Antihypertensives 1

Antihypertensives
Alexander Scriabine, Miles Laboratories, Inc., Institute for Preclinical Pharmacology, New Haven,
Connecticut 06511, United States
David G. Taylor, Miles Laboratories, Inc., Institute for Preclinical Pharmacology, New Haven, Connecticut
06511, United States

1. Introduction . . . . . . . . . . . . . . 1 4.2.1.1. Reserpine . . . . . . . . . . . . . . . . 11

2. Diuretics . . . . . . . . . . . . . . . . 2 4.2.1.2. Guanethidine . . . . . . . . . . . . . . 12
2.1. Sulfonamide Diuretics . . . . . . . 2 4.2.2. α-Adrenoceptor Antagonists . . . . 12
2.1.1. Hydrochlorothiazide . . . . . . . . . 3 4.2.2.1. Prazosin . . . . . . . . . . . . . . . . . 12
2.1.2. Chlorthalidone . . . . . . . . . . . . . 3 4.2.2.2. Indoramin . . . . . . . . . . . . . . . . 13
2.1.3. Furosemide . . . . . . . . . . . . . . . 3 4.2.2.3. Urapidil . . . . . . . . . . . . . . . . . 13
2.1.4. Mefruside . . . . . . . . . . . . . . . . 4 4.2.3. β-Adrenoceptor Antagonists . . . . 14
2.1.5. Indapamide . . . . . . . . . . . . . . . 4 4.2.3.1. Propranolol . . . . . . . . . . . . . . . 14
2.2. K+ -Retaining Diuretics . . . . . . . 4 4.2.3.2. Metoprolol . . . . . . . . . . . . . . . 15
2.2.1. Amiloride . . . . . . . . . . . . . . . . 4 4.2.3.3. Nadolol . . . . . . . . . . . . . . . . . 15
2.2.2. Triamterene . . . . . . . . . . . . . . . 5 4.2.3.4. Pindolol . . . . . . . . . . . . . . . . . 15
2.3. Other Diuretics . . . . . . . . . . . . 5 4.2.3.5. Timolol . . . . . . . . . . . . . . . . . . 16
2.3.1. Ethacrynic Acid . . . . . . . . . . . . 5 4.2.3.6. Acebutolol . . . . . . . . . . . . . . . . 16
2.3.2. Indacrinone . . . . . . . . . . . . . . . 6 4.2.3.7. Labetalol . . . . . . . . . . . . . . . . . 17
2.3.3. Muzolimine . . . . . . . . . . . . . . . 6
5. Smooth Muscle Relaxants . . . . . 17
3. Inhibitors of Angiotensin Con-
5.1. Ca2+ Channel Antagonists . . . . 17
verting Enzyme . . . . . . . . . . . . 6
5.1.1. Nifedipine . . . . . . . . . . . . . . . . 17
3.1. Captopril . . . . . . . . . . . . . . . . 7
5.1.2. Nitrendipine . . . . . . . . . . . . . . . 18
3.2. Enalapril . . . . . . . . . . . . . . . . 7
4. Inhibitors of the 5.1.3. Verapamil . . . . . . . . . . . . . . . . 19
Sympathetic Nervous System . . . 8 5.1.4. Diltiazem . . . . . . . . . . . . . . . . 19
4.1. Drugs with Primarily Central Ac- 5.2. Vasodilators with Other Mecha-
tions . . . . . . . . . . . . . . . . . . . 8 nisms of Action . . . . . . . . . . . . 20
4.1.1. Methyldopa . . . . . . . . . . . . . . . 9 5.2.1. Hydralazine . . . . . . . . . . . . . . . 20
4.1.2. Clonidine . . . . . . . . . . . . . . . . 9 5.2.2. Diazoxide . . . . . . . . . . . . . . . . 21
4.1.3. Guanfacine . . . . . . . . . . . . . . . 9 5.2.3. Minoxidil . . . . . . . . . . . . . . . . 21
4.1.4. Guanabenz . . . . . . . . . . . . . . . 10 5.2.4. Sodium Nitroprusside . . . . . . . . . 21
4.2. Drugs with Primarily Peripheral 6. Perspectives in the Development of
Action . . . . . . . . . . . . . . . . . . 10 Antihypertensive Drugs . . . . . . 22
4.2.1. Amine Depleting and Adrenergic 7. Summary and Conclusions . . . . 22
Neuron Blocking Agents . . . . . . . 11 8. References . . . . . . . . . . . . . . . 23

1. Introduction The available antihypertensive drugs can be

In spite of the fact that many drugs are now avail-
able for the treatment of hypertension, new drugs
are being introduced every year. The existence of
a lucrative and still expanding market as well as
the medical need for effective antihypertensive
drugs with minimal side effects stimulate con-
tinuous research activity in this field.
classified on the basis of their mechanism of ac-
tion as follows: (1) diuretics, (2) inhibitors of an-
giotensin converting enzyme (ACE), (3) drugs
which interfere with the sympathetic nervous
system, and (4) vascular smooth muscle relax-
ants. This article describes the major represen-
tatives of each of the above classes of antihyper-
tensive drugs.

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a04 235
2 Antihypertensives
2. Diuretics
The chemistry, pharmacology, and clinical use
of diuretics in hypertension and edema are dis-
cussed in [1], also → Diuretics. The rapid ex-
pansion of the diuretic field occurred after the
introduction of acetazolamide [2] and chlorothi-
azide [3], [4]. The discovery of the effectiveness
of chlorothiazide in the therapy of hypertension
[5] greatly expanded the market for diuretics and
led to the synthesis of many chemically related
compounds. Since hypokalemia is one of the ma-
jor side effects of chlorothiazide and related thi-
azides, attempts were made to develop diuretics
with K+ -retaining or isokalemic properties. Al-
dosterone antagonists, such as spironolactone or
other K+ retaining diuretics, e.g., amiloride [6]
or triamterene [7] were shown to produce diure-
sis while reducing excretion of potassium. Com-
binations of thiazides with potassium retaining
diuretics (e.g., Moduretic or Dyazide) have di-
uretic effects and lower arterial pressure without
any change in the excretion of potassium. These
combinations are widely used in general prac-
tice.
The mechanism of antihypertensive action
of diuretics is still a subject of controversy, al-
though numerous studies suggested that the na-
triuretic action of diuretics is primarily responsi-
ble for their antihypertensive effect. The kidneys
of hypertensive animals or humans can excrete
salt in normal amounts but only at elevated ar-
terial pressure levels and diuretics increase the
excretion of salt independent of blood pressure
level [8]. Also the increase in sodium in the vas-
cular smooth muscle cell was correlated with the
increase in the intracellular calcium, and there-
fore, with the vasoconstrictor tone leading to the
elevation of arterial pressure [9], [10]. The na-
triuretic effect of diuretics tends to prevent ex-
cessive accumulation of sodium.
2.1. Sulfonamide Diuretics
The first sulfonamide shown to have diuretic ac-
tivity in humans was sulfanilamide [63-74-1]
[11]. Subsequent attempts to improve the ac-
tivity and to reduce the side effects of sulfa-
nilamide led to the development of acetazol-
amide [59-66-5] [12], which can be considered
the prototype of sulfonamide diuretics. Its con-
tinuous use led to metabolic acidosis and to the
development of tolerance to its diuretic effect.
The search for a better diuretic led to the devel-
opment of chlorothiazide [58-94-6] [13]. The
diuretic activity of chlorothiazide, unlike that
of acetazolamide, is not determined by its car-
bonic anhydrase inhibitory activity. At therapeu-
tic doses, chlorothiazide increases the excretion
of chloride rather than that of hydrogen carbon-
ate. By repeated administration chlorothiazide
produces effective diuresis without metabolic
acidosis.
Extensive structure – activity relationship
studies led subsequently to the development of
chemically and pharmacologically related thia-
zide diuretics which differed from chlorothia-
zide either in the relative potency or in the dura-
tion of action. The most commonly used thiazide
diuretic is hydrochlorothiazide [14], which is ca.
10 times more potent than chlorothiazide. The
most potent thiazide among marketed drugs is
cyclopenthiazide [15], while methylclothiazide
[16] and polythiazide [17] have exceptionally
long durations of action. Their longer duration
of action is due to higher lipid solubility (and
therefore greater reabsorption of the drug in the
proximal tubules) and higher protein binding.
Other clinically important sulfonamide diuretics
include mefruside [18], [19], indapamide [20],
and chlorthalidone [21].
A significant advance in diuretic therapy was
the introduction of furosemide [12], which has
much higher ceiling natriuretic and chloruretic
effects than thiazide diuretics. The high ceiling
effect of furosemide is determined by the site of
its tubular action: furosemide inhibits chloride
and sodium reabsorption in the ascending limb
of Henle’s loop (“loop” diuretic). Furosemide is
widely used clinically, although in hypertension
it is not more effective than thiazide diuretics.
An attempt to find a “loop” diuretic with a long
duration of action led to the development of mu-
zolimine [21], which is not yet available on the
United States market.

2.1.1. Hydrochlorothiazide
Hydrochlorothiazide [58-93-5], 6-chloro-
3,4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sul-
fonamide 1,1-dioxide, C7 H8 ClN3 O4 S2 , M r
297.72, mp 273 – 275 ◦ C, is insoluble in water,
soluble in NaOH, ethanol, and acetone. Hydro-
chlorothiazide is widely used in the treatment
of hypertension or edema.
Trade names: HydroDiuril, Esidrix.
Like other benzothiadiazine-type diuretics
(or thiazides), hydrochlorothiazide increases the
excretion of sodium and chloride independent
of acid – base balance. Hydrochlorothiazide also
increases the excretion of potassium. The result-
ing hypokalemia represents its major side ef-
fect. Other side effects include hyperuricemia,
hyperglycemia, and hyperlipoproteinemia. The
relative diuretic potency of hydrochlorothiazide
is ca. 10 times higher than that of chlorothia-
zide [14]. The efficacy (ceiling effect) is similar
to that of other thiazide diuretics and is con-
siderably lower than that of furosemide. Daily
clinical doses range from 25 to 200 mg and are
given with potassium supplements or in combi-
nation with potassium-retaining diuretics to pre-
vent hypokalemia.
2.1.2. Chlorthalidone
Chlorthalidone [77-36-1], 2-chloro-5-(1-
hydroxy-3-oxo-1-isoindolinyl)benzenesulfon-
amide, C14 H11 ClN2 O4 S, M r 338.78, mp
224 – 226 ◦ C, is slightly soluble in water
(12 mg/100 mL), more soluble in diluted NaOH
or warm ethanol.
Trade name: Hygroton.
Chlorthalidone is pharmacologically similar
to thiazide diuretics but is substantially longer
Antihypertensives 3
acting than hydrochlorothiazide [21]. The du-
ration of action is determined by its elimina-
tion half-life (t 1/2 ) of 49 h in humans. Be-
cause of longer duration of action, chlorthali-
done can be given every 72 h. Chlorthalidone
is widely used in the treatment of hyperten-
sion: it can be used alone or in combination
with methyldopa or β-adrenoceptor antagonists.
Side effects are also similar to those of thiazides
and include hypokalemia, hyperuricemia, hy-
perglycemia, and hyperlipoproteinemia (eleva-
tion of low-density lipoproteins). Clinical doses
range from 25 to 400 mg.
2.1.3. Furosemide
Furosemide [54-31-9], 5-(aminosulfonyl)-
4-chloro-2-[(2-furanylmethyl)amino]benzoic
acid, 4-chloro-N-furfuryl-5-sulfamoylanthran-
ilic acid, C12 H11 ClN2 O5 S, M r 330.77, mp
206 ◦ C, is only slightly soluble in water, sol-
uble in methanol, acetone, and dilute NaOH.
Trade name: Lasix.
The major site of action of furosemide is
in the ascending limb of Henle’s loop, prox-
imal to the thiazide diuretics. Like thiazides,
furosemide increases the excretion of sodium,
chloride, and potassium, but its efficacy (ceil-
ing effect) is much higher than that of thia-
zides and similar diuretics [12]. The duration
of diuretic action of furosemide is short and is
correlated with its elimination half-life (0.85 h).
Independent of its diuretic action, furosemide,
by i.v. administration, tends to increase venous
capacitance and to reduce left ventricular end
diastolic pressure. In spite of its greater di-
uretic efficacy, furosemide is not more effective
than thiazide diuretics in the treatment of hy-
pertension. Side effects of furosemide include
those of thiazide diuretics: hypokalemia, hy-
perglycemia, hyperuricemia, and hyperlipopro-
teinemia. In addition, furosemide tends to pro-
duce metabolic alkalosis and ototoxicity, which
is typical for “loop” diuretics. Daily clinical
doses of furosemide range from 20 to 200 mg.
4 Antihypertensives
2.1.4. Mefruside
Mefruside [7195-27-9], 4-chloro-N 1 -meth-
yl-N 1 -[(tetrahydro-2-methyl-2-furanyl)meth-
yl]-1,3-benzenedisulfonamide, 4-chloro-N 1 -
methyl-N 1 -(tetrahydro-2-methylfurfuryl)-m-
benzenedisulfonamide, C13 H19 ClN2 O5 S2 , M r
382.90, mp 149 – 150 ◦ C (dl-crystals), 146 ◦ C
(d-form). The d-form is more active as a diuretic
than the l-form.
Trade name: Baycaron.
The primary site of action of mefruside is the
cortical diluting segment; duration of action is
20 to 24 h. Mefruside has carbonic anhydrase in-
hibitory activity but is less potent than acetazol-
amide [18], [19]. One of its metabolites, oxome-
fruside, also has diuretic activity. Side effects of
mefruside are similar to those of thiazide diuret-
ics, in that it produces hyperuricemia and hypo-
kalemia. Daily clinical doses range from 25 to
200 mg. In hypertension, mefruside is effective
at 25 – 50 mg/d or every other day.
2.1.5. Indapamide
Indapamide [26807-65-8], 3-(amino-
sulfonyl)-4-chloro-N-(2,3-dihydro-2-meth-
yl-1H-indol-1-yl)benzamide, 4-chloro-N-(2-
methyl-1-indolinyl)-3-sulfamoylbenzamide,
C16 H16 ClN3 O3 S, M r 365.84, mp 160 – 162 ◦ C,
pK a 8.3, is lipid soluble.
Trade names: Fludex, Ipamox, Natrilix.
The site of diuretic action of indapamide is
similar to that of thiazide diuretics: the prox-
imal part of distal tubules. Its duration of di-
uretic action can exceed 24 h. Indapamidediffers
from thiazide diuretics in having additional di-
rect smooth muscle relaxant effect and hypoten-
sive effect at doses below those required to pro-
duce diuresis [20].
Side effects of indapamide include hypo-
kalemia, hyperuricemia, and metabolic alkalo-
sis, and are usually observed at doses higher
than required for satisfactory control of arterial
pressure in hypertensive patients (5 mg/d and
higher). The safe and effective clinical dose is
2.5 mg/d.
2.2. K+ -Retaining Diuretics
The development of K+ -retaining (or sparing)
diuretics was stimulated by the fact that K+ loss
and consequent hypokalemia represent the ma-
jor side effect of sulfonamide diuretics. It was
considered possible to develop K+ -retaining di-
uretics because aldosterone was known to retain
sodium while increasing the excretion of potas-
sium. The search for aldosterone inhibitors led
to the development of spironolactone [52-01-7]
[22], which is still used clinically. The activity
of spironolactone is determined by its ability to
compete with aldosterone at its receptor sites.
It is inactive in the absence of aldosterone but
has diuretic, natriuretic, and K+ retaining effects
in its presence. The pharmacological effects of
spironolactone are to a great extent due to its
active metabolite, canrenone, which is formed
within 3 min after administration of spironolac-
tone and has a half-life of ca. 12 h.
The clinical use of spironolactone is severely
limited by side effects, including hyperkalemia,
gynecomastia, impotence, and menstrual cycle
abnormalities. In rats chronic spironolactone
treatment was tumorigenic, and therefore, its
use is restricted. Because of these side effects
and the high cost of spironolactone, the search
for nonsteroidal aldosterone inhibitors contin-
ued and led to the development of K+ -retaining
diuretics that increase sodium excretion without
inhibiting aldosterone.
Two major K+ -retaining diuretics which do
not inhibit aldosterone are amiloride and tri-
amterene.
2.2.1. Amiloride

