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192
Hypertension
Present evidence suggests that sympathetic nervous system is important in the development of
hypertension in SHR.2-15-19 Folkow et al15 showed
that immunosympathectomy in very young rats
attenuated the development of hypertension.
Recently Lee et al,20 using an improved ablation
technique, found that hypertension could be prevented completely. One way in which increased
sympathetic neural activity in SHR could elevate
BP is through a net increase in vasoconstrictor tone
associated with a low threshold of the "defense"
reaction,1'2-16'17 so that the hypertrophy will occur
as a direct consequence of the rise in BP. An
alternative hypothesis is that the sympathetic nervous system exerts a local trophic role in the
development of cardiovascular hypertrophy.7-18-19
Such a role presupposes elevation of regional norepinephrine tissue concentration [NE] and high
turnover at the time of development of cardiovascular hypertrophy. However, there has been only
one detailed longitudinal study by Patel et al,21 who
determined the fractional rate constant of norepinephrine, but did not relate it to the development of
cardiovascular hypertrophy.
In the present experiments, we examined the
time course of development of cardiac and vascular
hypertrophy and how this related 1) to the development of hypertension and 2) to the various measures of regional sympathetic function. Accordingly, we compared the vascular properties of the
hindquarters in SHR and WKY rats and measured
the left ventricular and right ventricular weights at
six time points over an age span of 4-50 weeks of
age. Indexes of regional sympathetic function were
obtained in a parallel study in skeletal muscle
vessels, heart, and kidney.
Materials and Methods
193
TABLE 1. Linear Regression Equations in Spontaneously Hypertensive Rats and Wlstar-Kyolo Rats
Age
Group
BW-HQW relation
SHR+WKY
PP-flow relation
SHR
(wk)
4-40
23
WKY
8*
1*
6'
SHR
14
WKY
14
8*
SHR
27
4'
WKY
27
4'
SE b
HQW=24.97+0.031 BW
0.0023
0.95
P P ^ do=10.07+0.72 HQQ
PPm. <ffl=6.83+0.72 HQQ
PPmrc.do'-13.45 + 1.48 HQQ
PPmdii=9.84+1.48HQQ
PP mtdi =12.89+1.43HQQ
PPo-x ,8=8.70+1.43 HQQ
0.088
0.047
0.181
0.144
0.387
0.543
0.85
0.94
0.91
0.90
0.95
0.91
PPn*<ffl=13.34+0.046 BW
PPIOT<ffl=11.33+0.034BW
PPmDcc=225+0.319BW
PPmcc=159+0.274BW
0.0039
0.0039
0.32
0.27
0.91
0.85
0.89
0.85
Regression equation
PP-BW relation
SHR
WKY
SHR
WKY
40-50
40-50
40-50
40-50
31
32
31
32
n, number of rats; SEt,, standard error of regression coefficient; r, correlation coefficient; BW, body weight (g);
HQW, hindquarter weight (% of BW); SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; PP,
perfusion pressure; max dil, maximum dilatation; HQQ, hindquarter flow (ml/min/100 g HQW); max con, maximum
constriction.
'For PP-flow curves, number of data points were, in order, spontaneously hypertensive rats, Wistar-Kyoto rats:
4 weeks, 32 and 28; 14 weeks, 17 and 24; 27 weeks, 12 and 12.
