l t o n, 6 2 Ho f f and S h e e h an6 3 and
Ke l l e r .6 4 6 5 T h e s e w e r e m ade w i t h a b l u nt
p r o b e , and t h e l e s i o ns f r e q u e nt l y e x t e nde d i nt o
t h e t h i r d v e nt r i c l e . Mar t i n and S c h ne do r f , 6 7
f e l t t h at t h e u ni nt e nt i o nal t r au m a t o t h e s u r -
r o u ndi ng t i s s u e s w i t h u nc o nt r o l l e d s i de ac t i o ns
m ay w e l l h av e ac c o u nt e d f o r a f ai r nu m b e r o f
t h e g as t r i c c h ang e s . Ke l l e r 6 4 f o r a w h i l e s u p -
p o r t e d t h e v i e w t h at c h ang e s i n t h e g as t r o -
i nt e s t i nal t r ac t m ay p o s s i b l y b e du e t o a
di s t u r b anc e o f t h e c e r e b r o - s p i nal f l u i d c i r c u l a-
t i o n f r o m de b r i s o r b l o o d, m ak i ng i t s w ay i nt o
t h e v e nt r i c l e s , b u t f u r t h e r e x p e r i m e nt s di d no t
1 2 3
WENER A ND HOFF: PEPT I C ULCER
ECanad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
s u p p o r t t h i s v i e w . Ho f f and S h e e h an6 3 f o u nd
t h at e x t e ns i v e l e s i o ns , w i t h h am o r r h ag e i nt o
t h e v e nt r i c l e s , f r e q u e nt l y r e s u l t e d i n ne g at i v e
f i ndi ng s i n t h e g u t .
T h e b al anc e o f f ac t s i ndi c at e s , h o w e v e r , t h at
dam ag e t o t h e h y p o t h al am u s m ay p r e c i p i t at e
l e s i o ns , b u t b y w h at m e c h ani s m i s u nk no w n.
I t h as b e e n s u g g e s t e d t h at h y p e r ac t i v i t y o f t h e
s y m p at h e t i c c e nt r e , e i t h e r b y a r e l e as e o r an
i r r i t at i o n, l e ads t o s p as m o f t h e t e r m i nal
v e s s e l s i n t h e s u b m u c o s a o f t h e g as t r o - i nt e s t i nal
t r ac t w i t h t h e p r o du c t i o n o f l o c al i s c h w e m i a i n
t h e m u c o s a and t h e di g e s t i o n o f t h e ne c r o t i c
t i s s u e b y t h e ac i d g as t r i c s e c r e t i o ns ( S c h i f f , 3
Wat t s and Fu l t o n.6 2
I t i s no t k no w n at p r e s e nt w h e t h e r o v e r -
ac t i v i t y o f t h e s y m p at h e t i c i s b r o u g h t ab o u t b y
t h e de s t r u c t i o n o f t h e i nh i b i t o r y p at h w ay s i n
t h e m o r e ant e r i o r p ar t s o f t h e h y p o t h al am u s
o r i s du e t o i r r i t at i o n o f t h e s y m p at h e t i c c e nt r e
f r o m an adj ac e nt i nj u r y . Ho f f and S h e e h an6 3
w e r e m o r e i nc l i ne d t o f av o u r t h e l at t e r v i e w .
T h e f ac t t h at l e s i o ns i n t h e p o s t e r i o r h y p o -
t h al am u s w e r e ne v e r as s o c i at e d w i t h g as t r o -
i nt e s t i nal l e s i o ns w o u l d t e nd t o s u p p o r t t h i s
v i e w .
Cu s h i ng 1 " and o t h e r s ' 1 2 1 3 , 1 4 ap p e ar e d t o
f av o u r t h e v i e w o f t h e h y p e r ac t i v i t y o f t h e
p ar as y m p at h e t i c s y s t e m as t h e c au s e o f u l c e r
f o r m at i o n. T h e y b e l i e v e d t h at s t i m u l at i o n o f
t h e p ar as y m p at h e t i c c e nt r e o f t h e h y p o t h al -
am u s o r o f i t s de s c e ndi ng t r ac t s l e d t o h y p e r -
m o t i l i t y , h y p e r s e c r e t i o n w i t h r e s u l t ant f o c al
i s c h e e m i c ne c r o s i s and di g e s t i o n o f t h e dam ag e d
ar e as b y t h e i nc r e as e d ac i d s e c r e t i o n. Ho f f
and S h e e h an, 6 3 t h o u g h t t h at p r o b ab l y t h e r e i s
no r e al di f f e r e nc e i n t h e t w o v i e w s e x p r e s s e d
ab o v e , s i nc e t h e g as t r o - i nt e s t i nal l e s i o ns m ay
h av e r e s u l t e d b e c au s e o f a c o m p l e x i m b al anc e
b e t w e e n t h e t w o au t o no m i c s y s t e m s .
Mo r e r e c e nt l y Wo l f and Wo l f f 2 5 4 ' 2 7 1
o b s e r v e d
p r o f o u nd p h y s i o l o g i c al c h ang e s i n t h e h u m an
g as t r i c m u c o s a i n r e s p o ns e t o c e r t ai n e m o t i o nal
di s t u r b anc e s . Em o t i o nal s t at e s o f f e ar , de -
p r e s s i o n and o t h e r f e e l i ng s i nv o l v i ng a de s i r e
f o r w i t h dr aw al , w e r e al w ay s ac c o m p ani e d b y
a s y m p at h e t i c r e s p o ns e o f t h e s t o m ac h c o ns i s t -
i ng o f h y p o s e c r e t i o n, h y p o m o t i l i t y , m u c o s al
p al l o r , and de c r e as e d m u c i n p r o du c t i o n. Re -
ac t i o ns and e m o t i o ns i nv o l v i ng c o nf l i c t , h o s -
t i l i t y , r e s e nt m e nt and anx i e t y w e r e f o u nd t o
b e as s o c i at e d w i t h h y p e r ae m i a, h y p e r s e c r e t i o n,
h y p e r m o t i l i t y , and i nc r e as e d m u c i n p r o du c t i o n,
w h i c h w e r e p r e do m i nant l y p ar as y m p at h e t i c
e f f e c t s . Wh e r e c o nf l i c t i nv o l v i ng b o t h f e ar and
r e s e nt m e nt e x i s t e d, a di s s o c i at e d r e s p o ns e w as
o b s e r v e d r e s u l t i ng i n i nc r e as e d p ar as y m p a-
t h e t i c ac t i v i t y , nam e l y h y p e r ae m i a, h y p e r s e c r e -
t i o n and h y p e r m o t i l i t y . Ge l l h o r n and h i s
as s o c i at e s h av e no t e d t h at i n s o m e s t at e s o f
s t r e s s and h y p o t h al am i c s t i m u l at i o n, s t r i c t
r e c i p r o c i t y o f b o t h c e nt r e s w as s u s p e nde d and
t h e p ar as y m p at h e t i c and s y m p at h e t i c s y s t e m s
di s c h ar g e d s i m u l t ane o u s l y .2 7 2 ' 2 7 4 , 2 7 5
B ant i ng e t al ., and We ne r , h av e al s o o b s e r v e d
t h at w h e n ac e t y l c h o l i ne 8 5 ' 8 6 o r m e c h o l y l 2 7 6
w e r e adm i ni s t e r e d t o ani m al s , t h e r e w as a
di r e c t p ar as y m p at h e t i c e f f e c t and an i ndi r e c t
c o m p e ns at o r y s y m p at h e t i c r e s p o ns e , ag ai n i ndi -
c at i ng t h at b o t h di v i s i o ns o f t h e au t o no m i c
ne r v o u s s y s t e m r e s p o nde d t o g e t h e r .
S UMMA RY
Fr o m t h e e v i de nc e p r e s e nt e d i t m ay no t b e
j u s t i f i ab l e t o i nt e r p r e t t h e t y p e s o f r e s p o ns e s
o b t ai ne d f r o m h y p o t h al am i c l e s i o ns as p u r e l y
s y m p at h e t i c o r p ar as y m p at h e t i c , f o r e v i de nt l y
b o t h s y s t e m s w e r e f r e q u e nt l y ac t i v at e d s i m u l -
t ane o u s l y . I t t h e r e f o r e s e e m s m o r e c o r r e c t t o
c o ns i de r t h at l e s i o ns p l ac e d i n t h e h y p o t h al -
am u s u p s e t t h e au t o no m i c r e g u l at i ng m e c h an-
i s m , t h e r e b y s e t t i ng u p a s t at e o f au t o no m i c
i m b al anc e r e s u l t i ng i n v as o m o t o r c h ang e s i n
t h e g u t , w h i c h m ay b e s e v e r e e no u g h i n s o m e
c as e s t o c au s e m u c o s al h ae m o r r h ag e s , e r o s i o ns
and o c c as i o nal l y ac u t e u l c e r at i o n. T h e s e v as o -
m o t o r c h ang e s m ay h av e b e e n ag g r av at e d b y
t h e s h o c k - l i k e c o ndi t i o ns w h i c h ac c o m p ani e d
t h e o p e r at i o ns . I n m o s t i ns t anc e s w h e r e t h e
l e s i o ns di d o c c u r , t h e ani m al s w e r e m o r i b u nd
and di e d s o o n af t e r o p e r at i o n, w i t h i n t h e f i r s t
2 4 t o 9 6 h o u r s . S e l y e 2 7 7 ' 2 7 9 h as r e p o r t e d t h e
o c c u r r e nc e o f ac u t e g as t r o - i nt e s t i nal e r o s i o ns
w h i c h h e b e l i e v e d w e r e c h ar ac t e r i s t i c o f t h e
s h o c k - p h as e o f t h e al ar m r e ac t i o n. Mann2 8 0 ' 2 8 1
and El l i o t t 8 3 h av e al s o r e p o r t e d t h e o c c u r r e nc e
o f ac u t e m u c o s al h w m o r r h ag e s and e r o s i o ns as -
s o c i at e d w i t h t h e m o r i b u nd c o ndi t i o n o f
ani m al s f o l l o w i ng b i l at e r al adr e nal e c t o m y .
I n t h e e x p e r i m e nt s o f Mar t i n and S c h ne -
do r f , 6 7 t h e ani m al s r e c e i v e d v e r y c ar e f u l p r e -
o p e r at i v e and p o s t o p e r at i v e c ar e and m o s t o f
t h e m s u r v i v e d t h e o p e r at i o n and w e r e s ac r i -
f i c e d o nl y af t e r 4 0 day s o r m o r e . I t m ay v e r y
w e l l b e t h at h ad s o m e o f t h e s e ani m al s b e e n
e x am i ne d i n t h e f i r s t f e w day s af t e r t h e o p e r a-
1 2 4
Canad. M. A . J .
A u g . 1 9 4 8 , v o l . 5 9 1
WENER A ND
HOFF: PEPT I C ULCER
t i o n, s o m e g as t r o - i nt e s t i nal l e s i o ns w o u l d h av e
b e e n no t e d, b u t as t h e ani m al s r e c o v e r e d, any
ac u t e l e s i o ns t h at m ay h av e e x i s t e d h ad t i m e
t o h e al l e av i ng no t r ac e s at au t o p s y at t h e
l at e r dat e .
Fr o m t h e e x p e r i m e nt al e v i de nc e t h u s f ar
s u b m i t t e d, i t i s c l e ar l y e v i de nt t h at h y p o -
t h al am i c l e s i o ns and l e s i o ns o f t h e p o ns ,
m e du l l a and u p p e r s p i nal c o r d, b y c au s i ng de -
r ang e m e nt o f t h e au t o no m i c c e nt r e s o r i nt e r -
f e r i ng w i t h t h e de s c e ndi ng p at h w ay s , m ay
i ni t i at e ac u t e g as t r o - du o de nal l e s i o ns , b u t no
e v i de nc e t h at t h e s e l e s i o ns c an o r e v e r h av e
g o ne o n t o f o r m c h r o ni c u l c e r s o f t h e t y p e s e e n
i n m an.
T HE EFFECT OF LES I ONS OF T HE PERI PHERA L
NERVES OF T HE S T OMA CH
Vag u s . Kam m e r e r ' w as p r o b ab l y t h e f i r s t t o
o b s e r v e g as t r i c l e s i o ns i n r ab b i t s f o l l o w i ng
i nj u r y t o t h e v ag u s and s p l anc h ni c ne r v e s . I t
w as no t , h o w e v e r , u nt i l t h e l at t e r p ar t o f t h e
ni ne t e e nt h c e nt u r y t h at e x p e r i m e nt al w o r k w as
at t e m p t e d al o ng s i m i l ar l i ne s . I n 1 8 9 3 ,
Lo r e nz i 6 9 r e p o r t e d t h at f o l l o w i ng s e c t i o ns o f
t h e v ag i , e i t h e r i n t h e ne c k o r b e l o w t h e di a-
p h r ag m i n r ab b i t s , m u c o s al h e am o r r h ag e s w e r e
no t e d, and i f t h e ani m al s s u r v i v e d 2 4 h o u r s
o r l o ng e r , h ae m o r r h ag i c e r o s i o ns de v e l o p e d.
S ai t t a, 7 0 p e r f o r m e d b i l at e r al v ag o t o m y i n t h e
ne c k and o b s e r v e d m u c o s al h ae m o r r h ag e s and
e r o s i o ns i n 7 o u t o f 1 0 r ab b i t s . I n 4 r ab b i t s ,
f o l l o w i ng b i l at e r al v ag o t o m y , h e adm i ni s t e r e d
3 % HCl s o l u t i o n r e p e at e dl y b y m o u t h and
f o u nd m u l t i p l e u l c e r s . Fi nz i 7 ' l and Ke p p i c h 7 2
f o u nd h ae m o r r h ag i c ne c r o s i s and ac u t e and s u b -
ac u t e u l c e r s i n t h e s t o m ac h o f ani m al s s u b -
j e c t e d t o b i l at e r al c e r v i c al v ag o t o m y ; ac c o r d-
i ng t o
Gr e g g i o 7 3 ne g at i v e r e s u l t s w e r e no t e d b y
o t h e r w o r k e r s f o l l o w i ng c e r v i c al v ag o t o m y .
Vo n Yz e r e n7 4 c u t b o t h v ag i s u b di ap h r ag m at i -
c al l y i n 2 0 r ab b i t s and i n 1 0 o f t h e m c l ai m e d
h e f o u nd s i ng l e c h r o ni c u l c e r s i n t h e p y l o r i c
r e g i o n; t h e e ar l i e s t w as o b s e r v e d i n 5 day s and
t h e o l de s t af t e r 2 6 9 day s . Ent i r e l y ne g at i v e
r e s u l t s f o l l o w i ng s u b di ap h r ag m at i c v ag o t o m y
w e r e o b t ai ne d b y Do nat i , w h o b e l i e v e d t h at t h e
p o s i t i v e r e s u l t s c l ai m e d b y o t h e r s w e r e i nc i -
de nt al and t h at v ag o t o m y h ad no e f f e c t o n t h e
m u c o u s m e m b r ane o f t h e s t o m ac h . On t h e
o t h e r h and, Op h u l s 7 6 r e p e at e d and c o nf i r m e d
t h e w o r k o f Vo n Yz e r e n, b u t i n
o nl y
6 o u t o f
3 0 r ab b i t s di d h e p r o du c e u l c e r s w h i c h h e
c l ai m e d r e s e m b l e d t h o s e s e e n i n m an. T h e s e
di d no t ap p e ar b e f o r e t h e 2 4 t h day and t h e
l as t o ne o n t h e 1 8 t h day . Ex am i nat i o n o f
t h e s e u l c e r s s h o w s t h e m t o b e ac u t e e r o s i o ns
i n no w ay r e s e m b l i ng u l c e r s s e e n i n m an.
Op h u l s c o nc l u de d t h at t h e l e s i o ns w e r e ne u r o -
t r o p h i c and t h at t r o p h i c i nf l u e nc e s w e r e ne c e s -
s ar y t o p r e s e r v e t h e no r m al r e s i s t anc e o f t h e
m u c o u s m e m b r ane t o t h e di g e s t i v e ac t i o n o f
t h e g as t r i c j u i c e . Lat z e l 7 7 no t e d h aT m o r r h ag i c
e r o s i o ns and u l c e r s i n 1 0 do g s , 1 2 day s f o l l o w -
i ng s u b di ap h r ag m at i c v ag o t o m y .
Gr e g g i o 7 3 w h o p e r f o r m e d nu m e r o u s c e r v i c al
and s u b di ap h r ag m at i c v ag o t o m i e s i n r ab b i t s
and do g s , f o u nd am o ng ac u t e u l c e r s o nl y o ne
l e s i o n w h i c h r e s e m b l e d a c h r o ni c u l c e r , 3 0 day s
f o l l o w i ng t h e o p e r at i o n. T h e s e ani m al s w e r e
s ac r i f i c e d f r o m 1 5 t o 1 5 0 day s p o s t o p e r at i v e l y ,
and at au t o p s y o nl y o c c as i o nal g as t r i c m u c o s al
h aw m o r r h ag e s o r e r o s i o ns w e r e s e e n. I n s p i t e
o f t h e p au c i t y o f p o s i t i v e r e s u l t s , Gr e g g i o c o n-
c l u de d t h at al t e r e d g as t r i c m o t i l i t y and m o di f i -
c at i o n o f t h e g as t r o - p anc r e at i c j u i c e s p l ay a
r o l e i n t h e e t i o l o g y o f u l c e r . Mc Cr e a2 8 6 no t e d
t h at af t e r v ag o t o m y u l c e r s o c c u r r e d i n ap -
p r o x i m at e l y 5 0 % o o f h i s r ab b i t s , b u t no ne i n
c at s o r do g s . Mo r e r e c e nt l y , Fe r g u s o n7 8 f o u nd
e r o s i o ns i n 2 ani m al s w h i c h h ad b e e n s u b j e c t e d
t o v ag o t o m y ; o ne ani m al di e d f r o m p e r f o r at i o n
o n t h e 2 0 t h day .
B e az e l l and I v y 7 9 c l ai m e d an i nc r e as e d i nc i -
de nc e o f c h r o ni c u l c e r s i n r ab b i t s and do g s
p l ac e d o n a r o u g h di e t f o l l o w i ng s u b di ap h r ag -
m at i c v ag o t o m y . Ul c e r s de v e l o p e d i n 1 2 o u t
o f 2 9 ani m al s , and t h e m ax i m u m i nc i de nc e w as
no t e d ab o u t t h e 5 0 t h t o 6 0 t h day . T h e i nc i -
de nc e o f u l c e r de c r e as e d b y o ne - h al f i n ano t h e r
g r o u p p l ac e d o n a s o f t di e t . Ul c e r di d no t
o c c u r i n 6 0 do g s w h i c h w e r e s u b j e c t e d t o b i -
l at e r al v ag o t o m y ab o v e t h e di ap h r ag m and f e d
a s o f t di e t . Me e k 8 0 al s o r e p o r t e d t h at u l c e r s
ap p e ar e d i n 2 o u t o f 1 3 v ag o t o m i z e d do g s
w h i c h w e r e o n a r o u g h di e t . I t s h o u l d b e
p o i nt e d o u t t h at ade q u at e h i s t o l o g i c al e v i de nc e
t o c o nf i r m t h e e x i s t e nc e o f u l c e r at i o n w as no t
s u b m i t t e d b y B e az e l l and I v y 7 9 and Me e k .8 0
Ke l l e r 6 5 f o u nd t h at ac u t e m u c o s al h ae m o r -
r h ag e s and e r o s i o ns w e r e p r e c i p i t at e d i n t h e
g as t r i c m u c o s a i n a h i g h p e r c e nt ag e o f v ag o t o -
m i z e d do g s w h i c h w e r e s u b j e c t e d t o y ar d c o n-
di t i o ns du r i ng t h e w i nt e r m o nt h s . I n a f e w
i ns t anc e s s u c h l e s i o ns h e al e d w i t h e x t e ns i v e
s c ar r i ng . S u c h l e s i o ns w e r e ne v e r e nc o u nt e r e d
1 2 5
WENER A ND HOFF: PEPT I C ULCER
Canad. M. A . J .
L
A u g . 1 9 4 8 , v o l .