Amiloride [2609-46-3], 3,5-diamino-N-
(aminoiminomethyl)-6-chloropyrazinecarbox-
amide, N-amidino-3,5-diamino-6-chloropyra-
zinecarboxamide, C6 H8 ClN7 O, M r 229.65, mp
293.5 ◦ C, is soluble in water. It is widely used
in combination with hydrochlorothiazide (Mod-
uretic).
Trade names: Colectril and Midamor.
The site of action of amiloride is in the dis-
tal portion of distal tubules and in the collecting
duct, where amiloride inhibits sodium reabsorp-
tion and potassium secretion [6]. It is thought
to block the Na+ channel and the Na+ /H+ ex-
change pump. In addition to the renal tubules,
amiloride blocks Na+ channels in various ep-
ithelial membranes, including the salivary ducts.
In hypertension, if used alone, amiloride is not as
effective as hydrochlorothiazide. The major side
effect of amiloride is hyperkalemia. Other side
effects include nausea, anorexia, and abdominal
pain.
The clinical dose range of amiloride is
5 – 20 mg/d. Potassium supplements are contra-
indicated with amiloride; other K+ -retaining di-
uretics should not be combined with amiloride.
2.2.2. Triamterene
Triamterene [396-01-0], 6-phenyl-2,4,7-
pteridinetriamine, 2,4,7-triamino-6-phenyl-
pteridine, C12 H11 N7 , M r 253.26, mp 316 ◦ C,
is insoluble in water or chloroform and only
slightly soluble in alcohol.
Trade names: Dyrenium; Dyazide (combi-
nation with hydrochlorothiazide).
Triamterene increases urinary excretion of
sodium and chloride and decreases excretion of
potassium and hydrogen ions. The primary site
of triamterene action is in the distal tubules [7].
The biochemical effects of triamterene are not
well-known, although triamterene is capable of
forming “false” nucleotides.
The principal use of triamterene is in combi-
nation with hydrochlorothiazide. The natriuretic
effects of both diuretics are additive, but the kali-
Antihypertensives 5
uretic effect of hydrochlorothiazide is antago-
nized by triamterene.
The major side effect of triamterene alone is
hyperkalemia. Nausea, leg cramps, and dizzi-
ness have also been described. The initial clini-
cal dose is 100 mg twice daily. Dyazide capsules
contain 50 mg of triamterene and 25 mg of hy-
drochlorothiazide and are given 1 – 4 times daily.
2.3. Other Diuretics
In addition to sulfonamides and pyrazines, di-
uretic activity has been discovered among many
other chemical classes of drugs. Among them
are aryloxyacetic acids, 2-aminomethylphenols,
and various heterocyclic compounds. Because
all diuretics cannot be covered in this article,
compounds that are important therapeutically
as well as historically have been selected. The
three diuretics discussed (ethacrynic acid, in-
dacrinone, and muzolimine) differ from sulfon-
amides and pyrazines in their pharmacological
profiles and represent three different chemical
classes.
2.3.1. Ethacrynic Acid
Ethacrynic acid [58-54-8], [2,3-dichloro-4-
(2-methylene-1-oxybutyl)phenoxy]acetic acid,
C13 H12 Cl2 O4 , M r 303.14, mp 121 – 125 ◦ C, is
only slightly soluble in water but very soluble in
alcohol (1 g/1.6 mL).
The efficacy (ceiling effect) of ethacrynic
acid is similar to that of furosemide and con-
siderably higher than that of hydrochlorothia-
zide. Ethacrynic acid increases the excretion of
sodium and chloride. It also slightly increases
the excretion of potassium. The major site of
action is the ascending limb of Henle’s loop
[13]. The biochemical mechanism of action is
not known precisely, although at high concen-
trations ethacrynic acid inhibits renal Na+ −K+
dependent ATPase and oxygen consumption in
medullary tubules. Ethacrynic acid reacts with
thiols in the body fluids and forms adducts which
are likely to represent the active forms of this
6 Antihypertensives
drug. The side effects of ethacrynic acid include
abdominal discomfort, nausea, hyperuricemia,
neutropenia, thrombocytopenia, ototoxicity, and
metabolic alkalosis. The usual clinical doses are
50 mg twice a day; the maximal daily dose is
400 mg.
2.3.2. Indacrinone
Indacrinone [57296-63-6], [(6,7-dichloro-
2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-
inden-5-yl)oxy]acetic acid, M r 365.19. A 9 : 1
ratio of (+)- to (−)-indacrinone enantiomers was
studied as MK-286 and found to be isouricemic
during chronic use. The (+)-enantiomer is urico-
suric, whereas the (−)-enantiomer retains uric
acid. The racemic mixture was tested as MK-196
[23–25].
Indacrinone and its enantiomers lower arte-
rial pressure in hypertensive animals and in hu-
mans, inhibit sodium and chloride reabsorption
in the ascending limb of Henle’s loop, and in-
crease excretion of potassium. Hypokalemia can
be antagonized by amiloride. The site of action
of enantiomers in the renal tubules appears to
differ. The (−)-enantiomer has its primary action
in the medullary portion of the ascending limb,
while the (+)-enantiomer has its primary action
in the cortical diluting segment. The saluretic
efficacy of indacrinone is similar to or greater
than that of furosemide, while the duration of
action is longer. Side effects of indacrinone in
humans include headache, lethargy, weakness,
dry mouth, and slight, but transient elevations in
SGOT and/or SGPT. The clinical doses of the
(−)-enantiomer ranged from 10 to 40 mg, while
the (+)-enantiomer was given at doses from 10
to 400 mg.
2.3.3. Muzolimine
Muzolimine [55294-15-0], 5-amino-2-[1-
(3,4-dichlorophenyl)-ethyl]-2,4-dihydro-3H-
pyrazol-3-one, C11 H11 Cl2 N3 O, M r 272.13, mp
127 –129 ◦ C, is insoluble in water, but is solu-
ble in ethanol, polyethylene glycol, or dimethyl
sulfoxide. It is highly lipophilic, with a pK a
value of 9.3 and a partition coefficient in oc-
tanol/water of 2.29.
Trade name: Edrul.
The site of diuretic action of muzolimine is
the ascending limb of Henle’s loop. Unlike other
loop diuretics muzolimine does not act at the lu-
minal site. It appears to inhibit sodium and chlo-
ride transport at the peritubular site of the cell
membrane. Muzolimine exhibits a high-efficacy
(ceiling) effect similar to that of furosemide, but
has a considerably longer duration of action. The
duration of antihypertensive action of muzolim-
ine at a single dose exceeds 24 h [26], [27].
Clinical doses of muzolimine range from 10
to 480 mg; good therapeutic results were ob-
tained with doses of 30 mg/d in most patients.
Muzolimine is particularly useful in the treat-
ment of edema associated with renal failure.
3. Inhibitors of Angiotensin
Converting Enzyme
The renin – angiotensin system is involved in
the control of blood pressure in normotensive
and hypertensive states. The conversion of an-
giotensinogen to angiotensin II involves a two-
step sequence:

Pharmacological approaches for interference
with the renin – angiotensin system have fo-
cused on renin inhibitors, angiotensin con-
verting enzyme (ACE) inhibitors, and an-
giotensin II receptor antagonists [28]. Captopril
was the first orally effective ACE inhibitor ap-
proved for use in mild-to-moderate hyperten-
sion. Enalapril was developed later as a nonsulf-
hydryl-containing inhibitor.
3.1. Captopril
Captopril [62571-86-2], 1-(3-mercapto-2-
methyl-1-oxopropyl)-l-proline, C9 H15 NO3 S,
M r 217.28, mp 87 – 88 ◦ C, is soluble in water,
alcohol, and chloroform;
Trade name: Capoten.
The rationale and design of the angiotensin
converting enzyme (ACE) inhibitors have been
described [29], [30]. The effectiveness of cap-
topril on ACE was shown by its ability to in-
hibit the rise in blood pressure induced by an-
giotensin I, while leaving unchanged the re-
sponses to angiotensin II [31].
It has been postulated that the antihyper-
tensive mechanism may include not only in-
hibition of plasma ACE activity, but also in-
hibition of local tissue ACE, especially in the
vascular smooth muscle [32–35]. In addition,
a number of alternative mechanisms could ex-
plain the efficacy of ACE inhibitors in nonrenin-
dependent hypertension [36]. The alternatives
include (1) interference with α-adrenergic vaso-
constriction [37–42]; (2) a central inhibition of
sympathetic nervous outflow [35], [43]; (3) el-
evation in bradykinin or prostaglandins, due to
the similarity of kininase II and ACE [31], [32],
[44]; and (4) alteration in the permeability of
vascular smooth muscle to sodium ions [45].
Clinically, the antihypertensive actions of
captopril are associated with a reduction in total
peripheral resistance and a slight to moderate in-
crease in cardiac output [46], [47]. In malignant
hypertensive patients captopril was very effec-
tive during acute and long-term treatment [48].
Antihypertensives 7
The hypotensive responses are not usually ac-
companied by a reflex increase in heart rate. Cap-
topril facilitates the reflex slowing of heart rate
in some manner [38]. This could involve the re-
moval of facilitatory effects of angiotensin II on
sympathetic nervous transmission to the heart
or a central inhibitory effect of angiotensin II on
cardiac vagal tone [49]. Further studies have also
indicated that captopril possesses cardioprotec-
tive properties [50].
Captopril decreases renal vascular resistance,
and increases sodium and water excretion [51],
[52].
Renin levels are increased and aldosterone
levels are reduced by captopril. A certain num-
ber of patients with essential hypertension ex-
hibit a subnormal aldosterone secretory re-
sponse to angiotensin II challenge [53]. The ab-
normal responders also exhibit higher baseline
plasma angiotensin II and lower levels of aldos-
terone. Captopril treatment for 72 h removed the
difference in baseline values and partially cor-
rected the abnormal aldosterone response to an-
giotensin II.
The absorption of captopril in humans is rapid
and extensive; 75 % of the radioactivity after
a single oral dose of 14 C-captopril was recov-
ered in the urine within 48 h. The metabolites
of captopril include disulfides and endogenous
sulfhydryl compounds, e.g., cysteine.
The side effects of captopril include protein-
uria, maculopapular rash, itch, disturbance of
taste, and occasional leukopenia [54].
3.2. Enalapril
Enalapril [75847-73-3], 1-[N-[1-(ethoxy-
carbonyl)-3-phenylpropyl]-l-alanyl]-l-proline,
C20 H28 N2 O5 , M r 376.45, mp 143 – 144.5 ◦ C,
is a white to off-white crystalline powder, sol-
uble in methanol and slightly soluble in water.
Unlike captopril, enalapril does not contain the
sulfhydryl moiety which has been implicated in
some adverse side effects, such as rash and loss
of taste.
8 Antihypertensives
Enalapril is readily absorbed by oral admin-
istration while the active diacid form is poorly
absorbed. Deesterification of the prodrug takes
place primarily in the liver [55]. Enalapril is
about 17-fold more potent than captopril for in-
hibition of hog plasma ACE. In both rats and
dogs, enalapril inhibits the pressor responses to
angiotensin I for approximately 6 h. Although
the onset of action is somewhat slower, the po-
tency of enalapril in vivo is about 4 – 8 fold
greater than that of captopril in the same species
[56].
Similar to captopril, the antihypertensive ac-
tion of enalapril is most pronounced in high-
renin forms of hypertension and enalapril also
exhibits antihypertensive activity in low-renin
models [57].
In clinical studies, enalapril effectively low-
ers arterial pressure when given as sole therapy
or in combination with diuretics [58–60]. Simi-
lar to preclinical studies, the onset of inhibition
of ACE in humans is slower than with capto-
pril. This finding has been attributed to the time
needed for the deesterification reaction [61].
Reflex tachycardia is seldom observed with
enalapril [62], [63]. Cardiac function is well-
maintained [62], [64] and, in one group of hy-
pertensive patients, the left ventricular mass was
reduced during therapy [62].
With regard to renal function, enalapril in-
creases sodium excretion, glomerular filtration
rate, and renal blood flow in sodium-restricted
dogs [55]. In spontaneously hypertensive rats
(SHR), antihypertensive doses of enalapril do
not cause sodium and water retention upon
chronic administration [65]. Renal vasodilata-
tion and natriuresis have been observed in hy-
pertensive patients treated with enalapril [62],
[63].
Hormonal responses during acute and
chronic (3 months) enalapril treatment consist
of decreased angiotensin II and aldosterone lev-
els and a rise in plasma renin activity. In addi-
tion, bradykinin and PGE2 were unchanged by a
single dose of enalapril [63], [66]. Epinephrine
levels were consistently decreased by enalapril,
whereas, in hypertensive patients during chronic
therapy with enalapril, plasma norepinephrine
was reduced insignificantly [62]. In normoten-
sive subjects, the direction of change in nor-
epinephrine levels was dependent on the sodium
intake [66], [67].
The mechanism of action of enalapril remains
to be fully elucidated. The dominant mechanism
most certainly involves the renin –angiotensin
system; however, additional mechanisms must
also be considered.
The major toxicological findings in dogs
were renal functional changes, and renal tubu-
lar degeneration. Toxic actions of enalapril are
exacerbated by coadministration of hydrochlo-
rothiazide and attenuated by saline supplements
[55]. In humans the major side effects include
rash, angioedema, proteinuria, and renal insuf-
ficiency [54].
4. Inhibitors of the Sympathetic
Nervous System
4.1. Drugs with Primarily Central
Actions
Some of the widely used antihypertensive drugs
are thought to lower arterial pressure by centrally
induced blockade of sympathetic tone and con-
sequent reduction of peripheral vascular resis-
tance. The central control of the sympathetic ner-
vous system is mediated by various neurotrans-
mitters, including norepinephrine, and by drugs
which enhance norepinephrine release or stim-
ulate postsynaptic α-adrenoceptors involved in
the regulation of sympathetic tone. The 5HT
agonists, dopaminergic, or GABA ergic drugs,
were also shown or are assumed to control hy-
pertension by a central action. It is presently not
clear whether their effects are mediated through
central inhibition of the sympathetic nervous
system or by other central mechanisms.
The major goal in the development of new
centrally acting drugs is to achieve a high degree
of selectivity for blood pressure control, which
would lead to antihypertensive action without
sedative, skeletal muscle relaxant, or emetic side
effects. For further details on the central control
of arterial pressure by drugs see reviews [68],
[69].
 Antihypertensives 9