ing methoxamine. The concentration of methoxamine was related to the body weight of the rats, so
that in each experiment we used similar drug concentrations and increments. For each dose a perfusion pressure plateau was reached before giving the
next dose, up to a dose of methoxamine where there
was no further elevation in perfusion pressure. After
this we tested whether this corresponded to perfusion pressure at maximum constriction (PP^cd)*
which was obtained by means of a bolus of angiotensin II (Ang II, 50/x.g) or of BaCl2 (100-200 ^g)The rats were perfused at a constant flow of 4
ml/min/100 g body wt, which in adult rats corresponds to a flow of 10 ml/mih/100 g hindquarter
wt.24 The relation between hindquarter weight and
body weight was closely similar in SHR and WKY
rats, but differed at different stages of growth (Table
1). Thus, in low body weight (young) rats of each
strain, the hindquarter weight was a lower fraction
of the total body weight than in adult rats. For
example, in a 50-g rat, hindquarter weight was
26.50.4% body wt, whereas in a 450-g rat, hindquarter weight averaged 38.80.6% body wt, which
was close to the value of 40% that Folkow et al24
reported in adult rats. Thus, at constant perfusion
per unit body weight, young rats will receive a
higher flow per gram hindquarter weight than adult
rats, so that the vascular resistance at P P ^ m will
be overestimated. The body weight-hindquarter
weight relation accounted for about 90% of the
variance, and we used it to correct P P ^ ^ to the
value corresponding to a standard perfusion rate of
10 ml/min/100 g hindquarter wt. This was done from
perfusion pressure-flow lines obtained in a separate
194
Hypertension
Q/100g BVV,
g 30
E
I
_j
Q 20
X
wk
g-10
2
ml/mln/100g BW
4
6
8
10
15 20
0
5
10
FLOW- ml/min/100a HQW
15
20
195
Heart Weight
The left ventricle plus septum weight/body weight
ratio and the ratio of right ventricular weight/body
weight declined in both SHR and WKY rats from
4 weeks to reach stable values at about 14-20
weeks (Figure 2). At 4 weeks the left ventricle plus
septum weight/body weight ratio was only 8%
higher in SHR than in WKY rats (p=0.05), rising
to =*25% at 14 weeks and to a final value of =*40%
400
i
300
/
1f
1
1
* 200
a
o
"
IOO
?240
E
E
'.200
oc
Q.
B160
/r-*-n
J120
T^
, ^.
' ^
WKY
0)
80
9 14 20
30
40
AGE - weeks
60
0 14 20
30
40
AGE - weeks
60
196
Hypertension
400
SHR
WKY
E
I 300
^
ir
3
to
SO
_ 20
i
g
UJ
tr 200
-4
O 100
CO
3
60
9n
r/
T
J
100
1
METHOXAMINE - jjfl/ml
30
_,.
" '
10
14
9
100
Methoxamine con-
Adams et al
197
100
9 14 20
30
AQE -
4 9 14 20
30
AQE - *
30
Q
X
20
0.
Q.
10
400
300
2 200
a.
a.
100L0
100
200
300
BODY WEIGHT - g
400
198
Hypertension
TABLE 2. Differences Between Perfuskm Pressure at Maximum Constriction Produced by Methoxamine and by
Angiotensin II
SHR
Age (wk)
4
9
14-50t
Methoxamine
176.54.19
287.35.53
347.05.00
WKY
Angiotensin II
231.54.82*
314.87.15*
347.05.00
Methoxamine
130.215.09
210.0+9.51
264.3+3.90
Angiotensin II
161.8+19.39*
231.210.36*
264.3+3.90
Values for differences in perfusion pressure (mm Hg) are meanSEM. SHR, spontaneously hypertensive rats;
WKY, Wistar-Kyoto rats.
*p for difference <0.05.
tValues for methoxamine and angiotensin II responses between 14 and 50 weeks were similar at all times.
TABLE 3. Comparison of Range-Independent and Maximum Slopes in Spontaneously Hypertensive Rats and
WIstar-Kyoto Rats of Methoxamine/ConcentratJon-Response Curves
Range-independent slope
(normalized units)
Age (wk)
4
9
14
20
30
50
SHR
WKY
SHR
WKY
11916.9
904.6
12211.8
127+11.8
1303.6
18112.8
9714.5
717.3*
95 4.7*
976.2
1234.8
18625.8
19026.4
23415.3
36636.3
39740.8
42111.3
61643.0
12328.5
13315.2*
21414.2'
24219.9*
28419.5*
45247.7*
Adams et al
FORELIMB MUSCLES
KIDNEY
300
tNE]
ng/g
200
100
0
0.2
SHR
Rata
0.1
Constant
WKY
NE
20
Turnover
10
(ng/g)/h
9 14 20
30
60
7S
50
25
0
4 9 14 20
30
AQE - weeks
199
50
4 9 14 20
30
SO
200
Hypertension
201
References
1. Folkow B: Cardiovascular structural adaptation: Its role in
the initiation and maintenance of primary hypertension. (The
fourth Volhard lecture.) Clin Sci Mol Med 1978;