5 9
i n ani m al s u nde r a c ag e r e g i m e n. B e r g 8 ' f o u nd
no e v i de nc e o f u l c e r i n 6 do g s s ac r i f i c e d 3 0 t o
9 0 day s af t e r s u b di ap h r ag m at i c v ag o t o m y .
Re s u l t s o b t ai ne d b y s t i m u l at i o n o f t h e v ag i
h av e b e e n e q u al l y c o nt r adi c t o r y . Ke p p i c h 8 4
c l ai m e d t o p r o du c e c h r o ni c g as t r i c u l c e r s i n 1 0
o u t o f 1 1 r ab b i t s b y p l ac i ng e l e c t r o de s o n t h e
v ag i ne ar t h e c ar di a. T h e ne r v e s w e r e s t i m u -
l at e d w i t h f ar adi c c u r r e nt f o r 1 0 m i nu t e s
dai l y
f o r 5 t o 2 5 day s . S t ah nk e 8 2 s t i m u l at e d t h e
v ag i
i n do g s ne ar t h e c ar di a b y p l ac i ng t h e
e l e c t r o de s i n t h e l u m e n o f t h e l o w e r
c e s o p h ag u s ,
w i t h r e s u l t ant
h y p e r m o t i l i t y , h y p e r s e c r e t i o n,
p y l o r o s p as m , c h r o ni c g as t r i t i s and e r o s i o ns ,
b u t no u l c e r s . A c c o r di ng t o
Mc Cann, ' 0 ne g a-
t i v e r e s u l t s w e r e o b t ai ne d b y Gu nde l f i ng e r ,
Ko r t e and Do nat i . B e s t and Or at o r 2 9 4 f o u nd
t h e y c o u l d no t p r o du c e u l c e r s b y di r e c t s t i m u -
l at i o n o f t h e v ag u s w i t h
m ag ne s i u m , and t h at
i t di d no t p r o l o ng u l c e r al r e ady p r e s e nt .
Et t i ng e r , Hal l and B ant i ng , 8 5 b y r e p e at e d and
p r o l o ng e d v ag al s t i m u l at i o n i n t h e do g , p r o -
du c e d c o ng e s t i o n o f t h e m u c o s a o f t h e u p p e r
g as t r o - i nt e s t i nal t r ac t , b u t no e r o s i o ns o r
u l c e r s . T h e f o l l o w i ng y e ar , Manni ng , Hal l and
B ant i ng 8 6 u s i ng
c o nt i nu o u s
v ag al s t i m u l at i o n
i n do g s ( 3 1 t o 7 4 h o u r s ) p r o du c e d c o ng e s t i o n
and h ae m o r r h ag e i n u p p e r g as t r o - i nt e s t i nal
t r ac t , b u t w h e n e s e r i ne w as adde d, s m al l ac u t e
u l c e r at i o ns i n t h e p y l o r i c r e g i o n and du o de nu m
w e r e no t e d i n o ne do g . S i nc e t h e
m i c r o s c o p i c
de s c r i p t i o n o f t h e s e l e s i o ns w e r e no t f u l l y r e -
p o r t e d, i t i s no t k no w n w h e t h e r t h e s e l e s i o ns
w e r e m e r e l y ac u t e e r o s i o ns o r t r u e u l c e r s .
S p l anc h ni c ne r v e s .- Dal l a Ve do v a, 8 7 c l ai m e d
t o h av e p r o du c e d c h r o ni c u l c e r s i n r ab b i t s b y
i nj e c t i ng ' al c o h o l i nt o t h e s p l anc h ni c ne r v e s , o r
b y r e s e c t i ng t h e ne r v e s . Du r ant e 8 8 r e p e at e d
Ve do v a' s w o r k , b u t i ns t e ad o f an ab do m i nal
ap p r o ac h h e r e s e c t e d t h e ne r v e s e ' x t r ap e r i -
t o ne al l y v i a t h e l u m b ar r o u t e . He f o u nd t h at
s e c t i o n' o f t h e m aj o r s p l anc h ni c ne r v e s p r o -
du c e d o nl y a f e w s i g ns o f c o ng e s t i o n, w h i c h
c l e ar e d u p i n 1 0 t o 1 2 day s . Wh e n t h e m e di u m
s p l anc h ni c s w e r e c u t o r l i g at e d, h e e m o r r h ag i c
and no n- h w e m o r r h ag i c l e s i o ns o c c u r r e d i n t h e
m u c o s a o f t h e p y l o r i c r e g i o n. Re s e c t i o n o f t h e
m i no r s p l anc h ni c ne r v e s o nl y c au s e d ac u t e
h w e m o r r h ag i c l e s i o ns . Wh e n al l s y m p at h e t i c
ne r v e s w e r e c u t , m o r e p r o no u nc e d l e s i o ns w e r e
no t e d. A l t h o u g h nu m e r o u s ac u t e l e s i o ns r e -
s u l t e d, Du r ant e f o u nd o nl y 1 u l c e r af t e r 3 5
day s w h i c h h e c al l e d a c h r o ni c u l c e r . Ho w e v e r ,
ac c o r di ni g
t o o u r de f i ni t i o n o f
u l c e r s , t h e
l e s i o ni s
f o u nd w e r e
m ai nl y
ac u t e e r o s i o ns and s o - c al l e d
c h r o ni c u l c e r s w e r e i n f ac t a s u b ac u t e u l c e r a-
t i o n and i n no
w ay r e s e m i i b l e d c h r o ni c p e p t i c
u l c e r i n
m an.
Mo r e
r e c e nt l y , Ke l l e r 6 5 and
B e r g s 9 s u b j e c t e d
do g s
t o
s y m p at h e c t o m y i n w h i c h t h e ab do m i nal
p o r t i o n and l o w e r
p ar t
o f t h e t h o r ac i c
c h ai n
w e r e r e m o v e d
b i l at e r al l y and no t e d t h at t h e r e
w as no e v i de nc e o f m u c o s al c h ang e s i n t h e
s t o m ac h o r du o de nu m af t e r 2 w e e k s and
l o ng e r .
I t i s
i nt e r e s t i ng t h at i n
s p i t e o f t h e
l ar g e nu m b e r o f e x t e ns i v e
s y m p at h e c t o m i e s
p e r f o r m e d t o r e l i e v e
h y p e r t e i ns i o n, t h i s
o p e r a-
t i o n h as no t r e s u l t e d i n u l c e r f o r m at i o n. Ho w -
e v e r , B l e g e n
and Ki nt ne r 2 8 3 h av e
r e p o r t e d a
c as e i n w h i c h an
e x i s t i ng g as t r i c u l c e r
al ) -
p e ar e d
t o b e ag g r av at e d f o l l o w i ng a do r s o -
l u m b ar
s y m p at h e c t o m y . On t h e ' o t h e r
h anl d,
Fr o e h l i c h 2 8 4 h as r e p o r t e d t h at s e c t i o n o f t h e
s p l anc h ni c ne r v e s w i t h r e m o v al o f t h e f i r s t
l u m b ar g ang l i o n y i e l de d g o o d r e s u l t s i n 1 4 o u t
o f 2 5 c as e s w i t h g as t r o - du o de nal u l c e r .
Co e l i ac p l e x u s .- A c c o r di ng ' t o Gr e g g i o , 7 3 l e -
s i o ns o f t h e c c e l i ae p l e x u s w e r e f o u nd t o p r o -
du c e u l c e r s and i nu e o s al h ' e m o r r h ag e s
b y
Ve do v a, Kaw am u r a, Li l l a and Ge b e l l i .
Gr e g -
g i o 7 3 al s o r e p o r t e d t h at Pi nc u s and S am u e l , and
Po p i e l s k i no t e d
h y p e r ae m i a, m u c o s al
h ae m u o r -
r h ag e s and u l c e r s f o l l o w i ng e x t i r p at i o n o f t h e
c c e l i ae p l e x u s , w h i l e A dr i an, B u dg e , Lu s t i g and
o t h e r s
c o ns t ant l y o b s e r v e d ne g at i v e r e s u l t s i n
do g s and r ab b i t s .
Lat z e l 1 7 V al s o r e p o r t e d t h at
g as t r o - i nt e s t i nal l e s i o ns di d no t o c c u r f o l l o w i ng
r e m o v al o f t h e c o e l i ac p l e x u s . A c c o r di ng t o
I v y , 9 0 s e c t i o n o f b o t h v ag i and s p l anc h ni c
ne r v e s o c c as i o nal l y p r o du c e d p e t e c h i al
h ae m o r -
r h ag e s o f t h e p y l o r i c and du o de nal m u c o u s
m e m b r ane , b u t i n 1 0 do g s w h i c h w e r e k i l l e d
f r o m 1 w e e k t o 4 m o nt h s f o l l o w i ng do u b l e
v ag o t o m y and s p l anc h no t o m y w i t h e x t i r p at i o n
o f t h e
c o m l i ac p l e x u s , no g as t r i c o r du o de nal
l e s i o ns w e r e o b s e r v e d. T h i s c o nf i r m e d t h e f i nd-
i ng s o f Do nat i .
Ho w e v e r , A u e r 9 1 h as c l ai m e d
t h at u l c e r s de v e l o p e d af t e r c o m p l e t e
de ne r v a-
t i o n o f t h e s t o m ac h .
Di s c u s s i o n.- Fr o m t h e c o nt r adi c t o r y
e v i de nc e
s u b m i t t e d, i t i s e v i de nt t h at al t h o u g h
m any
i nv e s t i g at o r s h av e p r o du c e d g as t r i c o r du o -
de nal l e s i o ns
b y i nt e r f e r i ng w i t h t h e ne r v e
s u p p l y t o t h e s t o m ac h , o nl y r ar e l y , i f at al l ,
' h as i t b e e n p o s s i b l e f o r any o ne - t o p r o du c e
a
c h r o ni c u l c e r o f t h e t y p e c o m m o nl y
f o u nd' i n
1 2 6
Canad. M. A . J .
A u g . 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ULCER
m an. I t i s v e r y di f f i c u l t t o f i nd an ade q u at e
e x p l anat i o n f o r t h e e x t r e m e v ar i ab i l i t y i n t h e
r e s u l t s r e p o r t e d, e v e n w h e n e x p e r i m e nt s w e r e
do ne o n s i m i l ar s p e c i e s o f ani m al s and u nde r
s i m i l ar e x p e r i m e nt al c o ndi t i o ns .
Vo n B e r g m ann1 3 and o t h e r s b e l i e v e d t h at
h y p e r t o ni c i t y o f t h e v ag u s p r o du c e s g as t r i c
s p as m s w h i c h p u c k e r t h e g as t r i c - m u c o s a and s o
s t r ang l e i t t o p r o du c e l o c al i s c h ae m i a and a
ne c r o t i c f o c u s , w h i c h i s di g e s t e d b y t h e g as t r i c
j u i c e s l e adi ng t o e r o s i o n and u l c e r at i o n. Gr e g -
g i o 7 3 b e l i e v e d t h at t h e l e s i o ns f o l l o w i ng v ag o t o m y
w e r e t h e r e s u l t o f t h e al t e r e d g as t r i c m o t i l i t y and
m o di f i c at i o n o f t h e g as t r i c and p anc r e at i c j u i c e s .
Du r ant e 8 8 s t r e s s e d t h e " t r o p h i c " i nf l u e nc e o f t h e
s y m p at h e t i c ne r v o u s s y s t e m o n t h e g as t r i c
m u c o s a and c o nc l u de d t h at p s y c h i c o r p e r i p h e r al
i r r i t at i o n o f t h e s y m p at h e t i c s y s t e m c au s e d
al t e r at i o n i n t h e v as o m o t o r t o ne o f t h e g as t r i c
v e s s e l s w h i c h r e s u l t s i n m u c o s al h ae m o r r h ag e s ,
o r s p as t i c c o nt r ac t i o n o f t h e v e s s e l s w i t h r e -
s u l t ant i s c h aw m i a and u l c e r at i o n.
I n an at t e m p t t o m ak e o r de r o u t o f t h i s
c h ao t i c l i t e r at u r e , Cu s h i ng , ' 1 s t r e s s e d t h e c o n-
c e p t o f ant ag o ni s m o f t h e s y m p at h e t i c and
p ar as y m p at h e t i c s y s t e m s and s t at e d t h at m o s t
o f t h e l e s i o ns r e s u l t e d f r o m a h y p e r ac t i v e
v ag u s , du e t o a p ar al y s i s o f t h e s p l anc h ni c o r
b e c au s e o f i r r i t at i o n o f t h e v ag al f i b r e s o n
s e c t i o ni ng t h e ne r v e s . T h e s e e x p l anat i o ns do
no t s e e m ade q u at e t o e x p l ai n w h y s e c t i o n o f
t h e v ag i o r s p l anc h ni c s h av e l e d t o s u c h c o n-
f l i c t i ng r e s u l t s , e x c e p t t h at s u c h p o s i t i v e r e -
s u l t s as di d o c c u r w e r e i n r e s p o ns e t o no n-
s p e c i f i c t r au m a.
I t i s b e c o m i ng i nc r e as i ng l y e v i de nt t h at t h e
v ag u s and s y m p at h e t i c ne r v e s c an no l o ng e r
b e t h o u g h t o f as b e i ng m ai nl y ant ag o ni s t i c ,
no r c an t h e y b e c o ns i de r e d as b e i ng p u r e m o t o r
o r a p u r e i nh i b i t o r y ne r v e o f t h e s t o m ac h .
Vag u s f i b r e s h av e b e e n f o u nd t o b e p r e s e nt i n
t h e s p l anc h ni c ne r v e o f t h e c at ( Ras m u s s e n
and Du nc an
; 9 2 I w am a ; 9 3 Du nc an9 4 ) . I nh i b i t o r y
e f f e c t s h av e b e e n o b t ai ne d b y s t i m u l at i o n o f
t h e v ag u s and m o t o r e f f e c t s o n s t i m u l at i o n
o f t h e s y m p at h e t i c
ne r v e s ( Wh e e l an
and
T h o m as 9 5 ) . T h e l at t e r au t h o r s al s o no t e d a
de c r e as e i n t o nu s f o l l o w i ng s t i m u l at i o n o f t h e
v ag u s w i t h a w e ak c u r r e nt and m o t o r e f f e c t s
w e r e o b t ai ne d
w h e n t h e c u r r e nt w as i nc r e as e d
i n 2 c as e s . He s l o p 5 4
o b s e r v e d t h at s t i m u l at i o n
o f t h e s p l anc h ni c
ne r v e s c au s e d i nc r e as e d s e c r e -
t i o n o f ac i d g as t r i c j u i c e s , e v e n w h e n t h e v ag i
w e r e c u t .
Mc Cr e a, Mc S w i ne y and S t o p f o r d9 6 c o nc l u de d
t h at t h e e f f e c t s o f s e c r e t i o n o f t h e ne r v e s o f
t h e s t o m ac h m ay b e di v i de d i nt o 2 s t ag e s , a
t e m p o r ar y o r i m m e di at e e f f e c t o f i ni t i al p ar e s i s
and g as t r i c di l at i o n, p r o b ab l y du e t o s h o c k ,
l as t i ng 7 t o 1 0 day s , f o l l o w e d af t e r an i nt e r v al
b y a r e t u r n t o no r m al f u nc t i o n. T h e p e r m a-
ne nt e f f e c t w as a de c r e as e i n i ni t i al e m p t y i ng
o f t h e s t o m ac h . I t w as al s o s h o w n b y Mc Cr e a
e t al ., 9 8 t h at s t i m u l at i o n o f t h e p e r i p h e r al e nd
o f t h e c u t v ag u s m ay e i t h e r i ni t i at e m o v e m e nt ,
i f t h e o r g an b e i n a s t at e o f r e s t o r h y p o t o nu s ,
o r i f m o v e m e nt s ar e p r e s e nt , au g m e nt and
s o m e t i m e s ac c e l e r at e t h e m . I f h y p e r t o nu s o r
ac t i v i t y e x i s t s , s t i m u l at i o n o f t h e c u t e nd o f
t h e v ag i i s f o l l o w e d b y i nh i b i t i o ns and r e l ax a-
t i o n, b u t u l t i m at e l y i nc r e as e d c o nt r ac t i o ns
o c c u r . T h e r e s u l t s w e r e no t al t e r e d b y anae s -
t h e t i c s , de c e r e b r at i o n o r s p l anc h ni c ne r v e
s e c t i o n.
A c c o r di ng t o Mc S w i ne y 9 7 and o t h e r s , t h e i m -
m e di at e e f f e c t s o f v ag o t o m y , s p l anc h ne c t o m y
and de ne r v at i o n o f t h e s t o m ac h ar e q u i t e s i m i -
l ar , nam e l y r e t ar dat i o n o f f u nc t i o n. A t a
l at e r dat e , t h e p e r i p h e r al i nt r i ns i c ne r v o u s
m e c h ani s m t ak e s o v e r t h e c o nt r o l o f t h e
s t o m ac h and o nl y o ne i m p o r t ant ab no r m al i t y
i n m o t o r f u nc t i o n p e r s i s t s , nam e l y a de c r e as e
i n t h e i ni t i al e m p t y i ng t i m e o f t h e s t o m ac h .
A f t e r c ar e f u l l y r e v i e w i ng t h e e x t e ns i v e and c o n-
t r adi c t o r y l i t e r at u r e o n t h e i nne r v at i o n o f t h e
s t o m ac h , Mc S w i ne y 9 7 c o nc l u de d t h at t h e e x -
p e r i m e nt al e v i de nc e i ndi c at e d t h e p r e s e nc e o f
m o t o r i nh i b i t o r y f i b r e s i n t h e v ag u s and
s p l anc h ni c ne r v e s .
Fr o m t h e r e s u l t s o f v ag o t o m y f o r du o de nal
u l c e r t h u s f ar r e p o r t e d, i t h as b e c o m e ap p ar e nt
t h at t h e de c r e as e d t o nu s and di m i ni s h e d
am p l i t u de o f t h e c o nt r ac t i o ns o f t h e s t o m ac h
w al l w h i c h w e r e i nv ar i ab l y no t e d af t e r v ag -
o t o m y , w e r e no t p e r m ane nt .
I n m any p at i e nt s ,
t h e m o t o r ac t i v i t y o f t h e r e s t i ng s t o m ai c h
w as
p r ac t i c al l y no r m al i n l e s s t h an a y e ar af t e r
o p e r at i o n.3 0 9 ' 3 1 2 , 3 2 0 Mo s t o b s e r v e r s h av e ag r e e d
t h at t h e i ni t i al de l ay i n e m p t y i ng o f t h e s t o m -
ac h af t e r v ag o t o m y g r adu al l y di s ap p e ar e d
af t e r
s e v e r al m o nt h s t o a y e ar .3 0 9 ' 3 1 2 , 3 1 3 , 3 1 8 , 3 2 0 , 3 3 7
Ho w e v e r , s e v e r al i ns t anc e s h av e o c c u r r e d i n
*w h i c h t h e g as t r i c
r e t e nt i o n w as o f s u c h a
s e v e r e nat u r e t h at m any p at i e nt s r e q u i r e d
s u b s e q u e nt g as t r o - e nt e r o s t o m y .3 1 2 '
3 2 4 A no t h e r
1 2 7
WENER A ND HOFF: PEPT I C ULCER
E
Canad. M. A . J .
L
A u g . 1 9 4 8 , v o l . 5 9
m i no r c o m p l i c at i o n o f v ag o t o m y h as b e e n t h e
de v e l o p m e nt o f di ar r h c e a, w h i c h w as u s u al l y
f o u nd t o b e t r ans i e nt and m i l d i n c h ar ac t e r ,
b u t i n s o m e c as e s i t p e r s i s t e d f o r m any m o nt h s
and b e c am e v e r y t r o u b l e s o m e .A 1 2 3 2 0 A l t h o u g h
t h e p e r i o d o f p o s t o p e r at i v e o b s e r v at i o n i s s t i l l
t o o s h o r t , t h e r e i s e v e r y i ndi c at i o n t h at i n m o s t
i ns t anc e s b i l at e r al v ag o t o m y i n m an c au s e s
o nl y a t r ans i t o r y u p s e t i n t h e m o t o r ac t i v i t y
o f t h e g u t w h i c h g r adu al l y r e t u r ns t o no r m al
o r
ne ar l y no r m al , w i t h o nl y a s l i g h t de l ay i n
t h e e m p t y i ng t i m e o f t h e s t o m ac h p e r s i s t i ng .