4.1.1. Methyldopa ca. 300 ◦ C, pK a 8.2, is easily soluble in wa-

ter (1 g/13 mL) and ethanol (1 g/25 mL).
Trade names: Catapres, Catapressan.
Clonidine is an α-adrenoceptor stimu-
lant, which stimulates preferentially α2 -adren-
oceptors [81], [82]. The stimulation of central
α-adrenoceptors by clonidine leads to inhibition
The antihypertensive activity of methyldopa
of central sympathetic tone, resulting in a lower-
[555-30-6], 3-hydroxy-α-methyl-l-tyrosine,
ing of arterial pressure and of heart rate [83–87].
C10 H13 NO4 , M r 211.21, was first attributed
Clonidine has many other pharmacological
to the inhibition of aromatic amino acid de-
effects. The most prominent central effect of
carboxylase [70] and later to a formation of a
clonidine is sedation. Clonidine decreases spon-
“false transmitter” [71], [72]. It is postulated that
taneous motor activity and produces ataxia and
α-methylnorepinephrine, a methyldopa metabo-
catatonia as well as signs of increased periph-
lite, lowers arterial pressure by stimulating cen-
eral sympathetic activity in animals, i.e., pilo-
tral adrenoceptors, which causes a reduction in
erection and exophthalmus [88]. Clonidine has
sympathetic nervous outflow [73], [74].
antinociceptive activity in mice [89] and is ef-
The antihypertensive effect of methyldopa in
fective in the management of withdrawal reac-
humans is associated with a reduction in the pe-
tion in opiate addicts [90]. Intraocular pressure is
ripheral vascular resistance and in the plasma
decreased by clonidine [91]. Clonidine reduces
renin activity [74–76]. Methyldopa increases
salivary secretion and has a biphasic effect on
coronary and cerebral blood flow [77], [78].
gastric secretion: inhibition at lower and stimu-
The oral absorption of methyldopa in humans
lation at higher doses [88], [92]. In rats and dogs
was reported to vary from 26 to 74 % [79].
clonidine has a diuretic effect which appears to
The peak plasma levels of methyldopa are ob-
be mediated by inhibition of ADH release [93].
served 3 – 6 h after oral dose. The major urinary
Clonidine is almost completely absorbed by
metabolites of methyldopa are methyldopa-o-
oral administration; its bioavailability in hu-
sulfate and 3-methoxymethyldopa. About 80 to
mans is ca. 75 % and the drug has no extensive
90 % of the oral dose of methyldopa is elimi-
first-pass metabolism [94]. In humans ca. 50 %
nated within 48 h after treatment [80].
of clonidine is excreted unchanged. The major
The initial dose of methyldopa in mild hyper-
metabolites of clonidine are p-hydroxyclonidine
tension is 250 mg t.i.d. (3 times/d), whereas in
and dichlorophenylguanidine [84].
severe hypertension methyldopa is used at doses
The major undesirable effect of clonidine is
up to 500 mg q.i.d. (4 times/d). The clinical ad-
the withdrawal reaction, which consists of a sud-
vantages of methyldopa include its effectiveness
den rise in arterial pressure, nervousness, agi-
in controlling hypertension, many years of clin-
tation, and an increase in heart rate [95], [96].
ical experience, and favorable hemodynamic ef-
Other side effects include dry mouth and seda-
fects, including maintenance of renal circulation
tion.
and decrease in plasma renin activity. Side ef-
The recommended starting dose of clonidine
fects of methyldopa include sedation, positive
is 0.1 mg/d, but it should not exceed a total daily
direct Coomb’s test, hepatotoxicity, and allergic
dose of 1 mg. The pharmacology of clonidine is
reactions.
reviewed extensively elsewhere [84].

4.1.2. Clonidine 4.1.3. Guanfacine

Clonidine [4205-90-7], 2-(2,6-dichloroanilino)- Guanfacine [29110-47-2], N-amidino-2-(2,6-

2-imidazoline, C9 H9 Cl2 N3 , M r 230.10, mp dichlorophenyl)acetamide, C9 H9 Cl2 N3 O, M r
10 Antihypertensives
246.08, mp 214 – 218 ◦ C, is water soluble with
a pK a of 7.1. Guanfacine is one of the most
potent members of a class of antihypertensive
phenylacylguanidines [97].
Trade names: Estulic, Estuline.
Guanfacine is similar to clonidine in that
the mechanism of antihypertensive action is at-
tributed largely to stimulation of central adreno-
ceptors [98], [99]. Guanfacine is claimed to dif-
fer from clonidine in having less depressant ef-
fect on the central nervous system (CNS) and
possibly may act at a different site within the
CNS [100], [101]. Like clonidine, guanfacine
exhibits a peripheral vasoconstrictor effect that
is mediated most likely by stimulation of α2 -
adrenoceptors. Guanfacine is rapidly absorbed
following oral administration with a bioavail-
ability of 100 %. The half-life is approximately
21 h after oral dosing. The major metabolite in
humans is the 3-hydroxy derivative of guan-
facine [100].
Dryness of mouth and sedation are the major
side effects of guanfacine in the clinic. The inci-
dence of side effects declines considerably with
the duration of treatment. The withdrawal syn-
drome (rise in blood pressure and tachycardia)
was seen after abrupt discontinuation of guan-
facine in 2 – 4 % of the patients, but was less
pronounced than after withdrawal of clonidine.
The average dose of guanfacine in clinical trials
was 3 mg/d. The optimal effect without side ef-
fects was obtained at a single dose of 2 mg [100],
[102], [103].
4.1.4. Guanabenz
Guanabenz [5051-62-7], 2-[(2,6-dichloro-
phenyl)methylene]hydrazinecarboximidamide,
[(2,6-dichlorobenzylidene)amino]guanidine,
C8 H8 Cl2 N4 , M r 231.07, mp 227 – 229 ◦ C.
Trade names: Rexitene, Wytensin.
Like clonidine or guanfacine, guanabenz
stimulates central α-adrenoceptors and lowers
arterial pressure [104–108]. In hypertensive pa-
tients oral administration of guanabenz lowers
arterial pressure and total peripheral vascular re-
sistance with little or no effect on myocardial
function.
In animals or humans guanabenz has no ad-
verse effects on renal function except a slight and
transient fall in filtration rate after the first dose
[109], [110]. Under certain conditions guana-
benz increased excretion of water, and this effect
was attributed to the antagonism of vasopressin
[111].
In humans guanabenz is well absorbed and
exhibits a variable half-life of 7 – 10 h. Less
than 1 % of the dose is excreted as unchanged
drug. The major metabolites of guanabenz in
rat, swine, Rhesus monkeys, and humans are p-
hydroxyguanabenz and the glucuronide conju-
gate [110], [112]. Clinical studies demonstrated
antihypertensive efficacy of guanabenz at doses
from 16 to 65 mg/d [113], [114]. The most com-
mon side effects of guanabenz are dry mouth,
sedation, weakness, and tiredness.
4.2. Drugs with Primarily Peripheral
Action
Drugs can inhibit sympathetic transmission at
various peripheral sites: (1) sympathetic ganglia,
(2) sympathetic nerve endings, or (3) postsynap-
tic adrenoceptors. Ganglionic blocking drugs
were used in the treatment of hypertension 20
to 30 years ago. Hexamethonium [60-26-4], a
standard ganglionic blocking drug, is still used
today as a tool in experimental pharmacology.
Typical ganglionic blocking drugs (e.g., pen-
tolinium, chlorisondamine, mecamylamine, and
pempidine) block nicotinic receptors at the post-
synaptic membrane of the sympathetic ganglia
and prevent acetylcholine-induced depolariza-
tion. However, they are obsolete in the treat-
ment of hypertension because of unacceptable
side effects, which include atony of the gastroin-
testinal tract, inhibition of gastric and salivary
secretion, incomplete emptying of the urinary
bladder, cycloplegia, and impotence. These side
effects are to a great extent due to the blockade
of parasympathetic ganglia. Blockade of sympa-
thetic ganglia can lead to additional side effects,
e.g., postural hypotension, syncope, and inhibi-
tion of local vasomotor reflexes. Today the only
indication remaining for ganglionic blockade is
to produce so-called “controlled hypotension”

in surgery in order to reduce bleeding, facili-
tate small vessel surgery, and improve myocar-
dial performance by reducing preload and after-
load. For this indication, trimethaphan camsy-
late [68-91-7] (Arfonad) by infusion is the drug
of choice. Its short duration of action permits
precise control of blood pressure during infu-
sion and blood pressure returns to control levels
immediately after discontinuation of the infu-
sion.
The search for new ganglionic blocking drugs
was largely discontinued by 1960. It became
clear that hypertension could be controlled by
drugs relatively free from the disabling effects
accompanying ganglionic blockade. The drugs
which replaced the ganglionic blocking agents
included diuretics and drugs which inhibited the
sympathetic nervous system at loci peripheral to
the ganglia; namely, at adrenergic nerve endings
or at postsynaptic adrenoceptor sites.
4.2.1. Amine Depleting and Adrenergic
Neuron Blocking Agents
At the sympathetic nerve endings drugs can
decrease neurotransmitter (norepinephrine) re-
lease by depleting it from the storage sites in
the nerve terminals or by decreasing the re-
lease by stimulation of inhibitory presynaptic
α2 -adrenoceptors.
Antihypertensive drugs which lower arterial
pressure primarily by an action at the sym-
pathetic nerve endings include reserpine and
guanethidine, which are discussed in this sec-
tion. Other drugs which act by a mechanism sim-
ilar to that of guanethidine and are marketed in
some countries include: bethanidine, guanadrel,
debrisoquin, guanacline, and guanochlor. They
differ from guanethidine in potency, pharma-
cokinetics, and some aspects of their pharmacol-
ogy. The mechanism of their antihypertensive
action and the profile of their side effects are,
however, not essentially different from those of
guanethidine. Orthostatic hypotension is the ma-
jor side effect which restricts their therapeutic
usefulness.
Antihypertensives 11
4.2.1.1. Reserpine
Reserpine [50-55-5], 11,17-dimethoxy-18-
[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-
carboxylic acid methyl ester, C33 H40 N2 O9 , M r
608.70, mp 264 – 265 ◦ C (decomp.), is poorly
soluble in water, but is soluble in alcohol, glacial
acetic acid, and chloroform. Reserpine was orig-
inally isolated from roots of Rauwolfia ser-
pentina L. Benth [115].
Synthesis: [116].
Trade names: Alserin, Reserpex, Serpasil.
Reserpine depletes the transmitters from
adrenergic, dopaminergic, and serotonergic neu-
rons. Depletion of norepinephrine from adren-
ergic nerve endings is thought to be primarily
responsible for the antihypertensive action of re-
serpine. The onset of the antihypertensive action
is gradual. The maximal effect is seen 6 – 12 h
after a single dose of reserpine. The antihyper-
tensive effect is associated with a reduction in
cardiac output and in peripheral vascular resis-
tance. After repeated administration cardiac out-
put returns to control values, while peripheral
resistance remains at a reduced level [117–119].
Reserpine is well absorbed by oral adminis-
tration. The major metabolites of reserpine are
products of hydrolytic cleavage: methyl reser-
pate and trimethoxybenzoic acid. Urinary excre-
tion of reserpine metabolites accounts for 20 –
40 % of the administered doses and fecal excre-
tion for less than 10 % [120], [121].
The major side effects of reserpine are seda-
tion, nasal stuffiness, and a depressive reaction.
Reserpine is also known to increase prolactin re-
lease. Adrenocorticotrophic hormone (ACTH)
secretion is initially increased and subsequently
abolished by reserpine. Gastric secretion is in-
creased and formation of gastric ulcers is pro-
moted. The initial dose of reserpine utilized in
hypertension is 0.12 – 1.0 mg/d and the mainte-
nance dose is 0.25 mg or less. The use of reser-
pine alone has decreased because of the avail-
ability of drugs with less severe side effects. In
12 Antihypertensives
combination with thiazide diuretics reserpine is,
however, still widely used.
4.2.1.2. Guanethidine
Guanethidine [55-65-2], [2-(hexahydro-1(-
2H)-azocinyl)ethyl]guanidine, C10 H22 N4 , M r
198.31, mp 276 – 281 ◦ C.
Trade names: (sulfate salt) Ismelin, Guethi-
ne, Iporal, Isobarin.
The major pharmacological action of
guanethidine is inhibition of release and of
uptake of norepinephrine by sympathetic
nerve endings [122–125]. After treatment with
guanethidine, vasoconstrictor nerves do not
provide reflex compensation to the erect po-
sition. Thus, the hypotension after guanethidine
is largely orthostatically induced, which can
lead to undesirable effects, such as dizziness
and syncope. In addition to its adrenergic neu-
ron blocking action, guanethidine has also a
direct vasodilator activity, the mechanism of
which may involve stimulation of vascular β-
adrenoceptors [123], [126]. The hypotensive
action of guanethidine can be antagonized by
amphetamine, ephedrine, cocaine, or by tricyclic
antidepressants [123], [127].
By acute intravenous administrations to ani-
mals or humans, guanethidine produces a tran-
sient increase in arterial pressure which is fol-
lowed by hypotension. Peripheral vascular re-
sistance is not changed, while cardiac output
is decreased [128], [129]. In chronic oral ther-
apy guanethidine does not change cardiac output
[130].
Guanethidine is not completely absorbed
from the gastrointestinal tract, with 20 – 25 %
of oral dose being recovered from the fe-
ces [131]. 2-(6-Carboxyhexylamino)ethylguan-
idine and guanethidine N-oxide have been iden-
tified as metabolites of guanethidine [132],
[133]. Guanethidine is given once a day at doses
ranging from 12.5 to 150 up to 400 mg/d. The
doses are adjusted by 10 or 25 mg at 2-week in-
tervals. In addition to orthostatic hypotension,
side effects of guanethidine include water reten-
tion, failure of ejaculation, diarrhea, tenderness
in the region of parotid glands, and muscle weak-
ness.
4.2.2. α-Adrenoceptor Antagonists
α-Adrenoceptor antagonists, e.g., phentol-
amine, tolazoline, or yohimbine, were known for
many years [134], but were not used in the treat-
ment of hypertension, because of their question-
able effectiveness, rapid development of toler-
ance, and pronounced reflex tachycardia. The in-
troduction of prazosin [135], [136] and demon-
stration of its usefulness in the treatment of hy-
pertension resulted in the development of vari-
ous new α-adrenoceptor antagonists. The selec-
tive α1 -adrenoceptor antagonists are more ef-
fective in hypertension than antagonists affect-
ing both α1 - and α2 -adrenoceptors. The reduced
effectiveness is most likely due to an inhibi-
tion of presynaptic α2 -adrenoceptor by nonse-
lective antagonists. This leads to an increase in
neurotransmitter release and consequent tachy-
cardia and vasoconstriction, which oppose the
hypotensive effects of the drugs as a result of
blockade of postsynaptic α1 -adrenoceptors. The
three drugs discussed here are relatively selec-
tive α1 adrenoceptor antagonists.
4.2.2.1. Prazosin
Prazosin [19216-56-9], 1-(4-amino-6,7-di-
methoxy-2-quinazolinyl)-4-(2-furanylcarbon-
yl)piperazine, C19 H21 N5 O4 , M r 382.42, mp
278 – 280 ◦ C, is water soluble.
Trade names: Minipress, Hypovase, Sine-
tens.
The blockade of α1 -adrenoceptors represents
the major mechanism of antihypertensive action
of prazosin [135–139]. The α1 -adrenoceptor an-
tagonist action of prazosin leads to arterial and
venous dilatation, a reduction in preload and af-
terload, and, consequently, to an improvement
in cardiac efficiency. Because of the indirect im-
provement in cardiac function, prazosin is also