55(suppl 4):3s-22s
2. Folkow B: Physiological aspects of primary hypertension.
Physiol Rev 1982;62:347-504
3. Folkow B, KarlstrSm G: Age- and pressure-dependent
changes of systemic resistance vessels concerning the relationships between geometric design, wall distensibility, vascular reactivity and smooth muscle sensitivity. Acta Physiol
Scand 1984;122:17-33
4. HallbSck-Nordlander M, Noresson E, Thoren P: Hemodynamic consequences of left ventricular hypertrophy in spontaneously hypertensive rats. Am J Cardiol 1979;44:986-993
5. Broughton A, Korner PI: Left ventricular pump function in
renal hypertensive dogs with cardiac hypertrophy. Am J
Physiol 1986;251:H1260-H1266
6. Korner PI: Causal and homeostatic factors in hypertension:
(The sixth Volhard Lecture). Clin Sci 1982;63(suppl 8):5s-26s
7. Lever AF: Slow pressor mechanisms in hypertension: A role
for hypertrophy of resistance vessels? / Hypertens 1986;
4:515-524
8. Korner PI, Jennings GL, Esler MD, Anderson WP, Bobik A,
Adams M, Angus JA: The cardiovascular amplifiers in
human primary hypertension and their role in a strategy for
detecting the underlying causes. Can J Physiol Pharmacol
1987;65:1730-1738
9. Murvany MJ: The structure of the resistance vasculature in
essential hypertension. (The fourth Sir George Pickering
memorial lecture.) / Hypertens 1987;5:129-136
10. Yamori Y, Lovenberg W (eds): Contribution of SHR, strokeprone SHR and other substrains to progress in basic, therapeutic and preventive medicine: 25 year collection of references (1960-1985). Izumo, Japan, WHO Collaborating Center
for Research on Primary Prevention of Cardiovascular Diseases, 1985, pp 1-130
11. Lee RMKW, Garfield RE, Forrest JB, Daniel EE: Morphometric study of structural changes in the mesenteric blood
vessels of spontaneously hypertensive rats. Blood Vessels
1983;20:57-71
12. Mueller SM: Longitudinal study of the hindquarter vasculature during development in spontaneously hypertensive and
Dahl salt-sensitive rats. Hypertension 1983;5:489-497
13. Miller BG, Connors BA, Bohlen HG, Evan AP: Cell and
wall morphology of intestinal arterioles from 4- to 6- and 17to 19-week-old Wistar-Kyoto and spontaneously hypertensive rats. Hypertension 1987;9:59-68
14. Engelmann GL, Vitullo JC, Gerrity RG: Morphometric
analysis of cardiac hypertrophy during development, maturation, and senescence in spontaneously hypertensive rats.
Ore Res 1987;60:487-494
15. Folkow B, Hallback M, Lundgren Y, Weiss L: The effects of
"immunosympathectomy" on blood pressure and vascular
"reactivity" in normal and spontaneously hypertensive rats.