T h u s i t i s e v i de nt t h at i n m an t h e e f f e c t s o f
v ag o t o ni y c l o s e l y r e s e m b l e t h o s e f o u nd i n
ani m al s as w as s h o w n b y Mc Cr e a, Mc S w i ne y
and o t h e r s .9 6 ' 9 7 , 9 .8
T h e f u nc t i o nal and anat o m i c al di v i s i o n b e -
t w e e n t h e s y m p at h e t i c and p ar as y m p at h e t i c
s y s t e m s c an no l o ng e r b e c o ns i de r e d as c o m -
p l e t e , at l e as t i n s o f ar as t h e g as t r o - i nt e s t i nal
t r ac t i s c o nc e r ne d. I t i s b e l i e v e d t h at t h e
v ag u s and s y m p at h e t i c ne r v e s c an no l o ng e r
b e c o ns i de r e d t o b e ant ag o ni s t i c , b u t t h at t h e i r
ac t i o ns s u p p l e m e nt e ac h o t h e r t o c o nt r o l and
r e g u l at e t h e ac t i v i t y o f t h e s t o m ac h . Wh e n
e i t h e r t h e v ag i o r s p l anc h ni c s o r b o t h ar e s e c -
t i o ne d, a s t at e o f i m b al anc e r e s u l t s , w h i c h
al t e r s t h e m o t i l i t y o f t h e g u t and v as o m o t o r
s t at e o f t h e b l o o d v e s s e l s , and l e ads t o l o c al
i s c h w e m i a, ne c r o s i s and e r o s i o ns . I t i s b e l i e v e d
t h at t h i s al t e r e d s t at e i s t e m p o r ar y and s o o n
t h e c o nt r o l i s t ak e n o v e r b y t h e i nt r i ns i c ne r v -
o u s s y s t e m and t h e r e m ai ni ng s y m p at h e t i c o r
p ar as y m p at h e t i c s y s t e m , l e adi ng t o a no r m al
f u nc t i o nal ac t i v i t y . S u c h a v i e w r e c e i v e s s u p -
p o r t f r o m t h e c l i ni c al o b s e r v at i o ns o f t h e
nu m e r o u s i ndi v i du al s w h o h av e h ad b i l at e r al
e x t e ns i v e s y m p at h e c t o m y f o r h y p e r t e ns i o n and
v ag o t o m y f o r c h r o ni c u l c e r s . T h u s f ar , e x c e p t
f o r t h e t e m p o r ar y u p s e t s i n m o t i l i t y , di s t e ns i o n
o f t h e s t o m ac h , di ar r h o e a, e t c ., no p e r m ane nt
di s ab i l i t i e s as t o g as t r i c f u nc t i o ns h av e b e e n
r e p o r t e d i n s u c h i ndi v i du al s . B y t h i s c o nc e p t ,
o ne c an m o r e r e adi l y e x p l ai n t h e r e l at i v e l y
h i g h i nc i de nc e o f ac u t e g as t r o - du o de nal l e s i o ns
( e r o s i o ns , m u c o s al h w m o r r h ag e s , ac u t e u l c e r s ,
e t c .) , w h i c h h av e b e e n no t e d s o o n af t e r v ag -
o t o m y o r s p l anc h ne c t o m y i n e x p e r i m e nt al
ani m al s and w h y t h e s e r ar e l y g o o n t o
c h r o ni c i t y .
Ho w e v e r , i t i s s t i l l di f f i c u l t t o ac c o u nt f o r
t h e ab s e nc e o f g as t r i c o r du o de nal l e s i o ns f o l -
l o w i ng v ag o t o m y i n m an. I t m ay b e p o s s i b l e
t h at f o l l o w i ng v ag o t o m y g as t r i c m u c o s al
h ae m o r r h ag e s and e r o s i o ns do o c c u r , b u t s i nc e
t h e y c au s e d no o u t w ar d s i g ns h av e no t b e e n
c l i ni c al l y r e c o g ni z e d. Wi t h t h e r ap i d r e t u r n
t o no r m al ac t i v i t y , t h e s e l e s i o ns h e al o v e r l e av -
i ng no s c ar s .
S UMMA RY
T h e s t u di e s o n v ag o t o m i e s and
s p l anc h ne c -
t o m i e s al o ng w i t h t h e w o r k do ne o n
dam ag i ng
t h e h y p o t h al am u s i n e x p e r i m e nt al ani m al s h av e
t h u s f ar o nl y p ar t l y s o l v e d t h e p r o b l e m o f
u l c e r p at h o g e ne s i s . T h e y h av e s h o w n t h at b y
c r e at i ng an i m b al anc e i n t h e au t o no m i c i n-
ne r v at i o n o f t h e g u t , t h e r e s u l t i ng al t e r at i o ns
i n g as t r o - i nt e s t i nal m o t i l i t y , s e c r e t i o n and
v as o m o t o r s t at e o f t h e b l o o d v e s s e l s o f t h e
m u c o s a, e s p e c i al l y t h e v as c u l ar c h ang e s m ay ,
i f s e v e r e e no u g h p r o du c e ac u t e m u c o s al h w e m o r -
r h ag e s , e r o s i o ns and ac u t e u l c e r at i o ns w h i c h
r ar e l y , i f e v e r , h av e g o ne o n t o c h r o ni c i t y . I t
i s t h u s e v i de nt t h at o t h e r u nk no w n f ac t o r s
w o u l d b e ne c e s s ar y t o m ak e t h e s e ac u t e l e s i o ns
p e r s i s t and g o o n t o f o r m c h r o ni c u l c e r s o f
t h e t y p e s e e n i n m an. T h i s w i l l b e di s c u s s e d
m o r e f u l l y b e l o w .
PHYS I OLOGY OF GA S T RI C S ECRET I ON
One o f t h e e ar l i e s t i nv e s t i g at o r s t o no t e t h e
e f f e c t o f v ag o t o m y o n g as t r i c s e c r e t i o n w as
B r o di e , 1 0 0 w h o o b s e r v e d t h at l e t h al do s e s o f
ar s e ni c g i v e n i nt r av e no u s l y t o do g s al w ay s
c au s e d c o p i o u s w at e r y and m u c o u s g as t r i c s e c r e -
t i o ns , w h i l e i f t h e v ag i h ad b e e n s e c t i o ne d p r e -
v i o u s l y , s e c r e t i o ns w e r e ab s e nt . Fr o nm t h e s e
e x p e r i m e nt s h e c o nc l u de d t h at g as t r i c s e c r e t i o ns
w e r e u nde r ne r v o u s c o nt r o l . T h e s e o b s e r v at i o ns
w e r e l at e r c o nf i r m e d b y Wo o d.1 0 1 A l t h o u g h t h e
r e s u l t s o f B i dde r and S c h m i dt , 1 0 2 Ri c h e t , 1 0 3 Co n-
t e j e an1 0 4 and o t h e r s al s o i ndi c at e d t h at t h e v ag u s
ne r v e s w e r e i m p o r t ant i n r e g u l at i ng g as t r i c
s e c r e t i o n, i t w as no t u nt i l 1 9 1 0 t h at i t w as
de f i ni t e l y e s t ab l i s h e d b y Pav l o v 1 0 5 t h at t h e
v ag i c o nv e y e d s e c r e t o r y f i b r e s t o t h e g as t r i c
g l ands . Pav l o v ' s f i ndi ng s w e r e l at e r c o nf i r m e d
b y Far r e l l .1 0 6
B e au m o nt ' 0 7 and o t h e r s 1 0 5 h ad r e c o g ni z e d
t h at t h e g as t r i c g l ands c o u l d b e di r e c t l y s t i m u -
l at e d b y m e c h ani c al o r c h e m i c al ( f o o d) s t i m u l i ,
and Pav l o v de m o ns t r at e d t h e i m p o r t anc e o f
p s y c h i c s t i m u l i o n g as t r i c s e c r e t i o n. Fu r t h e r
s t u di e s o n t h i s s u b j e c t b y nu m e r o u s i nv e s t i -
g at o r s m ade i t c l e ar t h at t h e di g e s t i v e p e r i o d
o f s e c r e t i o n c o u l d b e di v i de d i nt o t h r e e
1 2 8
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 j
WENER A ND HOFF: PEPT I C ULCER
p h as e s , t h e c e p h al i c , t h e g as t r i c and t h e i n-
t e s t i nal .' 0 8 t o 1 2 1 T h e c e p h al i c o r p s y c h i c p h as e ,
u nde r ne r v o u s c o nt r o l o f t h e v ag i , i s c h ar ac t e r -
i z e d b y t h e ap p e ar anc e o f a h i g h l y ac i d j u i c e
r i c h i n p e p s i n and o r g ani c m at t e r . T h i s s e c r e -
t i o n i s ab o l i s h e d b y s e c t i o n o f t h e v ag i and b y
t h e adm i ni s t r at i o n o f at r o p i ne . T h e g as t r i c
and i nt e s t i nal p h as e s ar e c o nt r o l l e d b y a
h u m o r al m e c h ani s m and ar e no t af f e c t e d b y
s e c t i o n o f t h e v ag i o r adm i ni s t r at i o n o f at r o -
p i ne . T h e g as t r i c j u i c e s e c r e t e d du r i ng t h e
l at t e r t w o p h as e s o f di g e s t i o n i s h i g h l y ac i d,
b u t c o nt ai ns s m al l e r am o u nt s o f e nz y m e s and
o r g ani c m at t e r t h an t h at e v o k e d b y t h e v ag i ." 1 5
Pav l o v ,
1 0 5 B ab k i n1 " 4 and o t h e r s 1 2 ' t o 1 2 4 h av e
s t r e s s e d t h e c o m p ar at i v e p o t e nc y o f v ar i o u s
f o o ds as s t i m u l i o f g as t r i c s e c r e t i o n. T h u s t h e
v o l u m e and t h e q u al i t at i v e c h ar ac t e r o f t h e
g as t r i c j u i c e i s af f e c t e d b y f o o d i ng e s t e d. B ab -
k i n h as s h o w n t h at t h e " q u al i t at i v e c h ang e s
i n t h e g as t r i c j u i c e u nde r di f f e r e nt s e c r e t o r y
c o ndi t i o ns ar e c h i e f l y du e t o t h e u i l e q u al q u an-
t i t at i v e ac t i v i t y o f t h e di f f e r e nt g r o u p s o f
g l andu l ar c e l l s c o ns t i t u t i ng t h e g as t r i c m u c o u s
m e m b r ane " .1 1 5
A no t h e r i m p o r t ant p h as e o f s t o m ac h s e c r e -
t i o n o c c u r s i n t h e ab s e nc e o f f o o d and i s c o m -
m o nl y c al l e d t h e i nt e r - di g e s t i v e o r c o nt i nu o u s
s e c r e t o r y p h as e . Pav l o v ' 0 5 de ni e d t h e e x i s t e nc e
o f c o nt i nu o u s s e c r e t i o n, f o r h e f o u nd t h at
g as t r i c s e c r e t i o n w as i nt e r m i t t e nt i n do g s , and
any s e c r e t i o n t h at di d t ak e p l ac e i n t h e i nt e r -
di g e s t i v e p h as e c o u l d b e at t r i b u t e d t o p s y c h i c
f t i e t o r s . I n m an, h o w e v e r , t h e e x i s t e nc e o f a
c o nt i nu o u s s e c r e t i o n h ad b e e n o b s e r v e d b y
Car l s o n, 1 2 0 1 2 1
I v y , 1 2 5 Dr ag s t e dt 2 0 0 and o t h e r s ' 5 6
e v e n du r i ng p e r i o ds o f p r o l o ng e d f as t i ng . A c -
c o r di ng t o B ab k i n, 1 1 6 , Wi nk e l s t e i n, ' 0 5 '
Dr ag s t e dt 2 0 0
t o 2 0 2 and Me ar s 2 0 4 and o t h e r s , t h i s
c o nt i nu o u s s e c r e t i o n i s ne u r o g e ni c i n o r i g i n.
VA RI A T I ONS I N GA S T RI C S ECRET I ON I N
NORMA L S UB J ECT S
Fo l l o w i ng t h e i nt r o du c t i o n o f t h e m e t h o d o f
f r ac t i o nal anal y s i s b y Re h f u s s i n 1 9 1 4 , 1 2 7 nu -
m e r o u s s t u di e s h av e b e e n c ar r i e d o u t w h i c h
i ndi c at e t h at v o l u m e and t h e ac i di t y o f
g as t r i c s e c r e t i o n i n h e al t h y p e r s o ns v ar y
g r e at l y .
1 8 t o 1 5 6
T h e f r e e h y dr o c h l o r i c ac i d o f
t h e g as t r i c j u i c e ap p e ar e d t o i nc r e as e r ap i dl y
f r o m c h i l dh o o d u p t o t h e ag e o f 2 0 y e ar s w h e n
adu l t v al u e s w e r e o b t ai ne d, ' 3 0 and h as t e nde d
t o de c r e as e w i t h i nc r e as i ng ag e .' 3 0 1 4 8 , 1 3 4 T h e
i nc i de nc e o f ac h l o r h y dr i a i nc r e as e d s t e adi l y
f r o m y o u t h t o o l d ag e .' 3 0
1 3 4
T h e f l u i d c o nt e nt o f t h e e m p t y s t o m ac h
h as b e e n s h o w n t o v ar y i n v o l u m e f r o m
0 t o 1 5 0 c .c ., w i t h an av e r ag e o f 5 0 t o
6 0 c .c .1 2 0 ,
1 2 1 , 1 4 3 , 1 4 4 , 1 4 5 , 1 5 0
T h e ac i di t y o f t h e
e m np t y s t o m ac h c o nt e nt m ay v ar y f r o m al m o s t
z e r o t o f u l l g as t r i c j u i c e ac i di t y .' 2 ' Var i at i o ns
i n t h e p e p t i c p o w e r o f t h e f as t i ng c o nt e nt s
w e r e o b s e r v e d b y Vanz ant , Os t e r b e r g , A l v ar e z
and Ri v e r s .1 4 6 B ab k i n1 5 4 b e l i e v e d t h at o ne o f
t h e r e as o ns f o r t h e di s c r e p anc i e s i n t h e c o m -
p o s i t i o n o f t h e m o r ni ng f as t i ng c o nt e nt s m i g h t
p e r h ap s b e du e t o t h e v ar i ab l e de g r e e o f e x c i t a-
b i l i t y o f t h e g as t r i c g l andu l ar ap p ar at u s .
T h e c e p h al i c o r ap p e t i t e s e c r e t i o n i n m an
h as b e e n s h o w n t o v ar y f r o m 5 0 t o 1 5 0 c .c . i n
2 0 m i nu t e s , 1 2 1 1 2 5 , 1 3 5 and w as f o u nd t o b e
t r ans i t o r y , c e as i ng u s u al l y w i t h i n 1 5 t o 2 0
m i nu t e s af t e r c o m p l e t i o n o f m as t i c at i o n.1 ' 1 1 5 3
T h e r at e o f t h i s s e c r e t i o n h as v ar i e d di r e c t l y
w i t h t h e p al at ab i l i t y o f t h e f o o d and t h e de g r e e
o f h u ng e r and ap p e t i t e , b u t t h e q u al i t y o f t h i s
s e c r e t i o n i s i nde p e nde nt o f t h e c h ar ac t e r o f
t h e f o o d.1 2 ' T h e r at e o f s e c r e t i o n i n m an du r -
i ng t h e g as t r i c and i nt e s t i nal p h as e s o f di g e s -
t i v e s e c r e t i o n c an b e r o u g h l y ap p r o x i m at e d
o nl y , o w i ng t o t h e e x t r e m e di f f i c u l t y o f m ak i ng
ac c u r at e m e as u r e m e nt s , 1 2 5 ' 1 5 5 b u t i t h as b e e n
e s t i m at e d t o b e 4 5 t o 7 0 c .c . p e r h o u r du r i ng
t h e g as t r i c p h as e and ap p r o x i m at e l y 4 5 t o
8 5 c .c . p e r h o u r i n t h e i nt e s t i nal p h as e ." 5
No r m al h e al t h y s u i b j e c t s m ay r e ac t di f f e r -
e nt l y t o t h e s am e s t andar d t e s t m e al at v ar i o u s
t i m e s , 1 2 8 ,
1 2 9 , 1 4 4 , 1 5 0 ,
1 9 1
and t h e s e v ar i ant s m ay
b e s o g r e at t h at a s i ng l e g as t r i c anal y s i s de -
t e r m i nat i o n c o u l d e as i l y g i v e a m i s l e adi ng i m -
p r e s s i o n r e g ar di ng t h e s e c r e t o r y ac t i v i t y o f an
i ndi v i du al . Vanz ant , A l v ar e z and B e r k s o n, 1 3 1
f o u nd no de f i ni t e r e l at i o ns h i p b e t w e e n g as t r i c
ac i di t y and t h e w e i g h t and h e i g h t i n m an.
Vanz ant and A l v ar e z r e p o r t e d a c y c l i c v ar i a-
t i o n i n g as t r i c ac i di t y af t e r an Ew al d- t y p e t e s t
m e al - i n a l ar g e s e r i e s o f m e n and w o m e n.
T h e y f o u nd t h at t h e r e w as a t e nde nc y t o w ar d
h i g h e r ac i d v al u e s i n s p r i ng , au t u m n and m i d-
w i nt e r .' 3 ' T h e i nf l u e nc e o f dr u g s , t o b ac c o ,
al c o h o l , nu t r i t i o nal di s t u r b anc e s and o t h e r ab -
no r m al f ac t o r s h av e b e e n r e c e nt l y r e v i e w e d b y
S c h i f f r e n and I v y .' 5 5
Car l s o n, " 1 2 I h r e , 1 3 5 I v y 1 2 5 and o t h e r s h av e
s h o w n t h at t h e c o nt i nu o u s s e c r e t i o n v ar i e s b e -
t w e e n 1 0 t o 1 1 7 c .c . p e r h o u r . He l l e b r andt ,
1 2 9
WENER A ND HOFF: PEPT I C ULCER
[ Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
T e p p e r , Gr ant and Cat h e r w o o d, 2 ' 5 f o u nd t h at
t h e ac i di t y o f t h e f as t i ng s e c r e t i o n r i s e s and
f al l s i nt e r m i t t e nt l y i n t h e ab s e nc e o f an i nt e r -
v al s t i m u l at i o n, and t h at t h e ac i di t y o f t h e
f as t i ng s e c r e t i o n o b t ai ne d du r i ng t h e ni g h t w as
h i g h e r t h an t h at p r o du c e d i n t h e day t i m e .
S UMMA RY
B e c au s e o f t h e w i de v ar i at i o ns i n f r e e and
t o t al ac i di t y o f t h e g as t r i c j u i c e f o u nd i n ap -
p ar e nt l y h e al t h y i ndi v i du al s , no r i g i d l i m i t o f
no r m al i t y c an b e m ai nt ai ne d. T h u s w h e n c o n-
s i de r i ng w h at r ang e o f ac i di t y i s no r m al f o r
any o ne i ndi v i du al , m any f ac t o r s , e s p e c i al l y
t h e ag e and s e x o f t h e i ndi v i du al m u s t b e t ak e n
i nt o ac c o u nt .
GA S T RI C S ECRET I ON I N RELA T I ON T O
PEPT I C ULCER
Wh e n t h e m e t h o d o f f r ac t i o nal g as t r i c anal y -
s i s w as ap p l i e d t o t h e s t u dy o f g as t r i c s e c r e t i o n
i n p at i e nt s w i t h p e p t i c u l c e r , i t w as g e ne r al l y
r e c o g ni z e d t h at a h i g h e r p e r c e nt ag e o f s u c h
i ndi v i du al s s h o w e d e l e v at e d f r e e and t o t al ac i d
t h an do no r m al p e o p l e . Vanz ant l " and h i s
as s o c i at e s r e p o r t e d an av e r ag e i nc r e as e o f ap -
p r o x i m at e l y 1 2 u ni t s ab o v e " no r m al " i n t h e
c as e s o f du o de nal u l c e r , w h i l e i n t h e c as e s o f
g as t r i c u l c e r i t w as 6 u ni t s b e l o w " no r m al " .