useful in the therapy of heart failure [140]. In
spite of pronounced vasodilatation, heart rate un-
dergoes no change or only a slight increase after
prazosin [138].
A consistent decrease in peripheral vascular
resistance differentiates prazosin from methyl-
dopa, clonidine or β-adrenoceptor antagonists.
In spite of pronounced vasodilator action, pra-
zosin in patients either decreases or has no effect
on plasma renin activity [141], [142]. The peak
plasma concentration of prazosin is reached
2 – 3 h after an oral dose and its half-life is 3.9 h
[143]. The major metabolites of prazosin in rats,
dogs, and humans are 6-O- and 7-O-demethyl-
prazosin. Other minor metabolites have been
identified [144], [145].
The antihypertensive activity of prazosin is
comparable to, or better than, that of methyldopa
[146], hydralazine [147], or clonidine [148].
Prazosin is successfully used in combination
with thiazide diuretics [149] or β-adrenoceptor
antagonists [150].
The major side effect of prazosin is the so-
called “first dose phenomenon”, a syncope in
patients receiving a 2-mg tablet as the first dose
[151]. The syncope can be avoided if the ini-
tial dose is reduced to 0.5 mg and given at bed-
time. The dose can then be increased gradually
over a 2-week period. Other reported side effects
include an increase in the frequency of urina-
tion and in the frequency of anginal attacks. The
usual dose of prazosin is 2 mg three times a day,
but the drug was used at total daily doses up to
20 mg.
4.2.2.2. Indoramin
Indoramin [26844-12-2], N-[1-[2-(1H-
indol-3-yl)ethyl]-4-piperidinyl]benzamide,
C22 H25 N3 O, M r 347.46, mp 208 – 210 ◦ C. The
synthesis and pharmacological activity of indo-
ramin have been described [152–154].
Trade name: (hydrochloride salt) Baratol.
The mechanism of antihypertensive action of
indoramin involves primarily the blockade of
Antihypertensives 13
α1 -adrenoceptors. It is a competitive antagonist
of norepinephrine and a noncompetitive antag-
onist of 5-HT and histamine. At doses higher
than required for lowering of arterial pressure
(5 vs. 1 mg/kg, i.v. in cats) indoramin reduces
sympathetic nerve activity apparently by a cen-
tral action [154–157]. Other pharmacological ef-
fects of indoramin include local anesthetic and
antiarrhythmic effects [158], [159].
Indoramin is well absorbed orally. Its mean
half-life in humans was estimated to be 5.5 h
[160]. The metabolism of indoramin is exten-
sive. The major human metabolite was identified
as a conjugate of 6-hydroxyindoramin [161].
Extensive clinical studies have been con-
ducted with indoramin [162–164]. Indoramin
is effective in the treatment of hypertension
at doses ranging from 20 to 150 mg/d. The
major side effect is sedation. Indoramin does
not produce the “rebound” phenomenon after
discontinuation of therapy, nor syncope fol-
lowing the first dose. In addition to its anti-
hypertensive action, indoramin was reported to
produce therapeutic benefits in headache and
bronchial asthma.
4.2.2.3. Urapidil
Urapidil [34661-75-1], 6-({3-[4-(2-meth-
oxyphenyl)-1-piperazinyl]propyl}amino)-
1,3-dimethyl-2,4(1H,3H)-pyrimidine-dione,
C20 H29 N5 O3 , M r 387.49, mp 156 – 158 ◦ C, is
poorly soluble in water, but readily soluble in
dilute acids.
Synthesis: [165].
Trade name: Ebrantil.
Urapidil lowers arterial pressure in hyperten-
sive and normotensive animals. Its antihyper-
tensive activity is due to a combination of pe-
ripheral and central actions. The peripheral ac-
tion involves blockade of α1 -adrenoceptors in
vascular smooth muscle. By virtue of its central
action urapidil diminishes sympathetic outflow,
an effect which is probably mediated by central
14 Antihypertensives
α-adrenoceptors and is essentially similar to that
of clonidine [166], [167].
Urapidil is well absorbed orally. The maxi-
mal blood levels are reached after 0.5 – 1 h after
oral administration of tablets and 2.5 – 4 h af-
ter administration of slow-release capsules. The
plasma half-life of urapidil in humans was esti-
mated as 2.5 – 3.7 h. Urapidil is metabolized by
p-hydroxylation, O-demethylation of the meth-
oxyphenyl ring, and N 1 -demethylation of the
uracil residue. The same metabolites are found
in humans, dogs, rats, and mice. The p-hydroxyl-
ation product has antihypertensive activity but is
less potent than urapidil [167], [168].
In animals, urapidil exhibits sedative activ-
ity, while in humans, the major side effects in-
clude dizziness, headache, and nausea. In the
treatment of hypertension, urapidil is effective
at 30 – 90 mg/d given as slow-release capsules
[167], [169].
4.2.3. β-Adrenoceptor Antagonists
β-Adrenoceptor antagonists were introduced
in the treatment of hypertension on the basis
of clinical observations that pronethalol, one
of the first β-adrenoceptor antagonists, low-
ered arterial pressure in patients with angina
pectoris [170]. The mechanism of antihyper-
tensive action of β-adrenoceptor blocking drugs
is still controversial. Various hypotheses have
been critically reviewed [171]. Presently, re-
setting of baroreceptors and the inhibition of
sympathetic transmission by blockade of pre-
synaptic β-adrenoceptors are considered the
most likely mechanisms of antihypertensive ac-
tion, although lowering of plasma renin ac-
tivity and a decrease in cardiac output by β-
adrenoceptor antagonists may play a contribu-
tory role, particularly in the initial phase of ther-
apy.
β-Adrenoceptor antagonists differ in po-
tency, cardiac selectivity, intrinsic sympath-
omimetic activity (ISA), membrane stabilizing
action (MSA), duration of action, tissue distri-
bution, and metabolism.
A large number of β-adrenoceptor antago-
nists were developed and marketed during the
last decade. The seven drugs discussed are more
commonly used and represent different sub-
groups among β-adrenoceptor antagonists.
4.2.3.1. Propranolol
Propranolol [525-66-6], 1-(isopropylamino)-
3-(1-naphthyloxy)-2-propanol, C16 H21 NO2 ,
M r 259.34, pK a 9.5, is moderately soluble in wa-
ter and in ethanol. It is the most commonly used
β-adrenoceptor antagonist. The β-adrenoceptor
blocking and the antihypertensive activities re-
side in the (+)-isomer [172].
Trade names: Inderal, Inderex, Docitor,
Tesnol, and many others.
Propranolol is not cardioselective; β 1 - as
well as β 2 -adrenoceptors are blocked by the
drug. Propranolol has MSA but no ISA. β 2 -
Adrenoceptor blocking activity can lead to
bronchoconstriction and propranolol is, there-
fore, contraindicated in patients with bronchial
asthma. The MSA of propranolol is correlated
with local anesthetic as well as with the car-
diac depressant actions. At therapeutic doses the
MSA of propranolol is not prominent. The neg-
ative dromotropic activity of propranolol is ev-
ident following acute as well as chronic admin-
istration of the drug and is not opposed by the
ISA [173], [174].
Following acute intravenous administration
to animals or humans, propranolol reduces car-
diac output, mean arterial pressure, heart work,
left ventricular dp/dt, and blood flow in most
vascular beds. Total peripheral vascular resis-
tance is first increased but may be reduced during
chronic therapy. Plasma renin activity is consis-
tently reduced by the drug.
Propranolol is nearly completely absorbed
from the gastrointestinal tract but is a subject
of a large first-pass effect [175]. Peak plasma
levels of propranolol are seen within 1 – 3 h af-
ter treatment [176]. Propranolol is extensively
metabolized; 16 metabolites or conjugates have
been identified. The major metabolites are naph-
thoxylactic acid and 4-hydroxypropranolol (an
active metabolite) [177], [178].
In the treatment of hypertension propranol-
ol is usually used at 80 – 320 mg/d in four di-
vided doses, although it was used at doses as

low as 40 mg and as high as 2 g/d. The drug
is commonly used in combination with a di-
uretic and/or a peripheral vasodilator drug [179],
[180]. The side effects of propranolol include
bradycardia, A-V heart block, cardiac insuf-
ficiency, bronchoconstriction, cold extremities,
fatigue, vivid dreams, or even hallucinations.
Rapid withdrawal of propranolol is not recom-
mended because it may lead to coronary insuf-
ficiency or myocardial infarction.
4.2.3.2. Metoprolol
Metoprolol [37350-58-6], 1-[4-(2-methoxy-
ethyl)phenoxy]-3-[(1-methylethyl)amino]-2-
propanol, C15 H25 NO3 , M r 267.38.
Trade names: Beloc, Betaloc, Lopressor, Lo-
presor.
Unlike propranolol, metoprolol is relatively
specific for β 1 -adrenoceptors and is, therefore,
relatively free from bronchoconstrictor action
[181], [182]. At therapeutic doses, metoprolol
has no MSA, and therefore, has no local anes-
thetic or direct myocardial depressant effects.
As a β 1 -adrenoceptor antagonist, metoprolol is
equipotent to propranolol [183]. Metoprolol is
well absorbed by oral administration but has
a substantial first-pass effect. Its plasma half-
life is 3 – 4 h. Metoprolol is metabolized by O-
demethylation, subsequent oxidation, oxidative
deamination, and aliphatic hydroxylation. The
two metabolites, O-demethylated product and
α-OH-metoprolol, have β 1 -adrenoceptor antag-
onist activity but are 5 times less potent than
metoprolol [184], [185].
In clinical studies, metoprolol was shown to
be equally effective as hydrochlorothiazide as an
antihypertensive agent [186] and either equiva-
lent or superior to other β-adrenoceptor antago-
nists [183]. In a double-blind study metoprolol
was shown to reduce the mortality in patients
with myocardial infarction [187].
The side effects of metoprolol include tired-
ness, headache, insomnia, nausea, heartburn,
Antihypertensives 15
and depression. Withdrawal reactions consist-
ing of headache, malaise, and palpitation were
described for metoprolol. Thus, recommenda-
tions are to withdraw metoprolol slowly over a
10-d period. The initial dose of metoprolol in the
treatment of hypertension is 50 mg twice daily.
The maximal daily dose is 450 mg.
4.2.3.3. Nadolol
Nadolol [42200-33-9], 5-[3-[(1,1-dimeth-
ylethyl)amino]-2-hydroxypropoxyl]-1,2,3,4-
tetrahydro-2,3-naphthalenediol, C17 H27 NO4 ,
M r 309.42, mp 124 – 136 ◦ C, pK a 9.67.
Trade names: Corgard, Solgol.
Like propranolol, nadolol is not cardioselec-
tive and has no ISA. Unlike propranolol, nadolol
has no MSA and, therefore, no direct cardiac de-
pressant activity. The therapeutic advantages of
nadolol include ability to increase renal blood
flow, and a long duration of action (up to 24 h)
[188–190]. The oral absorption of nadolol in hu-
mans ranges from 20 to 34 %. Serum half-life
of nadolol in humans is significantly longer than
that of other β-adrenoceptor antagonists and was
estimated to equal 24 h [191].
In the treatment of hypertension nadolol is
given once a day at 40 – 240 mg [192]. In ad-
dition to its antihypertensive effect nadolol was
shown to be effective in the treatment of angina
pectoris [193] and of certain types of ventricu-
lar arrhythmias [194]. Most of the side effects of
nadolol are similar to those of propranolol.
4.2.3.4. Pindolol
Pindolol [13523-86-9], 1-(1H-indol-4-yl-
oxy)-3-[(1-methylethyl)amino]-2-propanol,
C14 H20 N2 O2 , M r 248.32, mp 171 – 173 ◦ C.
16 Antihypertensives
Like propranolol, pindolol is not cardioselec-
tive, but unlike propranolol, pindolol has strong
ISA, which is responsible for its acute vasodila-
tor effect and for absence of bradycardia. The
MSA of pindolol is considerably weaker than
that of propranolol. In spite of the absence of
cardioselectivity, pindolol is less likely to impair
pulmonary function than propranolol, probably
because of its strong ISA [195], [196].
Pindolol is well absorbed by oral admin-
istration and in comparison with other β-
adrenoceptor antagonists, has a lower first-pass
effect (13 %) [197]. The plasma half-life of pin-
dolol is 3 – 4 h and the maximal plasma levels
are reached 1.5 – 2 h after oral administration to
humans [198]. It has a more rapid onset of ac-
tion than propranolol and after withdrawal has
a longer carryover effect [199–201]. The dose
range of pindolol in the treatment of hyperten-
sion is 10 – 30 mg/d. The drug was initially ad-
ministered t.i.d. but subsequently the majority
of patients were found to respond equally well
to once-a-day therapy [202].
The side effects of pindolol include in-
somnia and vivid dreams. Heart failure, heart
block, bronchoconstriction, and circulatory dis-
turbances are rare with pindolol.
4.2.3.5. Timolol
Timolol [26839-75-8], 1-[(1,1-dimethyl-
ethyl)amino]-3-{[4-morpholinyl-1,2,5-thiadi-
azol-3-yl]oxy}-2-propanol, C13 H24 N4 O3 S, M r
316.42, is supplied as the hydrogen maleate salt,
C17 H28 N4 O7 S, M r 432.5, mp 201.5 – 202.5 ◦ C,
which is soluble in water and ethanol and is
less lipophilic than propranolol. Unlike other
β-adrenoceptor antagonists, timolol is available
as the (−)-isomer and not as a racemic mixture.
Trade names: (hydrogen maleate salt) MK-
950, Betim, Blocadren, Temserin, Timacor,
Timolate, Timoptic, Timoptol.
Like propranolol, timolol is not cardioselec-
tive and has no ISA. At therapeutic doses timolol
has little or no MSA and has practically no local
anesthetic action. As a β-adrenoceptor antago-
nist timolol is ca. 8 times more potent than prop-
ranolol. As a negative inotropic agent timolol is
40 times less potent than propranolol [203–205].
Timolol is rapidly absorbed by oral admin-
istration with 72 % of the dose excreted within
84 h. The plasma half-life of timolol in humans
was estimated as 5.5 h [206]. Five metabolites of
timolol were identified in humans [205]. They
have little or no β-adrenoceptor blocking activ-
ity.
The clinical study in essential hypertension
indicated that timolol at 30 mg and propranol-
ol at 120 mg had comparable antihypertensive
activity [207]. Timolol is used in the treatment
of hypertension at 10 – 30 mg/d. In patients sur-
viving after acute myocardial infarction, timolol
was shown to reduce mortality and reinfarction
rates [208]. The side effects of timolol include
tiredness, dizziness, increase in body mass, and
an occasional increase in serum urea and creati-
nine.
4.2.3.6. Acebutolol
Acebutolol [37517-30-9], N-(3-acetyl-4-{2-
hydroxy-3-[(1-methylethyl)amino]propoxy}-
phenyl)butanamide, C18 H28 N2 O4 , M r 336.43,
mp 128 – 129 ◦ C. Its synthesis and pharma-
cological activity were first described by
Wooldridge [209].
Trade names: Sectral, Neptall, Prent.
Unlike propranolol, acebutolol is cardiose-
lective and has weak ISA and MSA [210–214].
The major metabolite of acebutolol is diace-
tolol, RS-1-(2-acetyl-4-acetyl-amidophenoxy)-
2-hydroxy-3-isopropylaminopropane), which
has β-adrenoceptor blocking actions similar to
those of acebutolol, but has no MSA [215]. The
half-life of acebutolol and its metabolite is ca.
4 h. Acebutolol is metabolized in humans al-
most exclusively to diacetolol, 40 % of which is
excreted unchanged [213].
The antihypertensive effect of acebutolol is
more pronounced in severe than in mild hy-
pertension [216] and was confirmed in numer-