Acta Physiol Scand 1972;84:512-523
16. Yamori Y: Neurogenic mechanisms of spontaneous hypertension, in, Onesti G, Fernandes M, Kim KE (eds): Regulation of Blood Pressure by the Central Nervous System. 4th
Hahnemann International Symposium on Hypertension. New
York, Grune & Stratton, Inc, 1976, pp 65-76
17. HallbSck M: Consequence of social isolation on blood pressure, cardiovascular reactivity and design in spontaneously
hypertensive rats. Acta Physiol Scand 1975;93:455-465
18. Bevan RD: Trophic effects of peripheral adrenergic nerves
on vascular structure. Hypertension 1984;6(suppl III):
III-19-III-26
19. Simpson P, McGrath A, Savion S: Myocyte hypertrophy in
neonatal rat heart cultures and its regulation by serum and
by catecholamines. Ore Res 1982;51:787-801
20. Lee RMKW, Triggle CR, Cheung DWT, Coughlin MD:
Structural and functional consequence of neonatal sympa-
202
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Hypertension
thectomy on the blood vessels of spontaneously hypertensive rats. Hypertension 1987; 10:328-338
Patel KP, Kline RL, Mercer PF: Noradrenergic mechanisms
in the brain and peripheral organs of normotensive and
spontaneously hypertensive rats at various ages. Hypertension 1981;3:682-690
Kurtz TW, Morris RC: Biological variability in WistarKyoto rats: Implications for research with the spontaneously
hypertensive rat. Hypertension 1987;10:127-131
Head GA, McCarty R: Vagal and sympathetic components
of the heart rate range and gain of the baroreceptor-heart
rate reflex in conscious rats. J Auton Nerv Syst 1987;
21:203-213
Folkow B, Hallback M, Lundgren Y, Weiss L: Background
of increased flow resistance and vascular reactivity in spontaneously hypertensive rats. Acta Physiol Scand 1970;
80:93-106
Roizen MF, Kopin IJ: Effect of general anesthetics on
handling and decapitation-induced increases in sympathoadrenal discharge. J Pharmacol Exp Ther 1978;204:11-18
Adams MA, Hirst M: The ethanol withdrawal syndrome in
the rat: Effects of drug treatment on adrenal gland and
urinary catecholamines. Subst Alcohol Actions Misuse 1982;
3:287-298
Jackman G, Snell J, Skews H, Bobik A: Effects of noradrenergic neuronal activity on 3,4-dihydroxyphenylethylene
glycol (DHPG) levels. Quantitation by high performance
liquid chromatography. Life Sci 1982;31:923-929
Jackman GP, Oddie CJ, Skews H, Bobik A: Highperformance liquid chromatographic determinations of plasma
catecholamines during a-methyldopa therapy. JChromatogr
1984;308:301-305
Brodie BB, Costa E, Dlabac A, Neff NH, Smookler HH:
Application of steady state kinetics to the estimation of
synthesis rate and turnover time of tissue catecholamines. /
Pharmacol Exp Ther 1966;154:493-498
Spector S, Sjoerdsma A, Udenfriend S: Blockade of endogenous norepinephrine synthesis by a-methyl-tyrosine, an
inhibitor of tyrosine hydroxylase. / Pharmacol Exp Ther
1965;147:86-95
Marquardt DW: An algorithm for least-squares estimates of
non-linear parameters./ SoclndAppl Math 19f3;lVA31-4Al
Dorward PK, Riedel W, Burke SL, Gipps J, Korner PI: The
renal sympathetic baroreflex in the rabbit. Arterial and
cardiac baroreceptor influences, resetting, and effect of
anesthesia. Ore Res 1985;57:618-633
Snedecor GW, Cochran WG: Statistical Methods (ed 7).
Ames, Iowa, Iowa State University Press, 1980
Fuxe K, Sedvall G: The distribution of adrenergic nerve
fibres to the blood vessels in skeletal muscle. Acta Physiol
Scand 1965;64:75-86
DiBona GF: The functions of the renal nerves. Rev Physiol
Biochem Pharmacol 1982;94:75-181
Head GA, Adams MA: Time course of changes in baroreceptor reflex control of heart rate in conscious SHR and
WKY: Contribution of the cardiac vagus and sympathetic.
Clin Exp Pharmacol Physiol 1988;15:289-292
Gray SD: Spontaneous hypertension in the neonatal rat. A
Review. Clin Exp Hypertens [A] 1984^.6:755-781
Murvany MJ, Hansen PK, Aalkjaer C: Direct evidence that
the greater contractility of resistance vessels in spontaneously hypertensive rats is associated with a narrowed lumen,
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