S ag al , Mar k s and Kant o r " 1 4 al s o f o u nd h i g h e r
v al u e s t h an no r m al i n p at i e nt s w i t h u l c e r , p ar -
t i c u l ar l y i n c as e s o f du o de nal u l c e r . T h e
h y p e r s e c r e t i o n as s o c i at e d w i t h du o de nal u l c e r
and t h e s l i g h t l y e l e v at e d, b u t m o r e f r e q u e nt l y
no r m al s e c r e t i o n f o u nd i n c as e s o f g as t r i c u l c e r
h av e b e e n o b s e r v e d b y o t h e r s .' 3 5 '
1 4 1 , 1 5 9
Mo r e r e c e nt l y Pag e l 6 0 r e p o r t e d t h at t h e r e
w as no r e al di f f e r e nc e i n t h e f as t i ng f r e e
ac i di t y b e t w e e n 1 3 7 p at i e nt s w i t h x - r ay e v i -
de nc e o f p e p t i c u l c e r and 1 0 9 c o nt r o l s , and
t h at b o t h g r o u p s r e v e al e d ap p r o x i m at e l y s i m i -
l ar de g r e e s o f f r e e ac i di t y af t e r a f r ac t i o nal
t e s t m e al . S i m i l ar o b s e r v at i o ns w e r e r e p o r t e d
b y Gl e nn, ' 9 2 f o l l o w i ng a h i s t am i ne t e s t m e al .
B e r k , T h o m as and Re h f u s s , 1 8 5 '
2 2 2
f o u nd t h at
t h e f as t i ng du o de nal ac i di t y and t h e ac i di t y
af t e r an Ew al d t e s t m e al w as h i g h e r i n p a-
t i e nt s w i t h du o de nal u l c e r t h an i n no r m al p e r -
s o ns . S i m i l ar o b s e r v at i o ns w e r e m ade b y
o t h e r s .' 8 6 , 1 8 7 ,
2 2 3
Ne c h e l e s and Mas k i n1 5 3 s h o w e d
t h at al t h o u g h t h e r e w as no s i g ni f i c ant di f f e r -
e nc e i n b as al ac i di t y b e t w e e n u l c e r and h e al t h y
p e r s o ns , t h e c e p h al i c s e c r e t i o n c o nt ai ne d m o r e
f r e e ac i d i n t h e u l c e r p at i e nt s t h an i n t h e c o n-
t r o l s . Ho w e v e r t h e y c o nc l u de d t h at s i nc e t h i s
ap p e t i t e s e c r e t i o n w as o f s u c h s m al l v o l u m e ,
o f s h o r t du r at i o n and o nl y o f m o de r at e ac i di t y ,
i t di d no t m e r i t an i m p o r t ant r o l e i n t h e g e ne -
s i s o f u l c e r . On t h e o t h e r h anc d B ab k i n1 6 1 and
Wi nk e l s t e i n1 6 2 t o 1 6 4 h av e f r e q u e nt l y e m p h as i z e d
t h at an e x ag g e r at i o n o f t h e c e p h al i c s e c r e t o r y
m e c h ani s m w as o f c o ns i de r ab l e i m p o r t anc e i n
t h e p r o du c t i o n o f p e p t i c u l c e r .
A l t h o u g h , a h i g h e r p e r c e nt ag e o f p at i e nt s
s h o w a f r e e ac i di t y o f m o r e t h an 4 0 u ni t s and
a t o t al g as t r i c ac i di t y o f m o r e t h an 6 0 u ni t s ,
t h e s e v al u e s do no t al w ay s i ndi c at e h y p e r -
ac i di t y , as t h e e x t r e m e de g r e e o f v ar i at i o n o f
f r e e d t o t al g as t r i c ac i di t y i n no r m al s u b j e c t s
h as al r e ady b e e n no t e d ab o v e . T h e r ang e o f
t h e h y dr o c h l o r i c ac i d c o nc e nt r at i o n f o u nd i n
t h e g as t r i c s e c r e t i o n o f u l c e r p at i e nt s f o l l o w -
i ng a t e s t m e al , r ar e l y e x c e e ds t h at f o u nd i n
h e al t h y s u b j e c t s .
A l t h o u g h t h e f r e q u e nt as s o c i at i o n o f f r e e and
t o t al g as t r i c ac i di t y w i t h p e p t i c u l c e r h as l e d
m any
o b s e r v e r s , 5 5 '
1 6 5 , 1 6 7 , 2 7 3
t o adh e r e t o
S c h w ar t z ' s 1 6 6 l di c t u m o f " no ac i d, no u l c e r " ,
nu m e r o u s i ns t anc e s e b e e n c i t e d i n t h e
l i t e r at u r e w h e r e p e p t i c u l c e r h as b e e n f o u nd
i n t h e p r e s e nc e o f l o w ac i di t y o r ac h l o r -
h y dr i a.1 6 8 t o 1 7 8 Vanz ant and h i s as s o c i at e s ' 3 '
h av e no t e d t h e p r e s e nc e o f ac h l o r h y dr i a i n
t h e i r s e r i e s o f u l c e r p at i e nt s , b u t t h e i nc i de nc e
w as ap p r o x i m at e l y o ne - h al f o f t h at o b s e r v e d
i n no r m al p e r s o ns . Pal m e r 1 7 9 h as s t r o ng l y
q u e s t i o ne d t h e e x i s t e nc e o f c h r o ni i c u l c e r s and
ac h l o r h y dr i a and i n r e v i e w i ng a g r o u p o f c as e s
r e p o r t e d b y o t h e r s , ant i i n a s t u dy o f o v e r
1 , 0 0 0 c as e s o f p e p t i c u l c e r f o u nd no c o nc l u s i v e
e v i de nc e t h at c h r o ni c g as t r i c o r du o de nal
u l c e r s o c c u r r e d i n t h e c o m p l e t e ab s e nc e o f ac i d
g as t r i c j u i c e . I n a l at e r s t u dy , Pal m e r and
Nu t t e r 1 8 0 c o nc l u de d t h at s m al l and s u b ac u t e
u l c e r s m ay o c c u r i n t h e p r e s e nc e o f ac h l o r -
h y dr i a as p r o v e d b y t h e h i s t am i ne t e s t , b u t t h at
c h r o ni c g as t r i c u l c e r s o nl y o c c u r i n t h e
p r e s e nc e o f ac i d g as t r i c j u i c e .
Fo r a l o ng t i m e , c l i ni c i ans h av e r e al i z e d t h e
i m p o r t anc e o f t h e c o nt i nu o u s ni g h t s e c r e t i o n
i n u l c e r p at i e nt s , and t h e e x p e r i m e nt s o f
Ex al t o , 1 8 3 Mann and Wi l l i am s o n1 8 4 and t h e
" s h am - f e e di ng " p r o du c t i o n o f e r o s i o ns b y
S i l b e r m z ann, ' 9 3 f u r t h e r e m p h as i z e d t h e s i g i i i f i -
c au i c e o f t h e c o nt i nu o u s ac i d s e c r e t i o n. J e c i aB y
i n a f as t i ng s t o m ac h . S i p p y , ' 9 4 > al f e n, ' 9 5
1 3 0
Canad. M. A . J .
A u g . 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ULCER
He nni ng and No r p o t h , ' 9 6 Wi nk e l s t e i n, ' 9 7 Pal -
m e r , 1 9 8 Val De z 1 9 9 and o t h e r s h av e r e p o r t e d
t h at u l c e r p at i e nt s h av e g r e at e r ' v o l u m e and
ac i di t y i n t h e i r no c t u r nal s e c r e t i o ns t h an w e r e
f o u nd i n no r m al s u b j e c t s . T h e u l c e r di e t s
r e c o m m e nde d b y S i p p y 1 9 4 and Wi nk e l s t e i n1 6 2
w e r e di r e c t e d t o o v e r c o m e t h i s i nc r e as e d ac i d
s e c r e t i o n.
Dr ag s t e dt , 2 0 0
t o 2 0 2
Pal m e r 1 6 7 ,
2 0 8
and Wi nk e l -
s t e i n2 0 3 and t h e i r as s o c i at e s , h av e r e - e m p h a-
s i z e d t h e i m p o r t anc e o f t h e c o nt i nu o u s s e c r e -
t i o n, e s p e c i al l y t h e no c t u r nal s e c r e t i o n i n t h e
i ni t i at i o n and t h e p e r s i s t e nc e o f c h r o ni c u l c e r s
i n m an. Mo r e r e c e nt l y S andw e i s s e t a1 .2 0 6 '
2 0 7
h av e r e p o r t e d t h at t h e y f o u nd no s t at i s t i c al l y
s i g ni f i c ant di f f e r e nc e i n t h e v o l u m e and ac i di t y
o f t h e no c t u r nal g as t r i c s e c r e t i o n b e t w e e n
no r m al p at i e nt s and p at i e nt s w i t h u nc o m p l i -
c at e d du o de nal u l c e r s . T h e s e r e s u l t s di f f e r c o n-
s i de r ab l y f r o m t h o s e r e p o r t e d b y o t h e r
w o r k e r s .' 9 ' 1 9 9 2 0 4 T h e c as e s s t u di e d b y S and-
w e i s s e t al . w e r e am b u l at o r y and c o m p ar at i v e l y
f r e e f r o m any di s t r e s s , w h e r e as t h e c as e s
s t u di e d b y Wi nk e l s t e i n, I v y , Dr ag s t e dt and
o t h e r s w e r e c o m p l i c at e d c as e s as s o c i at e d w i t h
m o r e di s t r e s s .
S UMMA RY
A l t h o u g h t h e m ai n b o dy o f e v i de nc e at
p r e s e nt i ndi c at e s t h at t h e no c t u r nal g as t r i c
s e c r e t i o n o f u l c e r p at i e nt s i s g e ne r al l y g r e at e r
i n v o l u m e and ac i di t y t h an t h at f o u nd i n
no r m al s u b j e c t s , m o r e c ar e f u l s t u dy u nde r c o n-
t r o l l e d c o ndi t i o ns ar e ne c e s s ar y b e f o r e any
de f i ni t e c o nc l u s i o n m ay b e ar r i v e d at . Fr o m
t h e o b s e r v at i o ns o n t h e s e c r e t i o ns o f u l c e r p a-
t i e nt s , i t h as b e e n c l e ar l y s h o w n t h at t h e r ang e
o f ac i di t y o f t h e g as t r i c c o nt e nt s f o u nd i n i ndi -
v i du al s w i t h g as t r i c o r du o de nal u l c e r c l o s e l y
r e s e m b l e s t h at f o u nd i n no r m al p e r s o ns , v ar y -
i ng f r o m c o m p l e t e anac i di t y and h y p o ac i di t y
t o h y p e r ac i di t y . A l t h o u g h as a g r o u p , u l c e r
p at i e nt s m o r e f r e q u e nt l y f al l i nt o t h e r ang e o f
h y p e r ac i di t y , e s p e c i al l y c as e s o f du o de nal
u l c e r s , Car l s o n1 2 1 and o t h e r s h av e r e p e at e dl y
e m p h as i z e d t h at t h e ac i di t y o f t h e g as t r i c c o n-
t e nt s i n s u c h p at i e nt s o nl y r ar e l y ap p r o ac h e s
t h at o f p u r e g as t r i c j u i c e .
R6 LE OF T HE GA S T RI C S ECRET I ON I N T HE
PA T HOGENES I S OF ULCER
I t h ad b e e n s u s p e c t e d f o r a l o ng t i m e t h at
t h e di g e s t i v e p o w e r s o f t h e g as t r i c s e c r e t i o ns
b o r e s o m e i m p o r t ant e t i o l o g i c al r e l at i o ns h i p t o
t h e p r o du c t i o n o f p e p t i c u l c e r . T h e q u e s t i o n
nat u r al l y ar o s e , " Wh y di d t h e g as t r i c s e c r e -
t i o ns di s s o l v e t h e s t o m ac h i n s i t u ? " T h i s
t h o u g h t h as o c c u p i e d t h e at t e nt i o n o f m any
w o r k e r s , o ne o f t h e e ar l i e s t o f w h o m w as J o h n
Hu nt e r . I n 1 7 7 2 , Hu nt e r 2 0 9 c o nc l u de d t h at t h e
r e s i s t anc e o f t h e g as t r o - i nt e s t i nal m u c o s a t o t h e
di g e s t i v e ac t i o n o f i t s o w n s e c r e t i o ns w as p r i -
m ar i l y du e t o an i nh e r e nt p r o p e r t y o f t h e
l i v i ng c e l l . Pav y 2 1 0 i n 1 8 6 3 b e l i e v e d t h at t h e
al k al i ni t y o f t h e b l o o d i n t h e g as t r i c t u b u l e s
p r e v e nt e d t h e di g e s t i o n t h r o u g h a ne u t r al i z a-
t i o n o f t h e h y dr o c h l o r i c ac i d o f t h e g as t r i c
j u i c e . He b e l i e v e d i t w as p o s s i b l e f o r t h e
ac i di t y o f t h e g as t r i c s e c r e t i o n t o b e s o i n-
c r e as e d t h at t h i s m e c h ani s m w o u l d no l o ng e r
ne u t r al i z e t h e j u i c e and t h u s l e ad t o di g e s t i o n
o f t h e s t o m ac h w al l . T h e v i e w t h at p e p t i c
u l c e r w as i n s o m e w ay du e t o a l o c al l o s s o f
r e s i s t anc e o f t h e m u c o u s m e m b r ane t o t h e di -
g e s t i v e ac t i v i t y o f t h e g as t r i c j u i c e s l o w l y
g ai ne d addi t i o nal s u p p o r t , and i n 1 9 1 0 ,
S c h w ar t z e nu nc i at e d t h e t h e o r y o f " no ac i d,
no u l c e r " , a v i e w s t r o ng l y s u p p o r t e d t o day .
A t t e m p t s t o p r o du c e c h r o ni c p e p t i c u l c e r
e x p e r i m e nt al l y i n ani m al s b y t h e r e p e at e d
adm i ni s t r at i o n o f h y dr o c h l o r i c ac i d b y
m o u t h , 2 1 1 ,
2 1 2 , 2 1 7 , 3 2 6
o r b y f u s i o n o f t h e i n-
t e s t i ne w i t h ac i d al o ne 2 1 3 w e r e no t s u c c e s s f u l ,
e v e n w h e n f ar g r e at e r t h an p h y s i o l o g i c al
am o u nt s o f h y dr o c h l o r i c ac i d w e r e e m p l o y e d.
Wh e n 0 .4 % o o f h y dr o c h l o r i c
ac i d w as s l o w l y
adm i ni s t e r e d b y a c o nt i nu o u s dr i p f o r 8 h o u r s
dai l y , Mann2 1 1 o b s e r v e d t h at s u c h ani m al s
b e g an t o l o s e w e i g h t r ap i dl y af t e r 2 w e e k s ,
and i n ab o u t 4 w e e k s s u b ac u t e o r c h r o ni c u l c e r s
ap p e ar e d. Ho w e v e r , o nc e an ac u t e g as t r i c
o r du o de nal l e s i o n w as p r o du c e d b y
o t h e r
m e ans , t h e p r e s e nc e o f ac i d di d de l ay t h e h e al -
i ng o f t h e l e s i o n and e v e n c au s e d i t t o
s p r e ad.2 1 1 ,
2 1 4 , 2 1 5 , 2 1 7 , 2 1 8
B l o o m f i e l d and
Fr e nc h 2 1 9 h av e f o u nd no c o r r e l at i o n b e t w e e n
de g r e e s o f ac i di t y and s p e e d
o f h e al i ng
o f
g as t r i c o r du o de nal u l c e r . Mo r e r e c e nt l y
Wo l f
and Wo l f f 2 1 6 h av e s h o w n t h at p r o l o ng e d
e x p o s u r e o f a g as t r i c
e r o s i o n t o ' ac i d
g as t r i c
j u i c e i n m an r e s u l t e d i n de l ay e d h e al i ng
and
e x t e ns i o n o f t h e l e s i o n. B r o w n and Do l -
k ar t , 2 5 2 f o u nd no r e l at i o ns h i p
o f
g as t r i c ac i di t y
t o t h e o ns e t o f r e c u r r e nc e s i n
p at i e nt s
w i t h
u l c e r .
I n 1 9 2 4 , Dr ag s t e dt and Vau g h an2 2 3
de m o n-
s t r at e d t h at t h e r e s i s t anc e t o t h e
di g e s t i v e
1 3 1
WENER A ND HOFF: PEPT I C ULCER
E Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
ac t i o n o f t h e no r m al g as t r i c c o nt e nt s w as no t
l i m i t e d t o t h e g as t r i c and du o de nal m u c o s a
al o ne , b u t j e j u nu m , i l e u m , c o l o n, s p l e e n, p an-
c r e as , and k i dne y s w e r e ab l e t o r e s i s t g as t r i c
di g e s t i o n f o r m o nt h s w i t h l i t t l e o r no p at h o -
l o g i c al c h ang e s .
T h e u s u al g as t r i c c o nt e nt s c o ns i s t o f a
m i x t u r e o f s w al l o w e d f o o d, s al i v a, ac i d s e c r e t e d
b y t h e p ar i e t al c e l l s , m u c u s and v ar y i ng
am o u nt s o f r e g u r g i t at e d al k al i ne du o de nal
j u i c e s . Ho w e v e r , w h e n l i v i ng t i s s u e s w e r e
e x p o s e d t o p u r e g as t r i c j u i c e , di g e s t i o n o f t h e
t i s s u e o c c u r r e d. Mat t h e w s and Dr ag s t e dt " 1 4
p e r m i t t e d t h e s e c r e t i o n f r o m a s m al l He i de n-
h ai n o r Pav l o v p o u c h t o dr ai n i nt o t h e j e j u nu m
o r t h e i l e u m and o b s e r v e d a l ar g e p e r f o r at i ng
u l c e r i n t h e i nt e s t i nal m u c o s a adj ac e nt t o t h e
anas t o m o s i s w i t h t h e ac c e s s o r y p o u c h . T h e
p u r e u nc di l u t e d s e c r e t i o n f r o m t h e s e p o u c h e s
c o ns i s t s al m o s t e nt i r e l y o f a w at e r y s o l u t i o n o f
h y dr o c h l o r i c ac i d and p e p s i n.2 2 5 T h e s e e x p e r i -
m e nt s b y Dr ag s t e dt and h i s c o l l ab o r at o r s
c l e ar l y de m o ns t r at e d t h e m ar k e d di g e s t i v e
ac t i o n o f p u r e g as t r i c j u i c e as c o m u p ar e d w i t h
t h e r e l at i v e i nac t i v i t y o f no r m al g as t r i c c o n-
t e nt s o n g as t r o - i ni t e s t i nal t i s s u e s . T h u s i t i s
b e l i e v e d t h at u nde r no r ni al c o ni di t i o ns t h e
g as t r i c w al l i s no t di g e s t e d aw ay b e c au s e i t i s
no t e x p o s e d t o p u r e g as t r i c j u i c e .2 6
Car l s o n1 2 1 and o t h e r s h av e r e p e at e dl y e m p h a-
s i z e d t h at t h e ac i di t y o f t h e g as t r i c c o i nt e ni t s
f o u nd i n p at i e nt s w i t h du o de nal o r g as t r i c
u l c e r s o nl y r ar e l y ap p r o ac h e s t h at / o f p u r e
g as t r i c j u i c e . Car l s o n al s o b e l i e v e d t h at s i nc e
s o - c e a l l e d h y p e r ac i di t y w as c o m m o nl y s e e e n i n
no r m al p e r s o ns , g as t r i c o r du o de ni al u l c e r s do
no t p e r s e al t e r t h e ac t i v i t y o f t h e g as t r i c
g l ands . Har dt 2 2 " h as s h o w n t h at i n do g s ,
g as t r i c o r du o de l nal u l c e r s p r o du c e d e x p e r i -
m e nt al l y m ay o r nm ay no t r e s u l t i n a c o nt i nu o u s
o r di g e s t i v e h y p e r s e c r e t i o i i .