ous controlled trials [217], [218]. In hyperten-
sion acebutolol is given once or twice daily at
doses ranging from 200 to 1200 mg/d. Side ef-
fects of acebutolol include blurred vision, bron-
chospasm, and bradycardia.
4.2.3.7. Labetalol
Labetalol [36894-69-6], 2-hydroxy-5-{1-
hydroxy-2-[(1-methyl-3-phenylpropyl)amino]-
ethyl}benzamide, C19 H24 N2 O3 , M r 328.41; the
hydrochloride salt, C19 H25 ClN2 O3 , is soluble
in water and ethanol. Labetalol has two asym-
metric centers and exists as a mixture of four
isomers in equal proportions.
Trade names: (hydrochloride salt) Presdate,
Trandate.
Labetalol differs from other β-adrenoceptor
antagonists in its ability to block not only β-
but also α-adrenoceptors, although it is more
potent in blocking β-adrenoceptors. As a β-
adrenoceptor antagonist, labetalol is not car-
dioselective, has weak ISA, but has clearly de-
tectable MSA. As an α-adrenoceptor antago-
nist, labetalol is selective for α1 -adrenoceptors.
Because of its α1 -adrenoceptor blocking activ-
ity labetalol decreases peripheral vascular re-
sistance, particularly at higher doses. The anti-
hypertensive activity of labetalol is likely to be
due to α- as well as β-adrenoceptor blocking
effects [219–221].
Following oral administration labetalol is
well absorbed and excreted in the form of glu-
curonide conjugates. The major metabolite is
the alcoholic glucuronide of labetalol [221].
Plasma labetalol levels are well correlated with
its pharmacological actions [222]. Labetalol ex-
periences high first-pass metabolism [223].
Extensive clinical studies with labetalol were
published [224–226]. In humans labetalol low-
ers arterial pressure without any significant ef-
fect on resting heart rate or on cardiac output. It
is used in hypertension at 200 – 2000 mg/d, usu-
ally in two divided doses. Side effects of labetalol
include tiredness, dizziness, gastrointestinal dis-
Antihypertensives 17
turbances, postural hypotension, impotence, and
scalp tingling.
5. Smooth Muscle Relaxants
5.1. Ca2+ Channel Antagonists
The Ca2+ channel antagonists are a group
of vasodilators used extensively in the treat-
ment of angina pectoris (→ Calcium Antago-
nists, p. 519 ff.). However, their vasodilatory ac-
tions extend also to vascular beds other than the
coronary and, consequently, their usefulness in
hypertension has become apparent. The group
classification emanates from the fact that these
agents potently inhibit the entry of Ca2+ into
vascular smooth muscle [227–229], although
other mechanisms may contribute to their ef-
fectiveness as well [230], [231]. Considerable
chemical diversity is found in the representatives
of the Ca2+ channel antagonists [232], [233].
Nifedipine, nitrendipine, verapamil, and dilti-
azem have been studied most extensively in the
treatment of hypertension; therefore, the empha-
sis here is placed on these agents.
5.1.1. Nifedipine
Nifedipine [21829-25-4], 1,4-dihydro-2,6-
dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarb-
oxylic acid dimethyl ester, C17 H18 N2 O6 , M r
346.34, mp 172 – 174 ◦ C, is a yellow crystalline
compound, practically insoluble in water, but
soluble in organic solvents, such as ethanol,
polyethylene glycol, and chloroform. In solu-
tion, it decomposes quite rapidly under normal
laboratory light.
Trade names: BAY a 1040, Adalat, Procar-
dia, Duranifin, Pidilat.
The structure – activity requirements are re-
ported for several muscle systems, including
vascular, cardiac, and nonvascular smooth mus-
cle (see reviews [230], [234] ). Specific require-
ments are the following: (1) the 1,4-dihydro-
18 Antihypertensives
pyridine (DHP) ring is essential; (2) an unsub-
stituted NH-group on the DHP-ring; (3) 2,6-
substituents on the DHP-ring should be lower
alkyl substituents, but an NH2 group is accept-
able; (4) ester groups in the 3- and 5-positions of
the DHP-ring can be substituted to change the
vascular selectivity and duration of action; (5)
ester groups longer than COOMe will increase
activity; (6) the aryl substituent (i.e., phenyl
ring) is optimal in the 4-position of the DHP-
ring; (7) position of the substituent on the phenyl
ring is critical, i.e., para results in decreased ac-
tivity, while ortho or meta result in increased ac-
tivity; (8) stereoselectivity is obtained by differ-
ent ester substitutions on C-3 and C-5 of DHP-
ring [235–237].
Nifedipine lowers blood pressure in many ex-
perimental models of hypertension [238], [239].
It is efficacious in mild to moderate essentially
hypertensive patients [240], [241] and in patients
exhibiting severe hypertension [242], [243]. Fol-
lowing oral administration, the antihypertensive
responses are rapid in onset (30 – 60 min), with a
duration of about 3 h. Nifedipine exhibits dimin-
ished activity in normotensive subjects in com-
parison to hypertensives [240], [244–247].
The antihypertensive effect of nifedipine is
due to arterial vasodilatation and a reduced to-
tal peripheral resistance [240], [244], [248–252].
Compensatory increases in heart rate, plasma
norepinephrine, and renin levels are found after
single doses of nifedipine; however, these eleva-
tions usually subside during long-term therapy
[253–256].
Combined therapy of nifedipine with the β-
adrenoceptor antagonists, propranolol or meto-
prolol, slightly enhanced the antihypertensive
response in humans [240], [255]. The addition of
methyldopa to nifedipine in severely hyperten-
sive patients increased the antihypertensive re-
sponse and reduced blood pressure fluctuations
between dosing [242].
Sodium and water retention are not a prob-
lem during nifedipine treatment. Urinary vol-
ume and sodium excretion are elevated in hy-
pertensive patients during nifedipine treatment
[257], [258]. Should volume retention occur it
can be controlled by diuretic therapy [241].
Nifedipine is bound extensively to plasma
proteins (> 90 %) [259], [260]. The plasma
concentration of nifedipine correlates well
to the hemodynamic responses [261], [262].
Metabolism occurs primarily in the liver, with
the majority being excreted in the urine and fe-
ces as polar metabolites [260], [263].
The adverse reactions during therapy include
headache, flushing, and nausea. In some pa-
tients, a localized ankle edema has been ob-
served, which may be attributed to a change
in capillary permeability or perfusion pressure
[264]. The oral dosage form is presently ap-
proved for use in angina pectoris.
5.1.2. Nitrendipine
Nitrendipine [39562-70-4], 1,4-dihydro-2,6-
dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarb-
oxylic acid ethyl methyl ester], M r 360.4, forms
yellow crystals with solubility properties simi-
lar to nifedipine; however, nitrendipine is less
light sensitive, with a decomposition half-life of
about 7 h in laboratory light. It exhibits Ca2+
channel antagonism and produces antihyper-
tensive effects in a number of animal models.
It is more potent than nifedipine on vascular
strips in vitro, and has a longer duration of anti-
hypertensive action in the renal hypertensive
dog model [265–275].
Trade names: Bayotensin, Baypress.
Synthesis: [268].
In clinical studies, single or repeated daily
oral doses of nitrendipine (5 – 40 mg) effec-
tively lower arterial pressure. The onset of ac-
tion and peak effects are obtained at 15 min and
at 60 – 90 min, respectively. The duration of ac-
tion is approximately 8 h following a single oral
dose, although, with long-term therapy, blood
pressure can be controlled for up to 24 h with
one dose [276–279]. In hemodynamic studies,
nitrendipine lowered total peripheral resistance,
but did not significantly affect cardiac output
or heart rate [279], [280]. Plasma renin activ-
ity and catecholamines levels are increased by
nitrendipine, but aldosterone levels are not sig-
nificantly elevated [280].

In rats and humans, the metabolism of ni-
trendipine involves dehydrogenation, deesterifi-
cation, and hydroxylation reactions. The identi-
fied metabolites exhibit essentially no antihyper-
tensive activity [265]. Adverse reactions in hu-
mans include headache, flushing, and nausea.
5.1.3. Verapamil
Verapamil [52-53-9], α-(3-{[2-(3,4-dimeth-
oxyphenyl)ethyl]-methylamino}propyl)-3,4-
dimethoxy-α-(1-methylethyl)benzeneaceto-
nitrile, C27 H38 N2 O4 , M r 454.59, is a white
crystalline powder, soluble in water, chloro-
form, and methanol; the compound is not light
sensitive. It is a Ca2+ channel antagonist which
is unrelated chemically to nifedipine and ni-
trendipine.
Trade names: Isoptin, Calan, Cardibeltin,
Cordilox, Vasolan.
Comprehensive reviews and studies on the
pharmacology of verapamil have been published
[281–287].
In clinical studies, verapamil lowered blood
pressure in patients with essential hypertension
[288–290]. The dosage ranged between 120 to
160 mg, given three times daily. Total peripheral
resistance was decreased and cardiac output was
elevated by verapamil. Heart rate was either un-
changed or decreased during therapy. The anti-
hypertensive efficacy was directly related to pre-
treatment levels of blood pressure and inversely
related to plasma renin levels [290]. The va-
sodilator potency when given directly into the
forearm circulation was greater in hypertensive
patients in comparison with normotensive sub-
jects. In addition, the increase in forearm blood
flow correlated positively with basal concentra-
tions of plasma epinephrine but not with plasma
levels of renin or aldosterone [291]. Verapamil
fails to elevate plasma catecholamine, renin, or
aldosterone levels. The mechanism responsible
for this effect is unknown; however, possibil-
ities might involve catecholamine depletion, a
decreased neuronal norepinephrine release, or
depressed baroreceptor reflex sensitivity [292–
Antihypertensives 19
296]. Constipation is the most prevalent side ef-
fect of verapamil therapy [283].
5.1.4. Diltiazem
Diltiazem [42399-41-7], 3-(acetyloxy)-5-
[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-
methoxyphenyl)-1,5-benzothiazepin-4(5H)-
one, C22 H26 N2 O4 S, M r 414.52, is a white crys-
talline powder, freely soluble in water, methanol,
or chloroform. The chemical synthesis of dilti-
azem and related substances has been reported
[297], [298].
Trade names: Cardizem Herbesser, Dilzem.
The vasodilator structure – activity relation-
ships have been reported and summarized [299–
301]. Diltiazem is the d-cis isomer. The trans
isomeric forms exhibit much lower vasodila-
tor activity. Other substitutions which result
in lower activity include replacement of the
methoxy group with a hydroxyl group or addi-
tional alkoxy substituents on the aromatic ring.
In addition, removal of the alkyl-aminoalkyl
group at N5 will significantly reduce the activ-
ity, as will dealkylation or quaternization of the
terminal nitrogen. Other alterations, such as re-
placement of the methoxy group by a p-methyl
and chlorine substitution at the 7-position of a
condensed aromatic ring, do not reduce activity.
The antihypertensive activity of diltiazem has
been demonstrated in DOCA, renal, and sponta-
neously hypertensive rats [302–304]. Diltiazem
increased cardiac output, significantly elevated
cardiac and skeletal muscle blood flow, and pro-
duced lesser flow increases to the mesenteric,
cerebral, and renal vascular beds. Flow to the
skin is usually unchanged or reduced by dilti-
azem [301], [305–307].
In humans, diltiazem is effective in mild-to
moderate hypertension at oral doses ranging bet-
ween 180 – 270 mg/d. The reduction in blood
pressure (−10 to −15 %) was accompanied by
an increase in cardiac output. Similar to preclin-
ical studies, heart rate was not increased and
plasma catecholamines were only moderately
20 Antihypertensives
increased [308]. In another study, intravenous
diltiazem (0.2 mg/kg plus 0.1 mg/kg-min, i.v.)
dilated both arterioles and larger conduit arter-
ies in hypertensive patients. These results con-
trasted with dihydralazine which dilated arteri-
oles, but constricted larger arteries [309].
Details on the mechanism of action and other
pharmacological properties of diltiazem have
been summarized [305]. Metabolism occurs pri-
marily in the liver. Primary biotransformation
entails demethylation of the terminal nitrogen,
cleavage of the p-methoxy group, and oxida-
tive hydroxylation of the aromatic rings. The 3-
hydroxy compound is a major metabolite which
exhibits some pharmacological activity [301],
[310].
5.2. Vasodilators with Other
Mechanisms of Action
Vasodilator drugs with a direct action on vas-
cular smooth muscle were used in the therapy
of hypertension long before the discovery of
Ca2+ channel antagonists. Among vasodilator
drugs hydralazine is the most commonly used
drug, although its precise mechanism of action
is still controversial. The common pharmacolog-
ical properties of these drugs can be summarized
as follows:
1) Their hypotensive activity is independent of
the sympathetic tone.
2) They antagonize the vasoconstrictor effects
of various endogenous substances includ-
ing norepinephrine, serotonin, angiotensin
II, and K+ .
3) Their site of action is at the membrane of
vascular smooth muscle, at the contractile
elements, or on the enzymatic processes in-
volved in the delivery of energy for the con-
tractile activity.
4) Their common side effects include tachy-
cardia, salt and water retention, myocardial
necrosis, and hyperglycemia.
5.2.1. Hydralazine
Hydralazine [86-54-4], 1-(2H)-phthalazinone
hydrazone, C8 H8 N4 , M r 160.18, mp 172 –
173 ◦ C, is a yellow crystalline substance, soluble
in acetic acid. Hydralazine has been available for
the treatment of hypertension for about 30 years.
Trade names: Apresoline HCl, Hydralazine
HCl; (combination with hydrochlorothiazide)
Apresoline-Esidrix, Apresozide, Hydrap-ES;
(with reserpine) Serpasil-Apresoline; (with hy-
drochlorothiazide plus reserpine) Ser-Ap-Es.
Hydralazine lowers arterial pressure in many
experimental models of hypertension. Certain
structure requirements are necessary for maxi-
mal activity. Among the more important require-
ments are the presence of a free NH2 group and
the placement of the hydrazino-group in the 1-
position of the phthalazine moiety for optimal
duration of action. The activity is affected mini-
mally with the substitution of a carbon in the ph-
thalazine or a pyridine replacement of the benz-
ene ring [311].
Antihypertensive actions of hydralazine re-
sult primarily from arteriolar relaxation and a
decreased peripheral resistance, with essentially
no effects on venous tone. Heart rate and car-
diac output are increased by hydralazine. The
cardiotonic action results primarily from re-
flex adjustments to the decreased arterial pres-
sure (baroreceptor reflex) [312] or quite possibly
from elevation in central venous pressure (Bain-
bridge reflex) [313]. In addition, a direct car-
diac stimulant effect has been observed in anes-
thetized dogs by some [314], but not by other
investigators [313]. The direct and reflex actions
of hydralazine are antagonized by propranolol.
Cardiac hypertrophy occurring in SHR is not at-
tenuated by hydralazine, whether given alone or
in combination with propranolol [315]. Exten-
sive pharmacological studies with hydralazine
were published [316–328].
Clinically, the antihypertensive effect of
hydralazine is enhanced by the addition of
β-adrenoceptor antagonists, reserpine, guan-
ethidine, methyldopa, clonidine, or diuretics
[329], [330]. When given in combination with
venodilators (e.g., isosorbide dinitrate or nitro-
glycerin) hydralazine has proved especially use-
ful in the treatment of congestive heart failure
[331].

5.2.2. Diazoxide
Diazoxide [364-98-7], 7-chloro-3-meth-
yl-2H-1,2,4-benzothiadicazine-1,1-dioxide,
C8 H7 ClN2 O2 S, M r 230.70, mp 330 – 331 ◦ C, is
chemically related to chlorothiazide and other
benzothiadiazine diuretics, but it exhibits no
diuretic activity. It is an effective antihyper-
tensive agent in spontaneous, DOCA, and re-
nal hypertensive rat models [332], [333]. Anti-
hypertensive doses of diazoxide, when given
intravenously, range between 2 and 10 mg/kg in
animal studies. The duration of action is dose-
related and ranges between 0.5 – 4 h.
Trade name: Hyperstat I.V.
When given intravenously, diazoxide reduces
total peripheral resistance and increases stroke
volume and cardiac output [334].
In humans, heart rate and force of left ven-
tricular contractions are increased by diazoxide,
while left ventricular systolic and end-diastolic
pressures are decreased. β-Adrenoreceptor
blockade attenuates the elevations in heart rate
and in left ventricular dp/dt, but augments the
reduction in left ventricular systolic pressure
[335]. The mechanism of action of diazoxide
remains to be fully elucidated [336–340].
Hyperglycemia is observed during diazoxide
therapy. This effect is attenuated by propranol-
ol [341] and the ganglionic blocker chlorison-
damine [342]. The propensity of diazoxide to
cause hyperglycemia, and Na+ and fluid re-
tention has restricted its clinical use to acute
life-threatening hypertensive emergencies. The
dosage is titrated on the basis of individual
responsiveness, but ranges between 100 and
300 mg, i.v. [343].
5.2.3. Minoxidil
Antihypertensives 21
Minoxidil [38304-91-5], 6-(1-piperidinyl)-2,4-
pyrimidinediamine-3-oxide, C9 H15 N5 O, M r
209.25, mp 248 ◦ C, 259 – 261 ◦ C (decomp.), is a
white crystalline solid. Minoxidil is primarily a
dilator of arterial vasculature, thereby lowering
total vascular resistance and blood pressure.
Trade name: Loniten.
Extensive literature on pharmacology of mi-
noxidil exists [344–353].
Minoxidil is approved primarily for use in
severely hypertensive patients who do not re-
spond to maximal therapy with a diuretic or other
antihypertensive agents, or in patients where
side effects preclude other drug therapy. It is
also useful in moderately hypertensive patients
[354], those with impaired renal function [355],
but is used rarely in hypertensive emergencies
because of its availability in oral dosage form
only and its long onset of action [345]. Minoxi-
dil is combined with β-adrenoceptor blockade to
reduce effects of reflex sympathetic activation. It
is also effective when combined with other cen-
trally acting sympatholytics, such as clonidine
[356], or methyldopa, α-adrenoceptor antago-
nists, or neuronal blocking agents [357]. Capto-
pril has been used as an adjunct to minoxidil in
refractory hypertensive cases [358]. Because of
sodium and water retention, a diuretic is given in
almost all cases; however, this may not be nec-
essary in patients with less severe hypertension
[345].
The use of minoxidil is limited to a rela-
tively small population of hypertensive patients
because of the incidence of hypertrichosis, and
potential for the occurrence of atrophic and is-
chemic lesions of the heart [359]. The hyper-
trichosis occurs in about 80 % of the patients
treated. It occurs about 3 – 6 weeks after the on-
set of therapy and requires about 1 – 6 months
for recovery after discontinuation of minoxidil.
Cell culture experiments showed that minoxidil
may produce the hypertrichosis by a direct ac-
tion on epidermal cells [360].
5.2.4. Sodium Nitroprusside
Sodium nitroprusside [14402-89-2] is used
as the dihydrate, Na2 Fe(CN)5 NO · 2 H2 O, M r
216.91, readily soluble in water, but decomposes
in light.
22 Antihypertensives
Trade names: Nipride, Nitropress.
Nitroprusside is not absorbed orally and thus
must be given by systemic infusion. Vasodila-
tory effects are exerted on both the arterial and
venous sides of the vasculature. Infusion of
sodium nitroprusside at 1 to 100 µg kg−1 min−1
produces a uniform fall in systolic and diastolic
blood pressure. The onset of action is usually
rapid (< 60 s) and the effect is well-maintained
during the infusion. Recovery of blood pres-
sure occurs rapidly following cessation of drug
[361]. This most likely is the result of rapid cel-
lular degradation of sodium nitroprusside. Be-
cause of this rapid recovery the magnitude of
the hypotensive response can be controlled eas-
ily by varying the infusion rate. Tolerance to
repeated sodium nitroprusside infusions occurs
rarely [362]. Other pharmacological effects have
been described [363–367].
The vasodilator activity of sodium nitroprus-
side is attributed to the NO-group (nitroso) [368–
370]. The vasorelaxant effects do not directly in-
volve α- or β-adrenoceptors and are quite fully
manifested when vessels are contracted by an-
giotensin or vasopressin. Sodium nitroprusside
may reduce the transsarcolemmal influx of cal-
cium or enhance calcium efflux by stimulating
Na+ −K+ ATPase, although quite disparate data
have been found in both regards [371–373]. El-
evations in cellular levels of cyclic GMP are in-
timately involved in the vasodilatory responses
[369], [370].
A final metabolic product of sodium nitro-
prusside is thiocyanate. Toxicity during pro-
longed infusions is usually due to thiocyanate
accumulation (i.e., hypoxia, nausea, tinnitus)
and necessitates discontinuation of treatment.
6. Perspectives in the Development of
Antihypertensive Drugs
A large number of new antihypertensive drugs
have been introduced during the last 30 years.
These drugs were usually justified by an im-
proved side effect profile and/or by a more phys-
iological mechanism of action. This trend is
likely to continue during the next decade. Many
new inhibitors of angiotensin converting enzyme
have been introduced. The effectiveness of Ca2+
channel antagonists in the treatment of hyper-
tension was recognized and novel inhibitors of
Ca2+ channels are likely to be developed dur-
ing the next decade. Drugs interfering with in-
tracellular Ca2+ translocation, e.g., calmodulin
inhibitors, also can be conceivably useful in the
treatment of hypertension.
The central control of arterial pressure by
drugs is receiving renewed attention. The recog-
nition of the importance of various neurotrans-
mitters, e.g., 5-HT, GABA, dopamine, in the
central regulation of cardiovascular functions is
likely to lead to novel antihypertensive drugs
with central mechanism of action. Modification
of the synthesis or release of various neuropep-
tides may also represent a future mechanism of
antihypertensive action. The role of vasopressin
in the cerebral as well as peripheral control of
vascular tone has received renewed attention,
and vasopressin antagonists can conceivably be
useful in the treatment of hypertension.
The importance of the “natriuretic hormone”
in the control of Na+ levels in vascular smooth
muscle cell and consequently of Ca2+ levels is
now being recognized, and drugs controlling the
release or the effects of “natriuretic hormone”
may be useful in the treatment of hypertension.
7. Summary and Conclusions
In spite of the discovery of two new classes
of antihypertensive drugs, inhibitors of the
angiotensin converting enzyme and Ca2+
channel antagonists, the well-established anti-
hypertensive drugs, such as diuretics and β-
adrenoceptor antagonists, are still being widely
used.
Diuretics which do not produce hypokalemia,
hyperuricemia, hyperglycemia, or hyperlipopro-
teinemia, or diuretics with an additional direct
vasodilator action are still in demand and may
be introduced in the near future.
The novelty of the mechanism of action as
well as the clinical efficacy and safety will help
to expand the market for converting enzyme in-
hibitors. Their apparent usefulness in the treat-
ment of heart failure will also contribute to the
expansion of their market share.
Among drugs which interfere with the sym-
pathetic nervous system, α1 -, β-, and α1 /β-
adrenoceptor antagonists are widely used in the
treatment of hypertension. The advantages of