T h e c o nc e p t o f h y p e r ac i di t y o f t h e g as t r i c
s e c r e t i o n s l o w l y g av e w ay t o t h e ne w e r ani d
m o r e m o de r n i de a t h at t h e h y p e r s e c r e t i o n o f
t h e s t o m ac h w as t h e p r i m e e t i o l o g i c al f ac t o r
i n p e p t i c u l c e r . ( T h i s ne w e r v i e w w as b as e d
l ar g e l y o n t h e e x p e r i m e nt s o f Ex al t o , ' 8 ' Mann
and Wi l l i am s o n, ' 8 4 S i l b e r m an1 9 3 and Wang e n-
s t e e i i and h i s as s o c i at e s .3 4 t 0 2 3 7 )
T h e i m p o r t anc e o f t h e p r o l o ng e d ac t i o n o f
ac i d c h y m e o n t h e i nt e s t i i nal m u c o s a w as c l e ar l y
s h o w n b y Mann and Wi l l i am s o n, 1 8 4 w h o b y
di v e r t i ng t h e al k al i ne i nt e s t i nal j u i c e s aw ay
f r o m t h e s t o m ac h , c o ns i s t e nt l y p r o du c e d u l c e r s
i n t h e i nt e s t i nal m u c o s a adj ac e nt t o t h e anas t o -
m o s i s w i t h t h e g as t r i c m u c o s a. T h e s e u l c e r s
w e r e r e l at i v e l y l ar g e , 4 t o 1 5 m m . i n di am e t e r ,
u s u al l y s i ng l e , and g r o s s l y and m i c r o s c o p i c al l y
r e s e m b l e d t h e s u b ac u t e and c h r o ni c g as t r o -
j e j u nal u l c e r s s e e n i n ni an f o l l o w i ng g as t r o -
e nt e r o s t o m y . T h e s e r e s u l t s h av e b e e n r e -
p e at e dl y and c o ns i s t e nt l y p r o du c e d b y o t h e r
w o r k e r s and al s o s u g g e s t t h e p o s s i b i l i t y o f a
f ai l u r e o f t h e ne u t r al i z i ng m e c h ani i s m as an
e t i o l o g i c al f ac t o r i n u l c e r p r o du c t i o n.
I n 1 9 2 7 , S i l b e r m ann1 9 3 r e p o r t e d t h e p r o du c -
t i o n o f u l c e r s i n do g s w h i c h w e r e " s h am - f e d"
4 0 t o 6 0 m i nu t e s t h r e e t i m e s a day . T h e u l c e r s
r e p o r t e d w e r e u s u al l y m u l t i p l e , s h al l o w and
w e r e e i t h e r e r o s i o ns o r s h al l o w ac u t e s u p e r -
f i c i al u l c e r s , i n no w ay r e s e m b l i ng t h o s e f o u nd
i n m an. T h e s e e x p e r .i m e e nt s w e r e r e p e at e d b y
S c h m i dt and Fo g e l s o n2 2 s ar i d r i o u l c e r s o r
e r o s i o ns w e r e f o u nd. T h e s am e au t h o r s au g -
m e nt e d t h e ac i d i r r i t at i o n o f t h e g as t r o -
i i nt e s t i nal m u c o s a b y t h e addi t i o n o f 3 0 0 e .c .,
0 .3 6 % HCl i nt o t h e s t o m ac h o f s o m e do g s anr d
s t i l l i i o l e s i o ns w e r e r i o t e d. S i m i l ar e x p e r i -
m e nt s i n Dr ag s t e dt ' s l ab o r at o r y al s o g av e
ne g at i v e r e s u l t s .' 0 '
A l t h o u g h s o m e o b s e r v e r s r e p o r t e d t h e p r o -
du c t i o n o f g as t r i c u l c e r i n r at s 2 9 and c at s 2 " '
f o l l o w i ng t h e adm i ni s t r at i o i n o f s u b e u t ane o u s
i nj e c t i o ns o f h i s t am i ne , Or ni do r f f , B e r g h and
I v y " 3 1 f ai l e d t o f i nc d e r o s i o ns o r u l c e r s af t e r
r e p e at e d i nj e c t i o ns o f h i s t am u i ne i n do g s , e v e r y
2 h o u r s f o r 6 0 day s . He i nl e i n am i d Kas t r u p
al s o r e p o r t e d t h e f ai l u r e t o p r o du c e u l c e r s i n
c at s w i t h h i s t am i ne .' 3 8 T h e h e al i ng o f ar t i -
f i c i al l y p r o du c e d u l c e r s w as f o u nd t o b e de -
l ay e d b y t h e s u b c u t ane o u s i nj e c t i o n o f h i s t a-
2 3 0 , 2 3 3
ni i ne . Mo r e r e c e nt l y , Co de , Var c o ,
Wang e ns t e e n, Wal p o l e and Hay c l ai m e d t o
h av e p r o du c e d ac u t e , s u b ac u t e and a f e w
c h r o ni c u l c e r s i n do g s , r ab b i t s , and o t h e r
ani m al s b y t h e i ni j e c t i o n o f a s l o w l y ab s o r b ab l e
m i x t u r e o f h i s t am i ne and b e e s w ax ." 4 t o " 3 T h i s
t h e y h av e at t r i b u t e d t o t h e p r o l o i i g e d ac i d
s e c r e t i o n r e s u l t i ng f r o m t h e h i s t am i ne and
b e e s w ax i nj e c t i o ns .
Car e f u l e x am i nat i o ns o f t h e g r o s s ar i d t h e
m i c r o p h o t o g r ap h s o f t h e l e s i o ns p u b l i s h e d b y
t h e s e w o r k e r s s h o w t h e s e l e s i o ns t o b e c h i e f l y
e r o s i o ns and s u p e r f i c i al ac u t e u l c e r at i o n, s o m e
o f w h i c h ar e i n t h e s u b ac u t e s t ag e ar i d h av e
i nv ade d t h e m u s c u l ar i s . B e c au s e o f t h e l ac k
1 3 2
Canad. M. A . J .
A u g . 1 9 4 8 , v o l . 5 9 j
WENER A ND HOFF: PEPT I C ULCER
o f ade q u at e h i s t o l o g i c al de t ai l and t h e l ac k o f
any o f t h e f i b r o u s c h ang e s c h ar ac t e r i s t i c o f
c h r o ni c u l c e r s , t h e s e u l c e r s i n no w ay r e s e m b l e
t h e c h r o ni c p e p t i c u l c e r s s e e n i n m an. Mo r e -
o v e r i t h as b e e n s h o w n t h at h i s t am i ne t h r o u g h
i t s ac t i o n o n b l o o d v e s s e l s , e s p e c i al l y t h e c ap i l -
l ar i e s m ay p r o du c e a p r o l o ng e d s t as i s i n t h e
g as t r i c m u c o u s m e m b r ane w i t h r e s u l t ant l o c al
i s c h ae m i c ne c r o s i s , r e s e m b l i ng s m al l i nf ar c t s
( s e e B ab k i n, 1 5 4 p p . 4 7 9 t o 4 8 1 ) . I t s e e m s m o r e
l i k e l y t h e r e f o r e , t h at t h e e x c e s s h i s t am i ne p r o -
du c e d l o c al c i r c u l at o r y di s t u r b anc e s w i t h
r e s u l t ant ar e as o f ne c r o s i s and e r o s i o ns , w h i c h
w e r e ag g r av at e d o r p r e v e nt e d f r o m h e al i ng b y
t h e p r o l o ng e d and c o p i o u s s e c r e t i o n o f t h e ac i d
g as t r i c j u i c e . T h e f ac t t h at m any o f t h e i r
ani m al s w e r e anae m i c du e t o t h e f r e q u e nt r e c t al
b l e e di ng , m ay h av e b e e n ano t h e r c o nt r i b u t i ng
f ac t o r .
T h e o b s e r v at i o ns o f Wang e ns t e e n e t al ., r e -
ne w e d t h e i nt e r e s t i n t h e c o nt i nu o u s s e c r e t i o n,
and Dr ag s t e dt and h i s as s o c i at e s r e - af f i r m e d
t h at t h e no c t u r nal s e c r e t i o n i n u l c e r p at i e nt s
w as m o r e ac i d and m o r e c o p i o u s t h an i n no r m al
s u b j e c t s , and r e p e at e dl y e m p h as i z e d t h e r o l e
o f t h i s s e c r e t i o n i n t h e i ni t i at i o n and p e r s i s t -
e nc e o f c h r o ni c u l c e r at i o n.2 2 6 Mo r e r e c e nt l y ,
S andw e i s s e t al ., 2 0 6 , 2 0 7 f o u nd t h at t h e no c t u r nal
s e c r e t i o ns o f p at i e nt s w i t h du o de nal u l c e r w e r e
no t s i g ni f i c ant l y di f f e r e nt f r o m t h at o f no r m al
s u b j e c t s . T h e y b e l i e v e d. t h at w h i l e u l c e r p a-
t i e nt s di d no t s e c r e t e m o r e g as t r i c j u i c e o r
s h o w h y p e r ac i di t y , t h e i r dat a i ndi c at e d t h at
u l c e r p at i e nt s r e t ai ne d m o r e o f t h i s j u i c e i n
t h e i r s t o m ac h and t h e r e f o r e du r i ng t h e ni g h t
t h e h y dr o c h l o r i c ac i d o f t h e j u i c e s e c r e t e d
m i g h t b e h ar m f u l s i nc e i t w as no t p r o p e r l y
ne u t r al i z e d, du e t o t h e ab s e nc e o f f o o d.
S UMMA RY
T h u s i t i s e v i de nt t h at t h e e x p e r i m e nt al e v i -
de nc e o f S i l b e r m ann, Wang e ns t e e n, Co de ,
Var c o e t al ., w h i c h nu m e r o u s i nv e s t i g at o r s
h av e r e p e at e dl y q u o t e d as e v i de nc e o f t h e
h y p e r s e c r e t i o n o f ac i d as t h e p r i m e f ac t o r i n
u l c e r p at h o g e ne s i s i s as y e t no t c o nv i nc i ng .
Fu r t h e r o b s e r v at i o ns ar e al s o ne c e s s ar y t o de -
t e r m i ne t h e s i g ni f i c anc e o f t h e no c t u r nal s e c r e -
t i o ns i n c as e s o f u l c e r .
T HE R6 OE OF PEPS I N I N ULCER PRODUCT I ON
T h e r o l e o f p e p s i n i n u l c e r p r o du c t i o n h as
b e e n e m p h as i z e d b y S c h i f f r i n, 2 4 7 S c h i f f r i n and
I v y , ' 5 5 S c h i f f r i n and War r e n 2 4 8 and o t h e r s . A l -
t h o u g h t h e p e p s i n w as i nc r e as e d i n s o m e g r o u p s
o f p at i e nt s w i t h du o de nal u l c e r , " 4 6
2 5 1 Vanz ant
e t al ., " 6 ' 2 4 9 f o u nd no r m al v al u e s i n g as t r i c u l c e r
p at i e nt s , and r e p o r t e d t h at t h e r e w as no c o n-
s i s t e nt di f f e r e nc e b e t w e e n u l c e r p at i e nt s and
no r m al p e r s o ns , o r ne u r o t i c i ndi v i du al s , and
c o nt r ar y t o w h at o ne m i g h t e x p e c t i n a s t u dy o f
r e c u r r e nc e s o f u l c e r f o l l o w i ng g as t r o - e nt e r o s -
t o m y , t h e p e p s i n v al u e s w e r e l o w e r t h an t h o s e
f o u nd i n p at i e nt s w h o di d w e l l f o l l o w i ng
o p e r at i o n.2 5 0 Wang e ns t e e n i n 1 9 4 5 , s t r e s s e d t h e
i nt e r - r e l at i o ns h i p b e t w e e n t h e v as c u l ar and t h e
ac i d- p e p t i c di g e s t i v e f ac t o r s i n t h e e t i o l o g y o f
u l c e r .2 3 7
S UMMA RY
A l t h o u g h p e p s i n p l ay s s o m e r o l e i n t h e
p at h o g e ne s i s o f u l c e r , Dr ag s t e dt and Vau g h n2 2 3
and o t h e r s , 2 6 9 ' 3 2 7 h av e s h o w n t h at ac t i v e p e p s i n
i s no t t h e i m p o r t ant di g e s t i v e f ac t o r , b u t t h at
t h e ac i d m u s t i nj u r e t h e t i s s u e b e f o r e i t c an b e
di s s o l v e d b y t h e ac i d p e p s i n s e c r e t i o ns .
FA I LURE OF A DEQ UA T E NEUT RA LI Z A T I ON A S A
CA US E OF ULCER
Wh i l e f o o d i s u ndo u b t e dl y t h e m o s t e f f e c -
t i v e f ac t o r i n ne u t r al i z i ng t h e ac i d o f t h e
g as t r i c j u i c e , c o ns i de r ab l e e v i de nc e h as b e e n
p r e s e nt e d t o s h o w t h at t h e m u c o u s s e c r e -
t i o n 3 , 1 0 5 , 1 0 7 , 1 1 3 , 1 1 4 . 2 5 3 ,
2 5 4
t h e i no r g ani c c o m -
p o u nds o f t h e g as t r i c j u i c e , ' 5 4 and t h e
al k al i ne p anc r e at i c , b i l e and du o de nal
j u i c e s 1 8 4 ' 1 8 5 , 1 8 6 , 2 2 2 , 2 5 5 ,
2 5 6
p l ay an i m p o r t ant
p ar t i n ne u t r al i z i ng t h e h y dr o c h l o r i c ac i d o f
t h e g as t r i c j u i c e . T h e s i g ni f i c anc e o f t h e
ne u t r al i z i ng e f f e c t o f t h e du o de nal , b i l e and
p anc r e at i c j u i c e s i n p r e v e nt i ng t h e f o r m at i o n
o f du o de nal u l c e r s i n do g s h as b e e n c l e ar l y
s h o w n b y Mann and Wi l l i am s o n, ' 8 4 w h e n t h e y
c o ns i s t e nt l y p r o du c e d c h r o ni c j e j u nal u l c e r s b y
di v e r t i ng t h e al k al i ne i nt e s t i nal j u i c e s aw ay
f r o m t h e s t o m ac h . A l t h o u g h u l c e r s h av e b e e n
p r o du c e d e x p e r i m e nt al l y i n ani m al s w i t h v ar i -
o u s m o di f i c at i o ns o f t h e Mann- Wi l l i am s o n
o p e r at i o n, w h e r e b y t h e b i l e , p anc r e at i c and
du o de nal j u i c e s h av e b e e n di v e r t e d f r o m t h e
s t o m ac h , e x c e p t o n r ar e o c c as i o ns , 2 5 7 t h e r e i s
no e v i de nc e t h at t h e ab s e nc e o r a de f i c i e nc y o f
t h e s e s e c r e t i o ns i s t h e c au s e o f u l c e r i n
m an.2 0 2 Mann and B o l l m an, 2 5 5 and m o r e
r e c e nt l y B e r k , Re h f u s s and T h o m as 2 2 2 and
o t h e r s h av e s h o w n t h at i n p at i e nt s w i t h u l c e r ,
t h e r e w as a de f i c i e nc y i n t h e c ap ac i t y o f t h e
1 3 3
WENER.A ND HOFF: PEPT I C ULCER
ECanad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
du o de nal c o nt e nt s t o ne u t r al i z e t h e ac i d i n t h e
.s t o m ac h and i n t h e du o de nal b u l b . Co m f o r t
and Os t e r b e r g h av e s h o w n t h at t h e f as t i ng
c o nt e nt s i n 1 0 c as e s o f du o de nal u l c e r w e r e
s i m i l ar t o r t h o s e i n no r m al p e r s o ns .2 7 0
T h e ne u t r al i z i ng and p r o t e c t i ng p r o p e r t y
o f m u c u s and i t s c ap ac i t y t o ab s o r b ac i d
h av e b e e n s h o w n t o b e i m p o r t ant i n r e g u -
l at i ng t h e ac i di t y o f t h e g as t r i c j u i c e at t h e
b e g i nni ng and t h e e nd o f t h e s e c r e t o r y
p e r i o d.2 5 3 ' 2 5 4 , 2 5 8 , 2 5 9 , 2 6 0 , 2 6 1 , 2 6 2
A nde r s o n and
Fo g e l s o n2 6 5 h av e r e p o r t e d t h at u l c e r p at i e nt s
h av e a r e l at i v e m u c i n de f i c i e ne y p e r e .e . o f
g as t r i c c o nt e nt s i n r e s p o ns e t o an al c o h o l t e s t
ni e al , as c o m p ar e d w i t h t h at o f no r m al
s u b j e c t s .
S UMMA RY
A l t h o u g h t h e r e i s no ab s o l u t e e v s i de i nc e t h at
t h e ab s e nc e o r de f i c i e nc y o f i nt e s t i nal s e c r e -
t i o ns o r m u c u s ar e r e s p o ns i b l e f o r t h e p r o du c -
t i o ni o f u l c e r i n m an, y e t a r e l at i v e de f i c i e nc y
o f t h e ne u t r al i z i ng c ap ac i t y o f t h e s e s e c r e t i o ns
m ay b e o f s o m e i m p o r t anc e i n u l c e r p at h o g e ne -
s i s , e s p e c i al l y i n i ns t anc e s o f h y p e r s e c r e t i o n
w h e n t h e s t o m ac h i s e m p t y .
Mo s t o b s e r v e r s ar e o f t h e o p i ni o n t h at
g as t r i c h y p e r s e c r e t i o n r at h e r t h an h y p e r -
ac i di t y i s t h e i m p o r t ant f ac t o r i n u l c e r p at h o -
g e ne s i s . I t h as b e e n s h o w n b y Dr ag s t e dt e t al .,
t h at al t h o u g h s t o m ac h and i nt e s t i nal m u c o s a
c o u l d w i t h s t and t h e c o nt i nu e d ac t i o n o f t h e
no r m al g as t r i c c o nt e nt s , t h e y w e r e i m m e di at e l y
di g e s t e d b y p u r e g as t r i c j u i c e . Unde r o r di nar y
c i r c u m s t anc e s t h e g as t r i c and du o de nal m u c o s a
ar e p r o t e c t e d f r o m t h e ac t i o n o f t h e ac i d j u i c e
m ai nl y b y t h e b u f f e r i ng ac t i o n o f t h e i ng e s t e d
f o o d and s e c o ndar i l y b y t h e ne u t r al i z i ng ac t i o n
o f t h e m u c u s and al k al i ne i nt e s t i nal s e c r e t i o ns .
A l t h o u g h Car l s o n h as r e p e at e dl y e m p h as i z e d
t h at t h e ac i di t y o f t h e g as t r i c c o nt e nt s o f u l c e r
p at i e nt s o nl y r ar e l y r e ac h e s t h e l e v e l o f p u r e
g as t r i c j u i c e , i t i s v e r y p o s s i b l e , as h as f r e -
q u e nt l y b e e n s t at e d b y Wi nk e l s t e i n, Dr ag s t e dt
and o t h e r s , t h at t h e e x c e s s i v e s e c r e t i o n, p ar -
t i c u l ar l y w h e n t h e s t o m ac h i s e m p t y , m ay s o
o v e r p o w e r t h e ne u t r al i z i ng m e c h ani s m , t h at i t
m ay - e x e r t a de l e t e r i o u s e f f e c t u p o n t h e g as t r i c
o r du o de nal m u c o u s m e m b r ane s . A l t h o u g h
t h e r e i s no g o o d e v i de nc e t h at t h e i nc r e as e d
ac t i o n o f ac i d al o ne m ay l e ad t o u l c e r p r o du c -
t i o n, i t h as b e e n i ndi c at e d i n ani m al s and i n
m an, t h at t h e p r o l o ng e d ac t i o n o f ac i d c an
de l ay h e al i ng o r c au s e e x t e ns i o n o f any p r e -
e x i s t i ng l e s i o n i n t h e s t o m ac h and du o de nu m .
T I I E EFFECT S OF VA GOT OMY ON GA S T RI C
S ECRET I ON A ND PEPT I C U3 LCER
Vag o t o m ny i n ani m al s .- Fr o m a r e v i e w o f t h e
o b s e r v at i o ns o f o t h e r w o r k e r s and f r o m h i s
o w n e x p e r i m e nt al f i ndi ng s , Me Cr e a2 5 6 c o n-
e l u de d t h at v ag o t o m y p r e v e nt e d p s y c h i c s e c r e -
t i o n, b u t t h at an ac t i v e g as t r i c j u i c e w as s t i l l
s e c r e t e d, s i nc e t h e c h e m i c al p h as e o f s e c r e t i o n
h ad no t b e e n ab o l i s h e d. He p o i nt e d o u t m o r e -
o v e r , t h at af t e r s e c t i o ni ng e i t h e r t h e v ag i o r
s p l anc h ni c s , t h e m aj o r i t y o f ai ni m al s ap p e ar e d
t o l e ad no r m al l i v e s , e x c e p t i n t h e c as e o f
s o m e r ab b i t s . I n 1 9 3 0 , Har t z e l l 2 8 7 r e p o r t e d
t h at t r ans t h o r ac i c v ag o t o m y i n do g s r e s u l t e d
i n a m ar k e d r e du c t i o n i n b o t h f r e e and t o t al
ac i di t y ,
and t h at af t e r t r ans ab do m i nal v ag u s
s e c t i o n, t h e q u ant i t y o f f r e e h y dr o c h l o r i c ac i d
o c c as i o i nal l y r e t u r ne d t o t h e p r e o p e r at i v e l e v e l .
I f t h e v ag o t o m y w as i nc o m p l e t e , 1 1 o de c r e as e
i n ac i d s e c r e t i o n r e s u l t e d. S t u dy i ng 4 o f
Har t z e l l ' s do g s w h i c h h ad s u r v i v e d, Vanz ant 2 8 8
f o u nd t h at ac i di t y r e t u r ne d t o no r m al af t e r 1
t o 2 y e ar s . A r e t u r n o f t h e g as t r i c ac i di t y t o
no r m al i n 4 t o 6 w e e k s af t e r v ag o t o m y and s u b -
t o t al g as t r e c t o m y w as o b s e r v e d b y S h ap i r o and
B e r g .2 8 9 ' 2 9 3 Fr i e de nw al d am i d Fe l dm an2 9 0 f o u nd
o nl y a ne g l i g i b l e de c r e as e i n ac i di t y f o l l o w i ng
s e c t i o n o f t h e l e f t v ag u s o n do g s , w h i l e s e c t i o n
o f t h e r i g h t v ag u s r e s u l t e d i n l i t t l e o r no s e c r e -
t i o n.
T h o m p s o n2 9 1
al s o
r e p o r t e d
t h at b i l at e r al
v ag o t o m y i n t h e p y l o r e c t o m i z e d s t o m ac h i n
do g s de c r e as e d g as t r i c s e c r e t i o n. Co nt r ar y t o
t h e f i ndi ng s o f S h ap i r o and B e r g , Wi l h e l m j
e t al .2 9 5 no t e d a m ar k e d de c r e as e i n ac i di t y f o l -
l o w i ng p ar t i al g as t r e c t o m y ai i d t r ai i s t h o r ac i c
v ag o t o m y i n do g s , w h i c h p e r s i s t e d f o r at l e as t
3 m o nt h s , t h e du r at i o n o f t h e s t u dy .
On t h e o t h e r h and Fe r g u s o n, 2 9 2 f o u nd 1 1 0 r e -
du c t i o n i n g as t r i c ac i di t y f o l l o w i ng v ag o t o m y
i n m o nk e y s . Mo r e r e c e nt l y Ko m ar o v and
S h ay 3 2 5 o b s e r v e d i n ac u t e e x p e r i m e nt s t h at b i -
l at e r al v ag o t o m y al m o s t c o m p l e t e l y ab o l i s h e d
t h e i nt e r di g e s t i v e p h as e i n u nanc e s t h e t i z e d
r at s , w h i l e u ni l at e r al v ag o t o m y r e du c e d t h e
r at e o f s e c r e t i o n b y ap p r o x i m at e l y 5 0 % o w i t h -
o u t af f e c t i ng ac i di t y , t o t al c h l o r i de o r p e p s i n.
Ex p e r i m e nt s i n c h r o ni c v ag o t o m i z e d r at s r e -
v e al e d t h at t h e s e c r e t i o n r e m ai ne d at v e r y l o w
l e v e l s f o r ap p r o x i m at e l y 3 m o nt h s .
1 3 4
Canad. M. A . J . 1
A u g .. 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ULCER
Vag o t o m y i n m an.- A l t h o u g h v ag o t o m y w as
at t e m p t e d m any y e ar s ag o b y Lat ar j e t , 2 9 6
S c h i as s i 2 9 7 and o t h e r s , w i t h o nl y t e m p o r ar y
s u c c e s s , i t i s o nl y i n r e c e nt y e ar s t h at v ag o t o m y
h as b e c o m e p o p u l ar i n t h e t r e at m e nt o f c h r o ni c
g as t r i c and du o de nal u l c e r . I t s r e i nt r o du c t i o n
h as b e e n s t i m u l at e d i n l ar g e m e as u r e b y t h e
h i g h i nc i de nc e o f c o m p l i c at i o ns and r e c u r -
r e nc e s f o l l o w i ng p ar t i al g as t r e c t o m y o r g as t r o -
e nt e r o s t o m y . Fo l l o w i ng t h e o b s e r v at i o n b y
Wi nk e l s t e i n2 9 8 t h at m ar g i nal u l c e r s o c c u r r e d
af t e r p ar t i al g as t r e c t o m y o nl y w h e n t h e s e c r e -
t i o n o f a h i g h l y ac i d g as t r i c j u i c e p e r s i s t e d,
and t h at t h i s s e c r e t i o n w as i nh i b i t e d b y t h e
adm i ni s t r at i o n o f at r o p i ne , i ndi c at i ng t h at t h e
v ag u s m i g h t b e r e s p o ns i b l e f o r t h e p e r s i s t e nc e
o f t h i s ac i d s e c r e t i o n, Kl e i n2 9 9 s u g g e s t e d t h at
l e f t v ag u s s e c t i o n s h o u l d b e p e r f o r m e d al o ng
w i t h s u b t o t al g as t r e c t o m y f o r du o de nal u l c e r
w i t h a h i g h p r e o p e r at i v e ac i di t y . T h e f o l l o w -
i ng y e ar B e r g 3 0 0 r e p o r t e d
t h e r e s u l t s o b t ai ne d
af t e r di v i s i o n o f l e f t v ag u s al o ng w i t h a p ar t i al
g as t r e c t o m y i n 8 p at i e nt s w i t h du o de nal u l c e r
w h o h ad h i g h g as t r i c ac i di t y p r i o r t o o p e r at i o n.
Wh e r e as o nl y ap p r o x i m at e l y 2 5 %
o f p at i e nt s
b e c am e anac i d af t e r s u b t o t al g as t r e c t o m y
al o ne , al l o f t h e 8 c as e s w e r e anac i d i n 2 w e e k s
t o s e v e r al m o nt h s af t e r o p e r at i o n. Fu r t h e r
s u c c e s s e s i n r e du c t i o n o f g as t r i c ac i di t y w i t h
t h e c o m b i nat i o n o f v ag o t o m y p l u s p ar t i al
g as t r e c t o m y o r g as t r o - e nt e r o s t o m y w e r e r e -
p o r t e d i n m an3 0 1 ' 3 0 2 and i n do g s .2 9 5
Co l p , - Dr ag s t e dt and t h e i r as s o c i at e s w h o
f av o u r e d t h e v i e w t h at t h e h y p e r s e c r e t i o n,
p ar t i c u l ar l y o f t h e i nt e r di g e s t i v e and no c t u r nal
p h as e s o f g as t r i c s e c r e t i o n w as o f ne r v o u s
o r i g i n p i o ne e r e d i n t h e ap p l i c at i o n o f b i l at e r al
v ag o t o m y al o ne i n t h e t r e at m e nt o f p e p t i c
u l c e r . I n 1 9 4 4 , We i ns t e i n, Co l p e t a1 .3 0 5 r e -
p o r t e d t h at no ne o f t h e i r 6 c as e s h ad b e ne f i t e d
g r e at l y f r o m e i t h e r s u p r a- o r i nf r a- di ap h r ag m -
at i c v ag o t o m ny . T h e ac i d s e c r e t i o n w as o nl y
s l i g h t l y r e du c e d and b e c au s e o f t h e i l l e f f e c t s
o n g as t r i c m o t i l i t y w i t h . i t s r e s u l t ant i nc r e as e
i n o p e r at i v e r i s k and p o s t o p e r at i v e m o r b i di t y ,
t h e y c o nc l u de d t h at v ag o t o m y al o ne w as no t
t o b e r e c o m m e nde d i n u l c e r t h e r ap y . T h e r e -
s u l t s o f Dr ag s t e dt and h i s as s o c i at e s ap p e ar e d
t o b e m o r e f av o u r ab l e h o w e v e r ,
and i t w as
l ar g e l y du e t o t h e i r e nt u .- .i s i as m t h at t h e ap p l i -
c at i o n o f v ag o t o m y
i i c p e p t i c u l c e r b e c am ne
p o p u l ar and as w i de s - p r e ad a: i t i s t o day .
T h e i r f i r s t r e p o r t s s h o w e dl t h at ^ . m ar k e d r e
du c t i o n i n f r e e and t o t al ac i di t y , as w e l l as a
de c r e as e i n no c t u r nal s e c r e t i o n w as t o b e
e x p e c t e d af t e r t h e o p e r at i o n.2 0 0 ' 3 0 3 T h e y al s o
no t i c e d a de c r e as e i n g as t r i c t o nu s and h u ng e r
c o nt r ac t i o ns i n t h e e m p t y s t o m ac h .2 0 ' T h e s e
e ar l i e r s u c c e s s e s w i t h v ag o t o m y h av e b e e n c o n-
f i r m e d i n a l ar g e s e r i e s o f u l c e r p at i e nt s b y
Dr ag s t e dt and h i s c o - w o r k e r s .3 0 4 ' 3 0 6 3 2 4
Fr o m t h e l ar g e nu m b e r o f r e c e nt r e p o r t s o n
t h e p o s t o p e r at i v e e f f e c t s o f v ag o t o m y i n
m an3 4 0
t o 3 2 3
s e v e r al f ac t s h av e b e c o m e e v i de nt .
I t i s g e ne r al l y ag r e e d t h at f o l l o w i ng v ag o t o m y
m o s t o f t h e p at i e nt s e x p e r i e nc e d' an i m m e di at e
and c o m p l e t e .r e l i e f o f t h e i r u l c e r s y m p t o m s ,
and t h e e v i de nc e i ndi c at e s t h at t h e u l c e r s
h e al e d p r o m p t l y af t e r v ag o t o m y . Re c u r r e nc e s
o f u l c e r h av e b e e n r e p o r t e d, b u t u p t o t h e
p r e s e nt , t h e i nc i de nc e o f r e c u r r e nc e h as b e e n
s m al l .
I n g e ne r al v ag o t o m y h as l e d t o a m i ar k e d
r e du c t i o n i n v o l u m e and ac i di t y o f g as t r i c
s e c r e t i o n; e s p e c i al l y i m p o r t ant h as b e e n t h e
r e du c t i o n i n t h e v o l u m e o f t h e ni g h t s e c r e t i o n.
A l t h o u g h v ag o t o m y ab o l i s h e d t h e ' c e p h al i c
p h as e o f s e c r e t i o n i n m o s t i ns t anc e s t h e di g e s -
t i v e p h as e w as r ar e l y i nf l u e nc e d. T h e s e c r e -
t o r y r e s p o ns e t o i ns u l i n w as u s u al l y ab o l i s h e d
i f v ag o t o m y w as c o m p l e t e , b u t t h e r e s p o ns e t o
h i s t am i ne and c af f e i ne w as u naf f e c t e d. S e v e r al
r e p o r t s h av e i ndi c at e d t h at t h e e ar l y p o s t o p e r a-
t i v e r e du c t i o n i n v o l u m e and ac i di t y o f g as t r i c
s e c r e t i o n u s u al l y no t e d af t e r v ag o t o m y h as
s h o w n a t e nde nc y t o r e t u r n t o no r m al v al u e s ,
t h u s c o nf i r m i ng t h e e ar l i e r e x p e r i e nc e s i n
ani m al s .2 8 8 '
2 8 9 , 2 9 3
Di s c u s s i o n.' A l t h o u g h v ag o t o m y h as y i e l de d
i m m e di at e r e l i e f o f u l c e r s y m p t o m s and h as
al l o w e d t h e u l c e r s t o h e al p r o m p t l y , t h e p o s t -
o p e r at i v e p e r i o d o f o b s e r v at i o n h as t h u s f ar
b e e n t o o b r i e f t o k no w w h e t h e r t h e b e ne f i t s
de r i v e d w i l l b e l as t i ng . T h e i m m e di at e b e ne f i t s
b r o u g h t ab o u t b y v ag o t o m y m ay h av e b e e n du e
t o t h e i ni t i al de c r e as e i n g as t r i c m o t i l i t y and
ac i d s e c r e t i o n, b u t al t h o u g h i t h as al r e ady b e e n
no t e d t h e r e i s a t e nde nc y f o r t h e g as t r i c
m o t i l i t y and t h e v o l u m e and ac i di t y o f t h e
g as t r i c s e c r e t i o n t o r e t u r n t o al m o s t p r e o p e r a-
t i v e l e v e l s i n m any c as e s , t h e r e h as no t b e e n a
r e c u r i ; i c e o f u l c e r o r s y m p t o m s o f u l c e r i n
s u c h - at i e nt s . I n t h e l i g h t o f t h e s e o b s e r v a-
t i o ns ,
i t i s di f f i c u l t t o e v al u at e t h e c o nc e p t t h at
h v p e r m o t i l i t y and h y p e r s e c r e t i o n w as t h e i m -
1 3 5
WENER A ND HOFF: PEPT I C ULCER
E
Canad. M. A . J .
L A u g . 1 9 4 8 , v o l . 5 9
p o r t ant e t i o l o g i c al f ac t o r i n t h e de v e l o p m e nt
o f u l c e r .
Mo r e r e c e nt l y , i t h as b e e n s h o w n b y Wo l f
and A ndr u s 3 1 6 t h at g as t r i c h y p e r ae m i a and e n-
g o r g e m e nt o f t h e s t o m ac h m u c o s a du e t o v as c u -
l ar c o ng e s t i o n i ndu c e d b y f e e l i ng s o f ang e r and
r e s e nt m e nt i n a p at i e nt w i t h g as t r o s t o m y ,
f ai l e d t o o c c u r af t e r v ag o t o m y . T h u s , as h as
b e e n s u g g e s t e d b y B o c k u s , 3 1 8 any p e r m ane nt
b e ne f i t s w h i c h m ay b e de r i v e d f r o m v ag o t o m y
m ay b e du e t o t h e i nt e r r u p t i o n o f t h e c e p h al i c
i m p u l s e s c au s e d b y c e r t ai n t h r e at e ni ng s i t u at i o ns
w h i c h ar e k no w n2 5 4 t o g i v e r i s e t o p r o f o u nd
v as c u l ar c h ang e s i n t h e s t o m ac h .
EX PERI MENT A L PRODUCT I ON OF GA S T RO-
I NT ES T I NA L LES I ONS B Y T HE A DMI NI S T RA T I ON
OF CHEMI CA LS OR DRUGS
Hy dr o c h l o r i c ac i d. - Fr e q u e nt at t e m p t s t o
p r o du c e c h r o ni c p e p t i c u l c e r e x p e r i m e nt al l y i n
ani m al s b y t h e r e p e at e d adm i ni s t r at i o n o f
h y dr o c h l o r i c ac i d b y m o u t h 2 1 1 2 1 2 , 2 1 7 , 3 2 6 o r b y
p e r f u s i o n o f t h e i nt e s t i ne w i t h ac i d al o ne 2 1 3
w e r e no t s u c c e s s f u l , e v e n w h e n f ar g r e at e r
t h an p h y s i o l o g i c al am o u nt s o f h y dr o c h l o r i c
ac i d w e r e e m p l o y e d. A l t h o u g h Oc h s ne r , Gag e
and
Ho s o i 3 2 6
and o t h e r s h ad o b s e r v e d t h at r e -
p e at e d h y dr o c h l o r i c ac i d f e e di ng r e s u l t e d i n
m u l t i p l e ac u t e g as t r o - i nt e s t i nal l e s i o ns , s u c h as
p e t e c h i e , e r o s i o ns and s h al l o w ac u t e u l c e r s ,
c h r o ni c u l c e r s w e r e ne v e r o b t ai ne d e v e n af t e r
t h e p r o l o ng e d adm i ni s t r at i o n o f
t h e
ac i d.
Wh e n t h e ac i d ( 0 .4 % o HCl ) w as adm i ni s t e r e d
s l o w l y b y a c o nt i nu o u s dr i p f o r 8 h o u r s dai l y ,
Mann2 1 1 o b s e r v e d t h at s u c h ani m al s b e g an t o
l o s e w e i g h t r ap i dl y af t e r 2 w e e k s , and i n ab o u t
4 w e e k s s u b ac u t e o r c h r o ni c u l c e r s ap p e ar e d,
w h i c h h e r e l at e d t o an ap p ar e nt e x h au s t i o n o f
t h e ne u t r al i z i ng m e c h ani s m o f t h e s t o m ac h and
du o de nu m .
Pi l o c ar p i ne .- B as i ng h i s e x p e r i m e nt s o n t h e
c l i ni c al as s u m p t i o n t h at h y p e r t o ni c i t y o f t h e
v ag u s r e s u l t s i n t h e de v e l o p m e nt o f g as t r i c o r
du o de nal u l c e r s , as p u t f o r t h b y Ep p i ng e r and
He s s 1 2 and Vo n B e r g m ann, 1 3 We s t p h al l ' 4 i n-
j e c t e d p i l o c ar p i ne s u b c u t ane o u s l y i nt o ani m al s
and r e c o r de d t h e f o r m at i o n o f m u l t i p l e m u c o s al
h e e m o r r h ag e s and e r o s i o ns i n t h e s t o m ac h and
du o de nu m . Fr o m t h e s e o b s e r v at i o ns h e c o n-
c l u de d t h at p i l o c ar p i ne , b y i t s ac t i o n o n t h e
s m o o t h m u s c l e o f t h e g u t , p r o du c e d g as t r i c and
du o de nal s p as m w h i c h o c c l u de d t h e m u c o s al
e nd v e s s e l s , l e adi ng t o i s c h ae m i a, ne c r o s i s and
u l c e r at i o n. Fr i e dm an1 5 r e p e at e d and c o n-
f i r m e d t h e o b s e r v at i o ns b y We s t p h al ' 4 and i n
addi t i o n f o u nd a h i g h e r f r e q u e nc y o f du o de nal
l e s i o ns w h e n p i l o c ar p i ne and adr e nal i ne w e r e
g i v e n s i m u l t ane o u s l y t o r ab b i t s . T h e l e s i o ns
p r o du c e d b y We s t p h al 1 4 and Fr i e dm an1 5 w e r e
m ai nl y ac u t e m u c o s al h ae m o r r h ag e s and e r o -
s i o ns , and t h e r e w as no e v i de nc e s u b m i t t e d t o
s u p p o r t t h e i r c l ai m s f o r t h e p r o du c t i o n o f
ac u t e u l c e r s , i n ac c o r danc e w i t h o u r de f i ni t i o ns .
A l l at t e m p t s t o p r o du c e c h r o ni c u l c e r at i o n
f ai l e d.
T h e s e e x p e r i m e nt s w e r e r e p e at e d and e x -
t e nde d b y Unde r h i l l and Fr e i h e i t 1 6 w h o s t at e d
t h at s u b c u t ane o u s i nj e c t i o ns o f p i l o c ar p i ne
w i t h o r w i t h o u t adr e nal i ne , l e d t o p r o du c t i o n
o f m u c o s al h aw m o r r h ag e s o r e r o s i o ns i n t h e
s t o m ac h and du o de nu m , b u t i n no i ns t anc e
c o u l d a c h r o ni c u l c e r b e f o r m e d. T h e s e i n-
v e s t i g at i o ns s h o w e d t h at t h e p r o du c t i o n o f t h e
l e s i o ns w as no t du e t o c h ang e s
i n,
ac i di t y
al o ne , b u t w as m ai nl y r e l at e d t o t h e l o c al i z e d
ar e as o f i s c h w e m i c ne c r o s i s w h i c h w e r e as s o -
c i at e d w i t h c y ano s i s o f t h e w h o l e s t o m ac h , and
t h e s u b s e q u e nt ac t i o n o f t h e g as t r i c j u i c e o n
t h e s e dam ag e d ar e as . S u b c u t ane o u s i nj e c t i o ns
o f p i l o c ar p i ne i nt o t h e c at and t h e r at di d no t
e v o k e g as t r o - i nt e s t i nal c h ang e s and Unde r h i l l
and Fr e i h e i t ' 6 c o nc l u de d t h at t h e ac t i o n o f
p i l o c ar p i ne i n t h e p r o du c t i o n o f t h e l e s i o n w as
no t s p e c i f i c , b u t du e t o a s p e c i e s p e c u l i ar i t y .