α1 -adrenoceptor antagonists (e.g., prazosin) in-
clude increase in blood flow to vital organs
and lowering of peripheral vascular resistance.
βAdrenoceptor antagonists control arterial pres-
sure with minimal side effects, and reduce
mortality in patients with myocardial infarc-
tion. It remains to be seen whether new α1 /β-
adrenoceptor antagonists (e.g., labetalol) will
combine the benefits of both types of drugs.
With the discovery of the antihypertensive ac-
tion of Ca2+ channel antagonists the interest in
the direct acting smooth muscle relaxants has
been renewed and drugs which interfere with
vascular smooth muscle tone and affect intra-
cellular calcium translocation are likely to be
introduced in the near future.
8. References
1. E. J. Cragoe (ed.): Diuretics: Chemistry,
Pharmacology and Medicine, J. Wiley &
Sons, New York 1983.
2. T. H. Maren, Trans. N.Y. Acad. Sci. 15 (1952)
53.
3. F. C. Novello, J. M. Sprague, J. Am. Chem.
Soc. 79 (1957) 2028 – 2029.
4. K. H. Beyer, Ann. N.Y. Acad. Sci. 71 (1958)
363 – 379.
5. E. D. Fries, A. Wanko, I. M. Wilson, A. E.
Parrish, JAMA 166 (1958) 137 – 140.
6. J. E. Baer, C. B. Jones, S. A. Spitzer, H. F.
Russo, J. Pharmacol. Exp. Ther. 157 (1967)
472 – 485.
7. V. D. Wiebelhaus, F. T. Brennan, G. Sosnowski
et al., Arch. Int. Pharmacodyn. Ther. 169
(1967) 429 – 457.
8. A. C. Guyton, R. D. Manning, J. E. Hall, R. A.
Norman et al., J. Cardiovasc. Pharmacol. 6
(1984) S 151 – S 161.
9. M. P. Blaustein, Am. J. Physiol. 232 (1977)
C 165 – C 173.
10. L. Poston, H. H. Gray, A. Crowther, H. C.
Dittrich et al., J. Cardiovasc. Pharmacol. 6
(1984) S 16 – S 20.
11. M. B. Strauss, H. Southworth, Bull. John
Hopkins Hosp. 63 (1938) 41 – 45.
12. R. Muschaweck, P. Hajdú, Arzneim.-Forsch.
14 (1964) 44 – 47.
13. K. H. Beyer, J. E. Baer, J. K. Michaelson, H. F.
Russo, J. Pharmacol. Exp. Ther. 147 (1965)
1 – 22.
14. G. de Stevens, L. H. Weiner, A. Halamandaris,
S. Ricca, Experientia 14 (1958) 463.
Antihypertensives 23
15. W. E. Barrett, J. J. Chart, A. A. Renzi, Arch. Int.
Pharmacodyn. Ther. 131 (1961) 325 – 338.
16. R. V. Ford, Curr. Ther. Res. 2 (1960)
422 – 429.
17. A. Scriabine, B. Korol, B. Kondratas, M. Yu et
al., Proc. Soc. Exp. Biol. Med. 107 (1961)
864 – 872.
18. H. Horstmann, H. Wollweber, K. Meng,
Arzneim.-Forsch. 17 (1967) 653 – 659.
19. K. Meng, G. Kroneberg, Arzneim.-Forsch. 17
(1967) 659 – 671.
20. R. Rutsaert, M. Fernandes in A. Scriabine
(ed.): New Drugs Annual: Cardiovascular
Drugs, vol. 1, Raven Press, New York 1983,
pp. 49 – 67.
21. E. G. Stenger, H. Wirz, R. Pulver, Schweiz.
Med. Wochenschr. 89 (1959) 1126 – 1130.
22. C. M. Kagawa, F. M. Sturtevant, C. G. Van
Arman, J. Pharmacol. Exp. Ther. 126 (1959)
123 – 130.
23. L. S. Watson, G. M. Fanelli, H. F. Russo, C. S.
Sweet et al. in A. Scriabine, C. S. Sweet (ed.):
New Antihypertensive Drugs, Spectrum
Publications, Inc., New York 1976,
pp. 307 – 321.
24. G. M. Fanelli, Jr., D. L. Bohn, A. Scriabine,
K. H. Beyer, J. Pharmacol. Exp. Ther. 200
(1977) 402 – 412.
25. W. B. Abrams, J. D. Irvin, J. A. Tobert, R. K.
Ferguson et al. in A. Scriabine (ed.): New
Cardiovascular Drugs, Raven Press, New
York, 1985, pp. 1 – 20.
26. E. Moller, H. Horstmann, K. Meng, D. Loew,
Experientia 33 (1977) 382 – 383.
27. B. Garthoff, M. Hanisch in A. Scriabine (ed.):
New Drugs Annual: Cardiovascular Drugs,
vol. 2, Raven Press, New York 1984,
pp. 51 – 70.
28. C. S. Sweet, E. H. Blaine in M. J. Antonaccio
(ed.): Cardiovascular Pharmacology, 2nd ed.,
Raven Press, New York 1984, pp. 119 – 154.
29. M. A. Ondetti, B. Rubin, D. W. Cushman,
Science 196 (1977) 441 – 444.
30. D. W. Cushman, M. A. Ondetti, Prog. Med.
Chem. 17 (1980) 41 – 104.
31. B. Rubin, R. J. Laffan, D. G. Kotler, E. H.
O’Keefe et al., J. Pharmacol. Exp. Ther. 204
(1978) 271 – 280.
32. R. J. Laffan, M. E. Goldberg, J. P. High, T. R.
Schaeffer et al., J. Pharmacol. Exp. Ther. 204
(1978) 281 – 288.
33. R. J. Bengis, T. G. Coleman, D. B. Young,
R. E. McCaa, Circ. Res. 43 (1978) Suppl. 1,
I 45 – I 53.
24 Antihypertensives
34. C. S. Sweet, P. T. Arbegast, S. L. Gaul, E. H.
Blaine et al., Eur. J. Pharmacol. 76 (1981)
167 – 176.
35. M. L. Cohen, K. D. Kurz, J. Pharmacol. Exp.
Ther. 220 (1982) 63 – 69.
36. T. Unger, D. Ganten, R. E. Lang, Trends
Pharmacol. Sci. 4 (1983) 514 – 519.
37. M. J. Antonaccio, L. Kerwin, Hypertension 3
(1981) Suppl. 1, I 54 – I 62.
38. Y. Imai, K. Abe, M. Seino, T. Haruyama et al.,
Hypertension 4 (1982) 444 – 451.
39. R. Hatton, D. P. Clough, J. Cardiovasc.
Pharmacol. 4 (1982) 116 – 123.
40. A. DeJonge, B. Wilffert, H. O. Kalkman,
J. C. A. van Meel et al., Eur. J. Pharmacol. 74
(1981) 385 – 386.
41. C. Richer, M. P. Doussau, J. F. Giudicelli, Eur.
Heart J. 4 (1983) Suppl. G, 55 – 60.
42. T. Unger, I. Kaufmann-Bühler, B. Schölkens,
D. Ganten, Eur. J. Pharmacol. 70 (1981)
467 – 478.
43. R. E. McCaa, J. E. Hall, C. S. McCaa, Circ.
Res. 43 (1978) Suppl. 1, I 32 – I 39.
44. V. S. Murthy, T. L. Waldron, M. E. Goldberg,
Circ. Res. 43 (1978) Suppl. 1, I 40 – I 45.
45. K. Ito, H. Koike, M. Miyamoto, H. Ozaki et
al., J. Pharmacol. Exp. Ther. 219 (1981)
520 – 525.
46. B. Rubin, M. J. Antonaccio in A. Scriabine
(ed.): Pharmacology of Antihypertensive
Drugs, Raven Press, New York 1980,
pp. 21 – 42.
47. E. E. Muirhead, R. L. Prewitt, B. Brooks, W. L.
Brosius, Circ. Res. 43 (1978) Suppl. 1,
I 53 – I 59.
48. D. B. Case, S. A. Atlas, P. A. Sullivan, J. H.
Laragh, Circulation 64 (1981) 765 – 771.
49. W. B. Lee, M. J. Ismay, E. R. Lumbers, Circ.
Res. 47 (1980) 286 – 292.
50. W. H. Van Gilst, P. A. DeGraeff, J. H. Kingma,
H. Wesseling et al., Eur. J. Pharmacol. 100
(1984) 113 – 117.
51. B. G. Zimmerman, P. C. Wong, G. K.
Kounenis, E. J. Kraft, Am. J. Physiol. 243
(1982) H 277 – H 283.
52. S. Chiba, C. P. Quilley, J. Quilley, J. C. McGiff,
Eur. J. Pharmacol. 83 (1982) 243 – 252.
53. T. Taylor, T. J. Moore, N. K. Hollenberg, G. H.
Williams, Hypertension 6 (1984) 92 – 99.
54. W. B. Abrams, R. O. Davies, R. K. Ferguson,
Fed. Proc. 43 (1984) 1314 – 1321.
55. C. S. Sweet, E. H. Ulm in A. Scriabine (ed.):
New Drugs Annual: Cardiovascular Drugs,
vol. 2, Raven Press, New York 1984, pp. 1 – 17.
56. D. M. Gross, C. S. Sweet, E. H. Ulm, E. P.
Backlund et al., J. Pharmacol. Exp. Ther. 216
(1981) 552 – 557.
57. C. S. Sweet, D. M. Gross, P. T. Arbegast, S. L.
Gaul et al., J. Pharmacol. Exp. Ther. 216
(1981) 558 – 566.
58. J. Biollaz, M. Burnier, G. A. Turini, B. B.
Brunner et al., Clin. Pharmacol. Ther. 29
(1981) 665 – 670.
59. R. K. Ferguson, P. H. Vlasses, J. D. Irvin, B. N.
Swanson et al. J. Clin. Pharmacol. 22 (1982)
281 – 289.
60. H. Gavras, B. Waeber, I. Gavras, J. Biollaz et
al., Lancet 2 (1981) 543 – 547.
61. H. Gavras, J. Biollaz, B. Waeber, H. R.
Brunner et al., Clin. Exp. Hypertens. 4 (1), (2)
(1982) 303 – 314.
62. F. G. Dunn, W. Oigman, H. O. Ventura, F. H.
Messerli et al., Am. J. Cardiol. 53 (1984)
105 – 108.
63. P. W. deLeeuw, R. P. L. M. Hoogma, G. A. W.
van Soest, P. T. Tchang et al., J. Cardiovasc.
Pharmacol. 5 (1983) 731 – 736.
64. S. Morioka, G. Simon, J. N. Cohn, Clin.
Pharmacol. Ther. 34 (1983) 583 – 589.
65. C. Richer, M. P. Doussau, J. F. Giudicelli, Eur.
J. Pharmacol. 79 (1982) 23 – 29.
66. D. M. Shoback, G. H. Williams, S. L. Swartz,
R. O. Davies et al., J. Cardiovasc. Pharmacol.
5 (1983) 1010 – 1018.
67. O. Kohlmann, M. Bresnahan, H. Gavras,
Hypertension 6 (1984) Suppl. 1, I 1 – I 6.
68. A. Scriabine, D. G. Taylor, E. Hong, Prog.
Drug Res. 26 (1982) 353 – 371.
69. A. Scriabine, B. V. Clineschmidt, C. S. Sweet,
Annu. Rev. Pharmacol. Toxicol. 16 (1976)
113 – 123.
70. T. L. Sourkes, Arch. Biochem. Biophys. 51
(1954) 444 – 456.
71. L. Gillespie, J. A. Oates, J. R. Crout, A.
Sjoerdsma, Circulation 25 (1962) 281 – 291.
72. C. C. Porter, M. L. Torchiana, C. A. Stone in F.
Gross (ed.): Antihypertensive Agents,
Springer-Verlag, Berlin-Heidelberg-New York
1977, pp. 269 –297.
73. M. Henning, P. A. van Zwieten, J. Pharm.
Pharmacol. 20 (1968) 409 – 417.
74. A. Scriabine in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 43 – 54.
75. G. Onesti, A. N. Brest, P. Novack, H.
Kasparian et al., Am. Heart J. 67 (1964)
32 – 38.
76. S. Mohammed, T. E. Gaffney, A. C. Yard, H.
Gomez, J. Pharmacol. Exp. Ther. 160 (1968)
300 – 307.

77. A. Cohen, J. S. Maxmen, M. Ragheb, H.
Baleiron et al., J. Clin. Pharmacol. 7 (1967)
77 – 83.
78. J. S. Meyer, T. Sawada, A. Kitamura, M.
Toyoda, Neurology (N.Y.) 18 (1968) 772 – 781.
79. A. Sjöerdsma, A. Vendsalu, K. Engelman,
Circulation 28 (1963) 492 – 502.
80. L. F. Prescott, R. P. Buhs, J. O. Beattie, O. C.
Speth et al., Circulation 34 (1966) 308 – 321.
81. S. Z. Langer, Biochem. Pharmacol. 23 (1974)
1793 – 1800.
82. Y. Pommier, M. Andréjak, P. Mouillé, H.
Dabiré et al., Naunyn-Schmiedebergs Arch.
Pharmacol. 318 (1982) 288 – 294.
83. J. R. Boissier, J. F. Giudicelli, J. Fichelle, H.
Schmitt et al. Eur. J. Pharmacol. 2 (1968)
333 – 339.
84. W. Hoefke in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 55 – 78.
85. H. Schmitt in F. Gross (ed.): Antihypertensive
Agents, Springer-Verlag,
Berlin-Heidelberg-New York 1977,
pp. 299 – 396.
86. T. Hukuhara, Jr., Y. Otsuka, R. Takeda, F.
Sakai, Arzneim.-Forsch. 18 (1968)
1147 – 1153.
87. H. Schmitt, H. Schmitt, Eur. J. Pharmacol. 6
(1969) 8 – 12.
88. W. Hoefke, W. Kobinger, Arzneim.-Forsch. 16
(1966) 1038 – 1050.
89. G. A. Bentley, I. W. Copeland, J. Starr, Clin.
Exp. Pharmacol. Physiol. 4 (1977) 405 – 419.
90. M. S. Gold, D. E. Redmond, Jr., H. D. Kleber,
Lancet 2 (1978) 599 – 602.
91. R. C. Allen, M. E. Langham, Invest.
Ophthalmol. 15 (1976) 815 – 823.
92. H. O. Karppanen, E. Westermann,
Naunyn-Schmiedebergs Arch. Pharmacol. 279
(1973) 83 – 87.
93. W. Kobinger, Naunyn-Schmiedebergs Arch.
Pharmacol. 260 (1968) 153 – 154.
94. D. S. Davis, E. Neill, J. L. Reid in T. A. Baillie
(ed.): Stable Isotopes, MacMillan, London
1978, pp. 45 – 54.
95. M. A. Weber, J. Cardiovasc. Pharmacol. 2
(1980) Suppl. 1, S 73 – S 89.
96. M. J. M. C. Thoolen, P. B. M. W. M.
Timmermans, P. A. van Zwieten,
Naunyn-Schmiedebergs Arch. Pharmacol. 319
(1982) 82 – 86.
97. J. B. Bream, H. Lauener, C. W. Picard, G.
Scholtysik et al., Arzneim.-Forsch. 25 (1975)
1477 – 1482.
Antihypertensives 25
98. G. Scholtysik, H. Lauener, E. Eichenberger, E.
Bürki et al., Arzneim.-Forsch. 25 (1975)
1483 – 1491.
99. P. A. van Zwieten, Prog. Pharmacol. 1 (1975)
1 – 63.
100. G. Scholtysik, P. Jerie, C. W. Picard in A.
Scriabine (ed.): Pharmacology of
Antihypertensive Drugs, Raven Press, New
York 1980, pp. 79 – 98.
101. J. C. Doxey, Eur. J. Pharmacol. 54 (1979)
185 – 189.
102. A. Jaattela, Eur. J. Clin. Pharmacol. 10 (1976)
73 – 76.
103. A. J. Bune, J. P. Chalmers, J. R. Graham,
P. R. C. Howe et al., Eur. J. Clin. Pharmacol.
19 (1981) 309 – 315.
104. I. L. Natoff, B. G. Katzung, F. Weir, J. K.
Kodama, Pharmacologist 10 (1968) 157.
105. T. Baum, Fed. Proc. 28 (1969) 738.
106. P. Bolme, H. Corrodi, K. Fuxe, Eur. J.
Pharmacol. 23 (1973) 175 – 182.
107. E. Marmo, R. K. Saini, A. P. Caputi, C. Vaca,
Res. Commun. Chem. Pathol. Pharmacol. 6
(1973) 391 – 406.
108. T. Baum, G. Rowles, A. T. Shropshire, Arch.
Int. Pharmacodyn. Ther. 183 (1970) 75 – 84.
109. P. Bosanac, J. Dubb, B. Walker, M. Goldberg et
al., J. Clin. Pharmacol. 16 (1976) 631 – 636.
110. R. L. Wendt in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 99 – 111.
111. J. W. Strandhoy, B. D. Steg, V. M. Buckalew,
Jr., Life Sci. 27 (1980) 2513 – 2518.
112. R. H. Meacham, M. Emmett, A. A.
Kyriakopoulos, S. T. Chiang et al., Clin.
Pharmacol. Ther. 27 (1980) 44 – 52.
113. F. G. McMahon, J. R. Ryan, A. K. Jain, R.
Vargas et al., Clin. Pharmacol. Ther. 21
(1977) 272 – 277.
114. B. R. Walker, M. Geczy, J. A. Gold, Clin.
Pharmacol. Ther. 25 (1979) 252.
115. L. Dorfman, A. Furlenmeier, C. F. Huebner, R.
Lucas et al., Hel. Chim. Acta 37 (1954)
59 – 75.
116. R. B. Woodward, F. E. Bader, H. Bickel, A. J.
Frey et al., J. Am. Chem. Soc. 78 (1956)
2023 – 2025.
117. R. Sannerstedt, J. Conway, Am. Heart J. 79
(1970) 122 – 127.
118. A. Scriabine in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 119 – 125.
119. M. J. Rand, M. Jurevics in F. Gross (ed.):
Antihypertensive Agents, Springer-Verlag,
Berlin-Heidelberg-New York 1977,
pp. 77 – 159.
26 Antihypertensives
120. R. E. Stitzel, Pharmacol. Rev. 28 (1976)
179 – 208.
121. H. Sheppard, R. C. Lucas, W. H. Tsien, Arch.
Int. Pharmacodyn. Ther. 103 (1955)
256 – 269.
122. R. A. Maxwell, A. J. Plummer, F. Schneider,
H. Povalski et al., J. Pharmacol. Exp. Ther.
128 (1960) 22 – 29.
123. R. A. Maxwell in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 127 – 150.
124. R. A. Maxwell, W. B. Wastila in F. Gross (ed.):
Antihypertensive Agents, Springer-Verlag,
Berlin-Heidelberg-New York 1977,
pp. 161 – 261.
125. B. B. Brodie, C. C. Chang, E. Costa, Br. J.
Pharmacol. 25 (1965) 171 – 178.
126. F. M. Abboud, J. W. Eckstein, Circ. Res. 11
(1962) 788 – 796.
127. C. A. Stone, C. C. Porter, J. M. Stavorski, C. T.
Ludden et al., J. Pharmacol. Exp. Ther. 144
(1964) 196 – 204.
128. A. N. Brest, JAMA 192 (1965) 41 – 44.
129. J. N. Cohn, T. E. Liptak, E. D. Freis, Circ. Res.
12 (1963) 298 – 307.
130. H. Villarreal, J. E. Exaire, V. Rubio, H. Dávila,
Am. J. Cardiol. 14 (1964) 633 – 640.
131. C. T. Dollery, D. Emslie-Smith, M. D. Milne,
Lancet 2 (1960) 381 – 387.
132. F. B. Abramson, C. I. Furst, C. McMartin, R.
Wade, Biochem. J. 113 (1969) 143 – 156.
133. C. McMartin, Biochem. Pharmacol. 18 (1969)
238 – 243.
134. M. Nickerson, Pharmacol. Rev. 1 (1949)
27 – 101.
135. A. Scriabine, J. W. Constantine, H.-J. Hess,
W. K. McShane, Experientia 24 (1968)
1150 – 1151.
136. J. W. Constantine, W. K. McShane, A.
Scriabine, H.-J. Hess in G. Onesti, K. E. Kim,
J. H. Moyer (ed.): Hypertension, Mechanism
and Management, Grune & Stratton, Inc.,
Baltimore 1973, pp. 429 – 444.
137. A. Scriabine in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 151 – 160.
138. I. Cavero, A. G. Roach, Life Sci. 27 (1980)
1525 – 1540.
139. J. C. Schulz, D. P. Westfall, Blood Vessels 19
(1982) 79 – 87.
140. G. von der Lippe, O. J. Ohm, P.
Lund-Johansen, Acta Med. Scand. 210 (1981)
213 – 216.
141. J. M. Hayes, R. M. Graham, B. P. O’Connell,
E. Speers et al., Med. J. Aust. 1 (1976)
562 – 564.
142. P. Bolli, A. J. Wood, W. L. Phelan, D. R. Lee et
al., Clin. Sci. Mol. Med. 48 (1975)
177 S – 179 S.
143. I. S. Collins, P. Pek, Clin. Exp. Pharmacol.
Physiol. 2 (1975) 445 – 446.
144. T. H. Althuis, H.-J. Hess, J. Med. Chem. 20
(1977) 146 – 149.
145. J. A. Taylor, T. M. Twomey, M. S. von
Wittenau, Xenobiotica. 7 (1977) 357 – 364.
146. D. S. Bloom, C. Rosendorff, R. Kramer, Curr.
Ther. Res. 18 (1975) 144 – 150.
147. A. S. P. Hua, I. M. MacDonald, J. B. Meyers, P.
Fang et al., Med. J. Aust. 2 (1977) 5 – 9.
148. W. M. Kirkendall, J. J. Hammond, J. C.
Thomas, M. L. Overturf et al., JAMA 240
(1978) 2553 – 2556.
149. Y. K. Seedat, M. A. Seedat, R. Bhoola, S. Afr.
Med. J. 51 (1977) 461 – 463.
150. A. J. Marshall, D. W. Barritt, J. Pocock, S. T.
Heaton, Lancet 1 (1977) 271 – 274.
151. C. Rosendorff, Br. Med. J. 2 (1976) 508.
152. J. L. Archibald, Chim. Ther. (Paris) 3 (1968)
397.
153. J. L. Archibald, B. J. Alps, J. F. Cavalla, J. L.
Jackson, J. Med. Chem. 14 (1971)
1054 – 1059.
154. J. L. Archibald in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 161 – 177.
155. B. J. Alps, E. T. Borrows, E. S. Johnson, M. W.
Staniforth et al., Cardiovasc. Res. 6 (1972)
226 – 234.
156. T. Baum, A. T. Shropshire, D. K. Eckfeld, N.
Metz et al., Arch. Int. Pharmacodyn. Ther. 204
(1973) 390 – 406.
157. T. Baum, A. T. Shropshire, Eur. J. Pharmacol.
32 (1975) 30 – 38.
158. B. J. Alps, M. Hill, K. Fidler, E. S. Johnson et
al., J. Pharm. Pharmacol. 23 (1971)
678 – 686.
159. B. J. Alps, M. Hill, E. S. Johnson, A. B.
Wilson, Br. J. Pharmacol. 40 (1970) 153 P.
160. G. H. Draffan, P. J. Lewis, J. L. Firmin, T. W.
Jordan et al., Br. J. Clin. Pharmacol. 3 (1976)
489 – 495.
161. G. H. Draffan, Pharmacol. Clin. 1 (1973)
51 – 59.
162. R. B. Royds, D. J. Coltart, J. D. F. Lockhart,
Clin. Pharmacol. Ther. 13 (1972) 380 – 392.
163. C. Rosendorff, S. Afr. Med. J. 50 (1976)
764 – 768.
164. C. T. Dollery, D. G. George, P. J. Lewis, Br. J.
Pharmacol. 46 (1972) 542 P – 543 P.