Fo l l o w i ng Cu s h i ng ' s ' 7 o b s e r v at i o ns t h at t h e
i nj e c t i o n o f a s m al l do s e o f p i l o c ar p i ne i nt o
t h e l at e r al v e nt r i c l e s o f h u m ans w as s o o n f o l -
l o w e d b y a p ar as y m p at h e t i c r e s p o ns e w h i c h
i nc l u de d r e t c h i ng , v o m i t i ng w h i c h w as at t i m e s
b l o o d- t i ng e d, i ndi c at i ng a c e nt r al e f f e c t v i a t h e
v ag u s , B i s h o p , Ke ndal l and Li g h t ' 8 at t e m p t e d
t o r e p r o du c e t h e s e e f f e c t s i n r ab b i t s . T h e y
no t e d t h at t h e i nj e c t i o n o f 1 0 m g m . do s e s o f
p i l o c ar p i ne i nt o t h e l at e r al v e nt r i c l e s o f r ab b i t s
p r o du c e d g as t r i c l e s i o ns i n 9 4 % o f t h e i r
ani m al s . Mi c r o s c o p i c s t u dy o f t h e s e p at h o l o g i -
c al g as t r i c c h ang e s r e v e al e d e ar l y ac u t e
m u c o s al h aw m o r r h ag e s w i t h s u p e r f i c i al ne c r o s i s ,
w h i c h at t i m e s e x t e nde d do w n t o t h e l e v e l o f
t h e m u s c u l ar i s m u c o s u e , b u t r ar e l y de e p e r . T h e
c ap i l l ar i e s i n t h e s e p al e ar e as w e r e u s u al l y
c o nt r ac t e d and e m p t y i n c o nt r as t t o t h e
p ar t i al l y f i l l e d c ap i l l ar i e s o f t h e u naf f e c t e d
t i s s u e o n e i t h e r s i de . T h e l e s i o ns w h i c h w e r e
p r o du c e d w i t h i n 2 1 / 2
h o u r s af t e r t h e i nj e c t i o n
o f p i l o c ar p i ne w e r e m ai nl y ar e as o f s u p e r f i c i al
1 3 6
Canad. M. A . J . 1
A u g . 1 9 4 8 , v o l . 5 9 J
WENER A ND HOFF: PEPT I C ULCER
f o c al ne c r o s i s , w i t h o u t any e v i de nc e o f l e u c o -
c y t i c o r l y m p h o c y t i c i nf i l t r at i o n and i n no
i ns t anc e w as t h e r e any e v i de nc e o f t r u e ac u t e
o r c h r o ni c u l c e r at i o n. I t w as c o nc l u de d t h at
p i l o c ar p i ne ac t e d b y s t i m u l at i ng t h e h i g h e r
au t o no m i c c e nt r e s , and t h at t h e f o c al g as t r i c
ne c r o s i s w as t h e r e s u l t o f v as c u l ar dam ag e du e
e i t h e r t o ac t i v e v as o - c o ns t r i c t i o n o r t o m e c h ani -
c al o b s t r u c t i o n b y t h e i nc r e as e d c o nt r ac t i o ns
o f t h e s t o m ac h m u s c u l at u r e . I ndi r e c t e v i de nc e
f o r t h e c o nc e p t t h at s t i m u l at i o n o f t h e h i g h e r
au t o no m i c r e g i o ns m ay r e s u l t i n g as t r i c o r du o -
de nal l e s i o ns w as s e e n i n t h e s e r e s u l t s . On t h e
o t h e r h and, Fe r g u s o n2 9 2 r e p o r t e d t h at t h e ad-
m i ni s t r at i o n o f o v e r 1 0 0 i nt r av e nt r i c u l ar i n-
j e c t i o ns o f p i l o c ar p i ne i n do s e s 0 .1 5 t o 1 7 .1
m g m . p e r k i l o i n 1 5 m o nk e y s y i e l de d no e v i -
de nc e o f g as t r o - i nt e s t i nal l e s i o ns .
A c e t y l c h o l i ne .- Fo l l o w i ng t h e o b s e r v at i o n o f
Dal e and Fe l db e r g 3 2 8 t h at ac e t y l c h o l i ne w as
t h e c h e m i c al t r ans m i t t e r o f v ag u s e f f e c t s t o t h e
s t o m ac h , Ne c h e l e s and h i s as s o c i at e s 3 2 9 t o 5 3 1
de m o ns t r at e d t h at s m al l do s e s o f ac e t y l c h o l i ne ,
c o m np ar ab l e t o t h o s e l i b e r at e d w h e n t h e v ag i
w e r e s t i m u l at e d, 3 2 8 c au s e d di m i ni s h e d b l o o d
f l o w t h r o u g h t h e s t o m ac h o f do g s and o f h u -
m ans , i ndi c at i ng a v as o c o ns t r i c t o r e f f e c t . T h e s e
o b s e r v at i o ns l e d Ne c h e l e s 3 3 2 t o adv anc e t h e
t h e o r y t h at o v e r p r o du c t i o n o r t h e c o nt i nu o u s
f o r m at i o n o f ac e t y l c h o l i ne m ay p r o du c e ar e as
o f f o c al ne c r o s i s w h i c h w h e n ac t e d u p o n b y
t h e ac i d- p e p s i n c o nt e nt s o f t h e s t o m ac h l e ads
t o f o r m at i o n o f p e p t i c u l c e r s . T h u s f ar , t h i s
t h e o r y h as r e c e i v e d v e r y l i t t l e s u p p o r t f r o m
f u r t h e r ani m al e x p e r i m e nt s o r c l i ni c al o b -
s e r v at i o ns .
Hal l , Et t i ng e r and B ant i ng 3 3 3 and Ho r s -
w e l l 3 3 5 h av e no t e d a g e ne r al i z e d h y p e r e e m i a o f
t h e g as t r o - i nt e s t i nal t r ac t , w i t h f o c al m u c o s al
h ae m o r r h ag e s and e r o s i o ns f o l l o w i ng p r o l o ng e d
dai l y adm i ni s t r at i o n ( 5 0 t o 6 0 0 m g m .) o f
ac e t y l c h o l i ne i nt r av e no u s l y i n do g s . A l t h o u g h
m any o f t h e do g s r e c e i v e d 1 0 0 t o 2 0 0 o r m o r e
i nj e c t i o ns w h i c h w e r e f r e q u e nt l y ac c o m p ani e d
b y b l o o dy di ar r h e e a o r b l o o dy s t o o l s , no ac u t e
o r c h r o ni c p e p t i c u l c e r s r e s u l t e d. S i m i l ar o b -
s e r v at i o ns w e r e m ade b y Ne c h e l e s and
Mas u r 3 3 4 af t e r t h e c o nt i nu o u s i nj e c t i o ns o f
ac e t y l c h o l i ne f o r 2 8 t o 5 1 h o u r s i n 3 do g s , and
dai l y i nj e c t i o ns o v e r a p e r i o d o f 3 t o 6 day s
w i t h a t o t al i nj e c t i o n t i m e o f 1 8 t o 3 7 h o u r s
i n ano t h e r g r o u p o f 3 do g s . A l t h o u g h s o m e o f
t h e ani m al s h ad g r o s s g as t r i c and i nt e s t i nal
h o e m o r r h ag e s , no u l c e r s w e r e f o u nd.
MI e c h o l y l .- T h e r e p e at e d s u b c u t ane o u s i nj e c -
t i o ns o f m e c h o l y l t o m o nk e y s i n do s e s o f 2 5 t o
5 0 m g m . p e r k i l o b o dy w e i g h t e v e r y 2 t o 3
h o u r s f o r 3 t o 7 day s di d no t r e s u l t i n any
g as t r o - i nt e s t i nal c h ang e s .6 3 Mo r e r e c e nt l y , i t
w as o b s e r v e d t h at f o l l o w i ng t h e p r o l o ng e d
c o nt i nu o u s adm i ni s t r at i o n o f m e c h o l y l ( aq u e -
o u s ) o r e m b e dde d i n a b e e s w ax - m i ne r al o i l
m i x t u r e i nt o do g s , m u c o s al h ae m o r r h ag e s ,
e r o s i o ns and ac u t e o r s u b ac u t e g as t r i c o r du o -
de nal u l c e r s w e r e p r o du c e d.3 5 7 T h e s t r i k i ng
f e at u r e w as t h e h w m o r r h ag i c ap p e ar anc e o f t h e
g u t and t h e b l o o dy di ar r h e e a w h i c h w as o b -
s e r v e d af t e r al m o s t e v e r y i nj e c t i o n o f m e c h o l y l .
Fr o m t h e g r o s s and h i s t o l o g i c al c h ar ac t e r o f
t h e l e s i o ns , i t w as s t r o ng l y s u g g e s t e d t h at t h e
m o s t i m p o r t ant f ac t o r i n t h e i ni t i at i o n o f t h e
s e q u e ni c e o f p at h o l o g i c al c h ang e s i n t h e s t o m -
ac h and i nt e s t i ne s w as t h e m ar k e d c i r c u l at o r y
di s t u r b anc e s p r o du c e d b y t h e m e c h o l y l w h i c h
r e s u l t e d i n m ar k e d v as c u l ar di l at i o n, v as c u l ar
s t as i s , m u c o s al h o e m o r r h ag e s , l o c al t i s s u e ano x -
t e m i a, e r o s i o ns and f i nal l y l e d t o t h e f o r m at i o n
o f u l c e r s .
T h e ac i d s e c r e t i o n w h i c h w as de m o ns t r at e d
af t e r t h e m e c h o l y l i nj e c t i o ns i n a s e r i e s o f
ac u t e e x p e r i m e nt s and o n a do g w i t h a c h r o ni c
g as t r i c f i s t u l a w as p r o b ab l y o f s e c o ndar y i m -
p o r t anc e .3 5 8
T h e s e e x p e r i m e nt al r e s u l t s r e - e nf o r c e t h e
v as c u l ar c o nc e p t o f u l c e r f o r m at i o n and al s o
' f i t t h e p s y c h o s o m at i c v i e w s o n t h e i ni t i at i o n
and m ai nt e nanc e o f p e p t i c u l c e r .
A dr e nal i ne . - A f t e r r e p e at e d i nj e c t i o ns o f
e p i ne p h r i ne , du o de nal e r o s i o ns and ac u t e u l c e r s
w e r e o b s e r v e d b y Fr i e dm an i n do g s 3 3 8 and
r ab b i t s .3 3 9 I t w as al s o r e p o r t e d b y Fr i e dm anl 5
and Unde r h i l l and Fr e i h e i t 1 6 t h at t h e adm i n-
i s t r at i o n o f adr e nal i ne w i t h p i l o c ar p i ne r e -
s u l t e d i n a h i g h e r i nc i de nc e o f g as t r o - i nt e s t i nal
e r o s i o ns and ac u t e u l c e r s t h at w as no t e d af t e r
g i v i ng p i l o c ar p i ne al o ne t o r ab b i t s . A c u t e
p h l e g m o no u s u l c e r at i o ns o f t h e s m al l and l ar g e
i nt e s t i ne s o f do g s , c at s and r ab b i t s and g u i ne a
p i g s w e r e no t e d f o l l o w i ng t h e dai l y i nt r a-
p e r i t o ne al i nj e c t i o ns o f adr e nal i ne b y
Pe nne r
and B e r nh e i m .2 8 2 B ar o no f s k y
and Wang e n-
s t e e n2 3 7 '
3 4 9
al s o f o u nd t h at t h e i m p l ant at i o n o f
e p i ne p h r i ne i n b e e s w ax i nt o do g s i nv o k e d
m u l t i p l e e r o s i o ns ,
m u c o s al h w m o r r h ag e s
o f t h e
s t o m ac h and du o de nu m and t h e i nt r am u s c u l ar
1 3 7
WENER
A ND HOFF: PEPT I C
t ULCER
[
Canad. M. A . J .
1 A u g . 1 9 4 8 , v o l . 5 9
i nj e c t i o n o f aq u e o u s adr e nal i ne s u s p e nde d i n
g e l at i n i nt o 2 g u i ne a p i g s , l e d t o g as t r i c
e r o s i o ns and s h al l o w ac u t e u l c e r at i o n o f t h e
s t o m ac h . Wh e r e as i t w as i no t e d t h at i t w as
di f f i c u l t t o p r o du c e u l c e r s i n r ab b i t s w i t h h i s t a-
m i ne i n b e e s w ax al o ne , t h e addi t i o n o f e p i ne -
p h r i ne t o t h e h i s t am i ne i n b e e s w ax p r e p ar at i o n
i nc e r e as e d t h e i nc i de nc e o f t h e f o r m at i o n o f
g as t r i c and du o de nal e r o s i o ns ani d ac u t e
u l c e r s .2 3 7 ' 3 4 9 I n m an, Wo l f and Wo l f f 2 s 4 o b -
s e r v e d t h at w h e n e p i ne p h r i ne m w as ap p l i e d
l o c al l y t o t h e s t o m ac h o r g i v e n h v p o de r m i c al l y ,
t h e i ni t i al p al l o r o f t h e g as t r i c m u c o u s m e m -
b r ane w as s o o n f o l l o w e d b y a s e c o ndar y h y p e r -
ae m i a ani d an i nc r e as e i n ac i d s e c r e t i o i n. I t w as
g e ne r al l y ag r e e d t h at t h e e f f e c t s o b s e r v e d
f o l l o w i ng t h e adm i ni s t r at i o i n o f adr e nal i ne
w e r e du e m ai nl y t o i t s ab i l i t y t o p r o du c e v as o -
c o ns t r i c t i o n, c au s i ni g t i s s u e ani o - x nm i a, and
f o c al ne c r o s i s .
Pi t r e s s i n.- S e v e r e e x t e ns i v e h v p e r al i m i a w i t h
f o c al ar e as o f s u p e r f i c i al ne c r o s i s o f t h e f u ndi c
p o r t i o n o f t h e s t o m ac h w as f i r s t r e p o r t e d b y
Do dds e t al ., 3 4 0 f o l l o w i ni g a s i ni g l e i nj e c t i o n o f
p o s t e r i o r p i t u i t ar y l o b e e x t r ac t i nt o l ab o r a-
t o r y ani m al s . T h e f o l l o w i i ng y e ar , Do dds and
h i s as s o c i at e s 3 4 1 u s i nl g l ar g e r ani d r e p e at e d
do s e s o f t h e ac e t o ne p i c r i c ac i d e x t r ac t o f t h e
p i t u i t ar y g l and, c l ai m e d t o h av e p r o du c e d
c h r o ni c p e p t i c u l c e r s i n r ab b i t s r e s e m b l i ng
t h o s e s e e n i n m an, b u t no m i c r o s c o p i c dat a c o n-
c e r ni ng t h e s e u l c e r s w e r e f o u nd i n t h e i r r e p o r t .
T h e y al s o f o u nd t h at i nj e c t i o n o f t h e e x t r ac t
c au s e d a t e m p o r ar y i nh i b i t i o n o f HCl s e c r e -
t i o n, i n s u c h a w ay t h at t h e s t o m ac h w o u l d no t
r e ac t t o h i s t am i ne f o r a p e r i o d o f 6 h o u r s .
T h e s e o b s e r v at i o ns w e r e c o nf i r m e d and e x -
t e nde d b y Ne dz e l , 3 4 2 t o 3 4 -
B e r g , 8 , 3 4 5
Ne c h e l e s
and Mas u r , 3 3 4 and Me t z , 3 4 8 w h o s u b j e c t e d ( l o g s
and r ab b i t s t o r e p e at e d ani d c o ni t i nu o u s do s e s
o f p i t r e s s i n.3 3 4
T h e e r o s i o ns p r o du c e d i n t h e g as t r o - i nt e s t i nal
t r ac t v ar i e d f r o m s m al l m u c o s al h o e m o r r h ag e s
t o s u p e r f i c i al and de e p m u c o s al e r o s i o ns , and
s u p e r f i c i al ac u t e u l c e r at i o ns , and i n no i ns t anc e
w as a c h r o ni c l e s i o n f o r m e d. I t w as g e ne r al l y
ag r e e d t h at t h e i ni t i al s p as m o f t h e v e s s e l s
w h i c h w as s o o n f o l l o w e d b y i nt e ns e h y p e r s m i a
p r o du c e d b y t h e p i t r e s s i n, and t h e s p as i m i r e -
s u l t i ng i ndi r e c t l y f r o m t h e i nc r e as e d i nu s c u l ar
c o nt r ac t i o ns , i nt e r f e r e d w i t h l o c al nu t r i t i o n
and l e d t o f o c al i s c h e e m i c ne c r o s i s . T h e
ne c r o t i c ar e as w e r e f u r t h e r ac t e d u p o n b y t h e
ac i d- p e p s i ni c o ni t e ni t o f t h e s t o m aac h r e s u l t i ni g
i n u l c e r at i o n.
Mo r e r e c e nt l y Wo l f ani d Wo l f f 2 5 4 o b s e r v e d
t h at l o c al ap p l i c at i o i n o f l ) i t r e s s i n a( l m i ni s t e r e d
i nt r av e no u s l y o r h y p o de r m u i c al l y i n m nc i ai , c e -
s u l t e d i n a t r ans i t o r .y p al l o r o f t h e m u c o u s
m e m l b r ane , w h i c h w as S OOi i f o l l o w e d b y s e c o ni d-
ar y i nt e ns e h y p e r w i m i a, i ni e r e as e d i m i o t i l i t y and
i nc r e as e d ac i ( l s e c r e t i o ni , t h u s c o o nf i r m i ni g t h e
o l ) s e r v at i o i ns o f Ne dz e l ai nd B e r g i n t h e i r e x -
p e r i m i e i t s
o n
do g s and
r ab b i t s .
A l t h o u g h
l ar g e do s e s o f p i t r e s s i ni c au s e d ac u t e g as t r o -
i ni t e s t i ni al l e s i o i s , s m i i al l e r ( l o s e s i nh i b i t e d t h e
o g as t r i c m o t i l i t y al i ( l s e c r e t i o i an( l Me t z
e t a1 l ., 3 4 ' 4 7 ani d o t h e r s h av T e r e p o r t e d s o i u e
s u c c e s s i n t h e t r e at i u e nt o f u l c e r p at i e ni t s w i t h
s m i i al l am o u i nt s o f p o s t e r i o r p i t u i t ar y e x t r ac t .
A l t h o u g h t h e e x p e r i m e i nt al l e s i o ns i n n1 o w ay
r e s e m b l e dl t h e e h r o i ni e p e p t i c u l c e r c o m m i i i o i o nl y
s e e ni i n m ai n, t h e y do c al l at t e ni t i o n t o t h e p o s -
s i b l e i m np o r t anc e o f v as c u l ar s p as I m I an1 i d h y p e r -
, e i nm a i n t h e p r o du c t i o n o f u l c e r .
I Hi s t am ) i i n. - T i e ac t i o n o f h i s t am i ne o ni g as t r i c
s e c r e t i o n w as f i r s t s t u di e d b y Po p i e l s k i j 2 9 w h o
o b s e r v e d an i ni e r e as e d f l o w o f g as t r i c j u i c e i n
c l o g s f o l l o w i ni g t h e adm i ni i s t r at i o i n o f s u b -
c u t ane o u s i n j e c t i o ns o f h i s t am ni i ne . Va g o t o m y
o r adm i ni i s t r at i o ni o f at r o p i i ne di dl no t af f e c t
t h i s s e c r e t i o n, i ndi c at i ni g t h at h i s t am i ni e ac t e d
di r e c t l y o n t h e g l ands . l B ab k i n ani d h i s as s o -
c i at e s h av e s h o w n t h at h i s t am i ne ac t i v at e s
c h i e f l y t h e p ar i e t al c e l l s o f t h e g as t r i c g l ands
and t o a m u c h l e s s e r e x t e nt t h e p e p t i c and
m u c o i d c e l l s o f t h e s t o m ac h , g i v i ng a s e c r e t i o n
r i c h i i i h y dr o c h l o r i c ac i d, b u t s o m e w h at de f i -
c i e nt i n e i nz y m e s ani d o r g ani e s u b s t ai ne e s .2 4 t t o 2 4 4
T h i s j u i c e c l o s e l y r e s e m b l e d t h at o b t ai ni e d b y
s t i i m i u l at i o n o f t h e v ag i . Fr o m t h e m any o b -
s e r v at i o ns o f B ab k i i i and h i s as s o c i at e s , 1 5 4 '
1 6 1
i t w as c o ne l u de d t h at h i s t am i i ne w as l i b e r at e d
du r i ng t h e no r m al s e c r e t o r y p r o c e s s i n t h e
s t o m ac h and t h e r e f o r e w as p ar t o f t h e no r m al
s e c r e t o r - y m e c h ani s m . B ab k i n1 6 1 i n 1 9 3 8 p r e -
s e nt e d a t h e o r y t h at s o m e p at h o l o g i c al de -
r ang e m e nt o f t h i s no r m al s e c r e t o r y m u e c h ani s m ,
w h e r e b y e x c e s s i v e am o u nt s o f h i s t am i ne w e r e
l i b e r at e d, c o u l d g i v e r i s e t o p e p t i c u l c e r
f o r m at i o n.
T h e ac t i o n o f t h e e x c e s s h i s t am i ne l i b e r at e d
w as b e l i e v e d t o b e t w o - f o l d. Fi r s t l y , b y ac t i ng
OI n t h e p ar i e t al c e l l s i t p i r o du c e d e x c e s s i v e
q u ant i t i e s o f e x t r e m e l y ac i d j u i c e ; s e c o ndl y ,
b e c au s e o f t h e ac t i o n o f h i s t am i ne o n t h e c ap i l -
1 3 8
Canad. M. A . J .
A u g . 1 9 4 8 , v o l . 5 9 i
WENER A ND HOFF: PEPT I C ULCER
l ar i e s , a p r o l o ng e d s t as i s w i t h i nc r e as e d c ap i l -
ar y p e r m e ab i l i t y o c c u r r e d, r e s u l t i ng i n l o c al
t i s s u e ano x i a and ne c r o s i s , w h i c h w h e n ac t e d
u p o n b y t h e c o p i o u s ac i d j u i c e o f t h e s t o m ac h
p r o du c e d e r o s i o ns and u l c e r at i o n.' 5 4 1 6 1
T h e e f f e c t o f h i s t am i ne i n t h e p r o du c t i o n o f
u l c e r s h as al r e ady b e e n di s c u s s e d ( p ag e 1 3 2 ) .
T h e l e s i o ns p r o du c e d b y h i s t am i ne i n b e e s w ax
w e r e no t p r e v e nt e d b y v ag o t o m y p r i o r t o t h e
adm i ni s t r at i o n o f t h e h i s t am i ne and b e e s -
w ax .- 4 1
T h e f o r m at i o n o f t h e s e u l c e r s h as b e e n
at t r i b u t e d m ai nl y t o t h e p r o l o ng e d e f f e c t s o f
t h e h y p e r s e c r e t i o n and h y p e r ac i di t y o f t h e
g as t r i c j u i c e w h i c h w e r e i ndu c e d b y t h e h i s t a-
m i ne i n b e e s w ax i nj e c t i o ns .
Car e f u l s t u dy o f t h e g r o s s and m i c r o p h o t o -
g r ap h s o f t h e l e s i o ns p u b l i s h e d b y t h e s e
w o r k e r s s h o w t h e s e t o b e c h i e f l y e r o s i o ns and
s u p e r f i c i al ac u t e u l c e r at i o ns , s o m e o f w h i c h
ar e i n t h e s u b ac u t e s t ag e and h av e i nv ade d t h e
m u s c u l ar i s . B e c au s e o f t h e l ac k o f ade q u at e h i s -
t o l o g i c al de t ai l , and t h e l ac k o f any o f t h e f i b r o u s
c h ang e s c h ar ac t e r i s t i c o f c h r o ni c u l c e r s , t h e s e
i n no w ay r e s e m b l e t h e c h r o ni c p e p t i c u l c e r s
s e e n i n m an.
Di s c u s s i o n.- T h e g as t r i c and du o de nal e r o -
s i o ns and ac u t e u l c e r at i o ns p r o du c e d b y h i s t a-
m i ne l e nd s o m e e v i de nc e i n s u p p o r t o f B ab k i n' s
t h e o r y t h at e x c e s s h i s t am i ne p r o du c t i o n m ay
b e t h e c au s e o f u l c e r f o r m at i o n i n s o m e c as e s .
A l t h o u g h t h i s t h e o r y i s a p l au s i b l e o ne and de -
s e r v e s s e r i o u s c o ns i de r at i o n, i t r e q u i r e s ad-
di t i o nal e v i de nc e t o s u p p o r t i t s c l ai m s . S i nc e
as B ab k i n1 5 4 h as i ndi c at e d t h e ac t i o n o f t h e
e x c e s s h i s t am i ne i s t w o - f o l d, ac t i ng b o t h o n t h e
b l o o d v e s s e l s and t h e p ar i e t al c e l l s o f t h e
s t o m ac h , i t c anno t b e as s u m e d t h at t h e l e s i o ns
w e r e p r o du c e d b y t h e p r o l o ng e d ac t i o n o f t h e
ac i d j u i c e al o ne , as h as b e e n c l ai m e d b y
Wang e ns t e e n and o t h e r s . I t s e e m s as
l i k e l y
t h at t h e e x c e s s h i s t am i ne p r o du c e d l o c al
c i r c u l at o r y di s t u r b anc e s w i t h r e s u l t ant f o c al
ar e as o f ne c r o s i s and e r o s i o ns , w h i c h w e r e ag -
g r av at e d o r p r e v e nt e d f r o m h e al i ng b y t h e
p r o l o ng e d and c o p i o u s s e c r e t i o n o f t h e ac i d
g as t r i c j u i c e .
Caf f e i ne .- Re c e nt
s t u di e s
r e p o r t e d b y J u dd3 5 0
de m o ns t r at e d t h at dai l y i nt r am u s c u l ar i nj e c -
t i o ns o f c af f e i ne i n b e e s w ax w e r e c ap ab l e o f
i ndu c i ng s h al l o w ac u t e g as t r i c o r du o de nal
l e s i o ns i n g u i ne a p i g s and r at s i n
ap p r o x i -
m at e l y 4 .5 day s and 1 5 day s r e s p e c t i v e l y .
T h e s e o b s e r v at i o ns w e r e s o o n c o nf i r m e d
b y
Ro t h and I v y 3 5 ' w h o al s o o b s e r v e d t h at f o l l o w -
i ng t h e dai l y i m p l ant at i o n o f c af f e i ne i n b e e s -
w ax , 5 0 % o f t h e i r c at s de v e l o p e d m u c o s al
e r o s i o ns and ac u t e o r s u b ac u t e g as t r i c u l c e r a-
t i o ns . I t w as s u b s e q u e nt l y f o u nd t h at c af f e i ne
s t i m u l at e d g as t r i c s e c r e t i o n i n c at s and m an,
b u t no t i n do g s .3 5 0 ' 3 5 2 , 3 5 3
B i l at e r al v ag o t o m y
o r t h e adm i ni s t r at i o n o f at r o p i ne di d no t
ab o l i s h t h e s e c r e t o r y r e s p o ns e t o c af f e i ne i n
c at s ; ne i t h e r di d t h e adm i ni s t r at i o n o f 1 m g m .
o f at r o p i ne s u l p h at e af f e c t t h e s e c r e t o r y r e -
s p o ns e t o c af f e i ne i n m an.3 5 4 Gi ddi ng s e t al .3 5 5
f o u nd t h at t h e dai l y adm i ni s t r at i o n o f 7 5 m g m .
c af f e i ne p e r k i l o b o dy w e i g h t b y s t o m ac h t u b e
t o c at s f o r 2 1 day s , f ai l e d t o p r o du c e any
p at h o l o g i c al c h ang e s i n t h e s t o m ac h o r du o -
de nu m . A l t h o u g h dai l y i nj e c t i o ns o f t h e s am e
am o u nt o f c af f e i ne i n a b e e s w ax and o i l
m i x t u r e l i k e w i s e f ai l e d t o p r o du c e g as t r o - o r
du o de nal l e s i o ns , ac u t e e r o s i o ns and " u l c e r s "
w e r e no t e d w h e n l ar g e do s e s o f c af f e i ne i n
b e e s w ax ( s i m i l ar t o t h o s e u s e d b y Ro t h and
I v y ) w e r e g i v e n.
A t t e m p t s t o p r o du c e u l c e r i n do g s b y r e -
p e at e d dai l y i nt r am u s c u l ar i nj e c t i o ns o f c af -
f e i ne i n b e e s w ax w e r e no t s u c c e s s f u l , i ndi c at -
i ng a s p e c i e s di f f e r e nc e t o t h e r e s p o ns e t o
c af f e i ne .3 5 6 A c c o r di ng t o Ro t h and I v y 3 5 6 t h e
c af f e i ne i ni t i at e d m ar k e d h y p e r t e m i a o f t h e
g as t r i c m u c o s a w h i c h w as f o l l o w e d b y a p e r i o d
o f c y ano s i s i n t h e c at . S e c t i o ns o f t h e m u c o s a
f o l l o w i ng t h e adm i ni s t r at i o n o f c af f e i ne s h o w e d
m ar k e d h y p e r w e m i a and c o ng e s t i o n o f t h e b l o o d
v e s s e l s and s c at t e r e d f o c i o r s e r o u s t r ans u dat e
and e x t r av as c u l ar c o l l e c t i o ns o f r e d b l o o d c e l l s .
Fr o m t h e s e o b s e r v at i o ns i t w as c o nc l u de d t h at
t h e v as c u l ar c h ang e s i ndu c e d b y c af f e i ne p r o -
du c e d l o c al nu t r i t i o nal di s t u r b anc e s i n t h e
g as t r i c m u c o s a and t h e r e s u l t ant i s c h e e m i c
ar e as w e r e m o r e s u s c e p t i b l e t o t h e di g e s t i o n o f
t h e ac i d- p e p s i n s e c r e t i o ns o f t h e g as t r i c c o n-
t e nt s . A l t h o u g h g as t r i c l e s i o ns h av e f o l l o w e d
t h e i nj e c t i o n o f c af f e i ne i n c at s and g u i ne a
p i g s , t h u s f ar t h e r e i s no e v i de nc e t h at s u c h
l e s i o ns w e r e p r o v o k e d i n do g s o r i n m an.
S UMMA RY
T h e nu m e r o u s e x p e r i m e nt al s t u di e s h av e
s h o w n t h at t h e r e p e at e d adm i ni s t r at i o n o f
p i l o c ar p i ne , adr e nal i ne , ac e t y l c h o l i ne , m e c h o l y l
h i s t am i ne , p i t r e s s i n and c af f e i ne h ad f r e q u e nt l y
l e d t o t h e p r o du c t i o n o f g as t r o - i nt e s t i nal l e s i o ns ,
w h i c h w e r e m ai nl y o f t h e ac u t e t y p e . T h e s e
1 3 9
1 4 0 ROY A ND T URCOT : GA S T RECT OMY LA u g . 1 9 4 8
A .
v .5 9
l e s i o ns w e r e u s u al l y m u l t i p l e , i nv o l v i ng t h e
f u ndu s o f t h e s t o m ac h , m o r e o f t e n t h an t h e
p y l o r u s o r t h e du o de nu m , and c o ns i s t e d m ai nl y
o f m u c o s al h w e m o r r h ag e s , e r o s i o ns , s u p e r f i c i al
ac u t e u l c e r at i o ns and o c c as i o nal l y s u b ac u t e
u l c e r s w e r e s e e n. I n g e ne r al , t h e p at h o l o g i c al
c h ang e s o b s e r v e d w e r e s e c o ndar y t o p r o f o u nd
v as c u l ar di s t u r b anc e s i n t h e g as t r i c o r du o -
de nal ' m u c o u s m e m b r ane , v as o c o ns t r i c t i o n,
s p as m o r m ar k e d h y p e r w m i a w i t h c ap i l l ar y
s t as i s , w h i c h r e s u l t e d i n l o c al t i s s u e ano x aw m i a,
and i s c h aw m i c ne c r o s i s o f t h e m u c o u s m e m -
b r ane . T h e s e ne c r o t i c ar e as p r e s u m ab l y b e -
c am e m o r e s u s c e p t i b l e t o t h e di g e s t i v e ac t i o n
o f t h e ac i d- p e p s i n c o nt e nt s o f t h e s t o m ac h ,
l e adi ng t o u l c e r at i o n i n m any i ns t anc e s , w h i c h
r ar e l y , i f e v e r b e c am e c h r o ni c . T h e adm i n-
i s t r at i o n o f ac i d al o ne r ar e l y l e d t o u l c e r
f o r m at i o n, b u t o nc e a l e s i o n w as p r o du c e d
ar t i f i c i al l y i n t h e g as t r i c o r du o de nal m u c o u s
m e m b r ane , t h e p r e s e nc e o f ac i d de f i ni t e l y de -
l ay e d t h e h e al i ng o f t h e u l c e r and e v e n c au s e d
i t t o s p r e ad.
A l t h o u g h t h e g as t r o - du o de nal l e s i o ns p r o -
du c e d i n no w ay r e s e m b l e t h e c h r o ni c p e p t i c
u l c e r s s e e n i n m an, t h e y do s t r e s s t h e i m -
p o r t anc e o f r e p e at e d and o f p r o l o ng e d c i r c u l a-
t o r y di s t u r b anc e s ( c ap i l l ar y s p as m o r p r o f o u nd
v as o di l at i o n w i t h a s t as i s ) as a f ac t o r i n t h e
i ni t i at i o n o f s u c h l e s i o ns , w h i c h m ay b e f u r t h e r
ag g r av at e d b y t h e p r e s e nc e o f t h e ac i d- p e p s i n
c o nt e nt s o f t h e s t o m ac h .
CONCLUS I ON
T h e e s s e nc e o f t h e u l c e r p r o b l e m c o ns i s t s o f
t w o di s t i nc t , b u t c l o s e l y r e l at e d p r o c e s s e s ;
t h at w h i c h i ni t i at e s t h e u l c e r s , and t h at w h i c h
i s r e s p o ns i b l e f o r t h e p r o g r e s s i o n o f t h e s e
l e s i o ns t o t h e c h r o ni c f o r m . T h u s f ar , t h e
o b s e r v at i o ns o f t h e nu m e r o u s i nv e s t i g at o r s r e -
l at e d t o t h i s p r o b l e m h av e o nl y p ar t i al l y
ans w e r e d t h e q u e s t i o n o f t h e p at h o g e ne s i s o f
p e p t i c u l c e r . A l t h o u g h i t h as b e e n c l e ar l y
de m o ns t r at e d t h at v as c u l ar al t e r at i o ns l e adi ng
t o l o c al t i s s u e ano x am i a and ne c r o s i s ar e t h e
m o s t i m p o r t ant f ac t o r s i n t h e i ni t i at i o n o f
e r o s i o ns and u l c e r s , t h e l e s i o ns p r o du c e d h av e
r ar e l y i f e v e r g o ne o n t o c h r o ni c i t y . T h e r e -
p e at e d v as c u l ar i ns u l t s i ndu c e d b y t h e e x p e r i -
m e nt al m e t h o ds e m p l o y e d b y nu m e r o u s i n-
v e s t i g at o r s , al t h o u g h s e v e r e e no u g h h av e b e e n
r e l at i v e l y t r ans i t o r y i n nat u r e and t h u s f ar i t
h as no t b e e n p o s s i b l e t o r e p r o du c e s u s t ai ne d
r e f l e x ne r v o u s di s t u r b anc e s i n do g s , c o m p a-
r ab l e t o t h o s e s u s p e c t e d t o o c c u r i n m an du e
t o l o ng - l as t i ng e m o t i o nal c o nf l i c t s . A l t h o u g h
e r o s i o ns o r ac u t e u l c e r s o c c u r f r e q u e nt l y i n
m an, c o m p ar at i v e l y f e w p e o p l e de v e l o p c h r o ni c
p e p t i c u l c e r .3 5 9
3 6 0 , 3 1
Mo s t o f t h e s e l e s i o ns
h e al r ap i dl y and i t h as al s o b e e n s h o w n t h at
c h r o ni c p e p t i c u l c e r s h e al as r ap i dl y as t h e
ac u t e u l c e r s , w h e n t h e s t at e o f s u s t ai ne d e m o -
t i o nal c o nf l i c t s w as r e m o v e d.3 6 0
T h e s e o b s e r v at i o ns o f f e r a p h y s i o l o g i c al
b as i s f o r t h e ne u r o g e ni c c o nc e p t o f u l c e r f o r m a-
t i o n, and r e - e m p h as i z e t h e i m p o r t anc e o f
m ar k e d c i r c u l at o r y di s t u r b anc e s i n t h e i ni t i a-
t i o n o f ac u t e g as t r o - i nt e s t i nal l e s i o ns , r ang i ng
f r o m m u c o s al h am o r r h ag e s t o e r o s i o ns and
u l c e r s . T h i s al s o f i t s t h e p s y c h o s o m at i c c o nc e p t
o f u l c e r f o r m at i o n, w h i c h r e g ar ds t h e ap p e ar -
anc e o f u l c e r s as t h e p at h o l o g i c al s e q u e l t o t h e
i m b al anc e o f t h e au t o no m i c ne r v o u s s y s t e m
c r e at e d du r i ng s u s t ai ne d e m o t i o nal c o nf l i c t s .
NOT E- A b i b l i o g r ap h y o f m o r e t h an 3 5 0 r e f e r e nc e s
w i l l b e av ai l ab l e i n t h e r e p r i nt s o f t h i s ar t i c l e .
T OT A L GA S T RECT OMY*
( Re p o r t o f 1 1 c as e s )
Fr ang o i s
Ro y , F.A .C.S . and J ac q u e s T u r c o t ,
F.R.C.S .[ C.]
Q u e b e c , Q u e .
T OT A L
g as t r e c t o m y
h as b e e n de f i ne d as t h e
c o m p l e t e r e m o v al o f t h e s t o m ac h , w i t h t h e
p y l o r u s and t h e c ar di a. Unt i l r e c e nt y e ar s , t h i s
p r o c e du r e w as r ar e l y e x e c u t e d and w as a v e r y
s e r i o u s o p e r at i o n, e nt ai l i ng a h i g h m o r t al i t y .
B u t , i n 1 9 3 8 , A l l e n i nt r o du c e d a t e c h ni q u e
t h at i m p r o v e d t h e r e s u l t s o f t h e o p e r at i o n.
Hi s m e t h o d e m p h as i z e d t h e i m p o r t anc e o f c e s o -
p h ag o - j e j u no s t o m y , o f t h e s u t u r i ng o f t h e j e j u nal
l o o p t o t h e di ap h r ag m , o f an e nt e r o - e nt e r o s t o m y
and a c o m p l e m e nt ar y j e j u no s t o m y u s e d t o f e e d
t h e p at i e nt .
T h e m o r t al i t y o f t o t al g as t r e c t o m y t h e n de -
c r e as e d f r o m 5 0 % as i t w as p r e v i o u s l y t o ar o u nd
3 0 % o . T h e m ai n c au s e o f de at h w as s t i l l p o s t -
o p e r at i v e p e r i t o ni t i s . S o , Ro s c o e Gr ah am , i n
1 9 4 0 , c am e al o ng w i t h a ne w t e c h ni c al de t ai l ,
ai m e d at de c r e as i ng t h e adv e nt o f a l e ak i n t h e
*
Fr o m t h e De p ar t m e nt
o f
S u r g e r y , H8 t e l - Di e u
Ho s -
p i t al , Q u e b e c .