165. K. Klemm, W. Prüsse, U. Krüger,
Arzneim.-Forsch. 27 (1977) 1895 – 1897.
166. W. Schoetensack, P. Bischler, E. C. Dittmann,
V. Steinijans, Arzneim.-Forsch. 27 (1977)
1908 – 1919.
167. W. Schoetensack, E. G. Bruckschen, K. Zech
in A. Scriabine (ed.): New Drugs Annual:
Cardiovascular Drugs, vol. 1, Raven Press,
New York 1983, pp. 19 – 48.
168. K. Zech in W. Kaufman, E. G. Bruckschen
(ed.): Proc. 1st Symposium on Urapidil,
Excerpta Medica,
Amsterdam-Oxford-Princeton 1982,
pp. 50 – 64.
169. E. G. Bruckschen, F. Henze, G. Michael,
Arzneim.-Forsch. 28 (2) (1978) 1176 – 1184.
170. B. N. C. Prichard, Br. Med. J. 1 (1964)
1227 – 1228.
171. A. Scriabine, Ann. Rev. Pharmacol. Toxicol.
19 (1979) 269 – 284.
172. R. Howe, V. A. Cullum, Nature (London) 210
(1966) 1336 – 1338.
173. A. M. Barrett, R. G. Shanks, Br. J. Pharmacol.
34 (1968) 43 – 55.
174. J. D. Fitzgerald in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 195 – 208.
175. A. S. Nies, D. G. Shand, Circulation 52
(1975) 6 – 15.
176. D. G. Shand, E. M. Nuckolls, J. A. Oates, Clin.
Pharmacol. Ther. 11 (1970) 112 – 120.
177. A. Hayes, R. G. Cooper, J. Pharmacol. Exp.
Ther. 176 (1971) 302 – 311.
178. T. Walle, E. C. Conradi, U. K. Walle, T. C.
Fagan, Clin. Pharmacol. Ther. 27 (1980)
22 – 31.
179. L. Hansson, R. Olander, H. Aberg, H.
Malmcroma et al., Acta Med. Scand. 190
(1971) 531 – 534.
180. A. P. Douglas-Jones, J. Int. Med. Res. 7 (1979)
221 – 223.
181. B. Åblad, K.-O. Borg, E. Carlsson, L. Ek et al.,
Acta Pharmacol. Toxicol. 36 (1975) 7 – 24.
182. E. Carlsson, B. Åblad, A. Brändström, B.
Carlsson, Life Sci. 11 (1972) 953 – 958.
183. B. Åblad, E. Carlsson, G. Johnsson, C.-G.
Regårdh in A. Scriabine (ed.): Pharmacology
of Antihypertensive Drugs, Raven Press, New
York 1980, pp. 247 –262.
184. K.-O. Borg, E. Carlsson, K.-J. Hoffmann, K.-J.
Jönsson et al., Acta Pharmacol. Toxicol. 36
(1975) Suppl. 5, 125 – 135.
185. C.-G. Regårdh, G. Johnsson, L. Jordö, L.
Solvell, Acta Pharmacol. Toxicol. 36 (1975)
Suppl. 5, 45 – 58.
Antihypertensives 27
186. O. Lederballe Pedersen, Eur. J. Clin.
Pharmacol. 10 (1976) 381 – 385.
187. Å. Hjalmarsson, D. Elinfeldt, J. Herlitz, S.
Holmberg et al. Lancet 2 (1981) 823 – 827.
188. R. J. Lee, D. B. Evans, S. H. Baky, R. J. Laffan,
Eur. J. Pharmacol. 33 (1975) 371 – 382.
189. D. B. Evans, M. T. Peschka, R. J. Lee, R. J.
Laffan, Eur. J. Pharmacol. 35 (1976) 17 – 27.
190. M. J. Antonaccio, D. B. Evans in A. Scriabine
(ed.): Pharmacology of Antihypertensive
Drugs, Raven Press, New York 1980,
pp. 295 – 301.
191. R. A. Vukovich, J. E. Foley, B. Brown, D. A.
Willard et al., Br. J. Clin. Pharmacol. 7 (2)
(1979) 167 – 172.
192. G. Frithz, Curr. Med. Res. Opin. 5 (1978)
383 – 387.
193. B. Furberg, A. Dahlqvist, A. Raak, U. Wrege et
al., Curr. Med. Res. Opin. 5 (1978) 388 – 393.
194. R. A. Vukovich, A. Sasahara, P. Zombrano, J.
Belko et al., Clin. Pharmacol. Ther. 19 (1976)
118.
195. K. Saameli in H. J. Dengler (ed.): Die
Therapeutische Anwendung β
-sympathikolytischer Stoffe, F. K. Schattauer
Verlag, Stuttgart-New York 1972, pp. 3 – 30.
196. C. Weil in A. Scriabine (ed.): Pharmacology of
Antihypertensive Drugs, Raven Press, New
York 1980, pp. 237 – 246.
197. J. Meier, Curr. Med. Res. Opin. 4 Suppl. 5,
(1977) 31 – 38.
198. R. Gugler, W. Herold, H. J. Dengler, Eur. J.
Clin. Pharmacol. 7 (1974) 17 – 24.
199. M. C. Laver, P. Fang, P. Kincaid-Smith, Med.
J. Aust. 1 (1974) 174 – 176.
200. A. E. Doyle, Drugs 8 (1974) 422 – 431.
201. A. S. Turner, J. S. Peel, Med. J. Aust. 2 (1972)
Spec. Suppl., 48 – 51.
202. J. Rosenthal, H. Kaiser, A. Raschig, D. Welzel,
Br. J. Clin. Pract. 33 (1979) 165 – 174.
203. A. Scriabine, M. L. Torchiana, J. M. Stavorski,
C. T. Ludden et al., Arch Int. Pharmacodyn.
Ther. 205 (1973) 76 – 93.
204. R. A. Hall, R. O. Robson, N. N. Share, Arch.
Int. Pharmacodyn. Ther. 213 (1975),
pp. 251 – 263.
205. A. Scriabine in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 275 – 282.
206. D. J. Tocco, A. E. W. Duncan, F. A. De Lauwa
et al., Drug Metab. Dispos. 3 (1975)
361 – 370.
207. G. Lohmoller, E. D. Frohlich, Am. Heart J. 89
(1975) 437 – 442.
28 Antihypertensives
208. The Norwegian Multicenter Study Group, N.
Engl. J. Med. 304 (1981) 801 – 807.
209. K. R. H. Wooldridge, Experienta 28 (1972)
1404.
210. B. Basil, R. Jordan, A. H. Loveless, D. R.
Maxwell, Br. J. Pharmacol. 50 (1974)
323 – 333.
211. R. H. Briant, C. T. Dollery, C. F. George, Clin.
Trials J. 11 (1974) Suppl. 3, 25 – 28.
212. B. Levy, J. Pharmacol. Exp. Ther. 186 (1973)
134 – 144.
213. B. Basil, R. Jordan in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 283 – 294.
214. J. P. Amlie, S. Lessum, R. F. Collins, K.
Landmark, Acta Pharmacol. Toxicol. 40
(1977) 378 – 388.
215. D. R. Maxwell, R. F. Collins, Clin. Trials J. 11
(1974) Suppl. 3, 9 – 18.
216. W. L. Ashton, Curr. Med. Res. Opin. 4 (1976)
442 – 454.
217. M. Lucsko, J. Guedon, Clin. Trials J. 11
(1974) Suppl. 3, 86 – 91.
218. L. Hansson, G. Berglund, O. Andersson, H.
Holm, Eur. J. Clin. Pharmacol. 12 (1977)
89 – 92.
219. B. Carey, E. T. Whalley, J. Pharm. Pharmacol.
31 (1979) 791 – 792.
220. J. B. Farmer, I. Kennedy, G. P. Levy, R. J.
Marshall, Br. J. Pharmacol. 45 (1972)
660 – 675.
221. G. P. Levy, D. A. Richards in A. Scriabine
(ed.): Pharmacology of Antihypertensive
Drugs, Raven Press, New York 1980,
pp. 325 – 347.
222. D. A. Richards, J. G. Maconochie, R. E. Bland,
R. Hopkins et al., Eur. J. Clin. Pharmacol. 11
(1977) 85 – 90.
223. L. E. Martin, R. Hopkins, R. E. Bland, Br. J.
Clin. Pharmacol. 3 (1976) Suppl. 1, 695 – 710.
224. B. N. C. Prichard, A. J. Boakes, Br. J. Clin.
Pharmacol. 3 (1976) Suppl., 743 – 750.
225. P. Bolli, H. J. Waal-Manning, A. J. Wood, F. O.
Simpson, Br. J. Clin. Pharmacol. 3 (Suppl.)
(1976) 765 – 771.
226. H. J. Dargie, C. T. Dollery, J. Daniel, Br. J.
Clin. Pharmacol. 3 (1976) Suppl., 751 – 755.
227. A. Fleckenstein, Ann. Rev. Pharmacol.
Toxicol. 17 (1977) 149 – 166.
228. T. B. Bolton, Physiol. Rev. 59 (1979)
606 – 718.
229. C. Cauvin, R. Loutzenhiser, C. Van Breemen,
Ann. Rev. Pharmacol. Toxicol. 23 (1983)
373 – 396.
230. R. A. Janis, D. J. Triggle, J. Med. Chem. 26
(1983) 775 – 785.
231. R. A. Janis, A. Scriabine, Biochem.
Pharmacol. 32 (1983) 3499 – 3507.
232. D. J. Triggle in S. F. Flaim, R. Zelis (ed.):
Calcium Blockers: Mechanisms of Action and
Clinical Applications, Urban &
Schwarzenberg, Baltimore 1982,
pp. 121 – 134.
233. R. G. Rahwan, D. T. Witiak, W. M. Muir,
Annu. Rep. Med. Chem. 16 (1981) 257 – 268.
234. H. Meyer in L. H. Opie (ed.): Calcium
Antagonists and Cardiovascular Disease,
Raven Press, New York 1984, pp. 165 – 173.
235. H. Meyer, F. Bossert, E. Wehinger, K. Stoepel,
W. Vater, Arzneim.-Forsch. 31 (1981)
407 – 409.
236. R. Towart, E. Wehinger, H. Meyer,
Naunyn-Schmiedebergs Arch. Pharmacol. 317
(1981) 183 – 185.
237. R. Rodenkirchen, R. Bayer, R. Steiner, F.
Bossert et al., Naunyn-Schmiedebergs Arch.
Pharmacol. 310 (1979) 69 – 78.
238. M. Hiwatari, K. Satoh, N. Taira,
Arzneim.-Forsch. 29 (1979) 256 – 260.
239. B. Garthoff, S. Kazda, Eur. J. Pharmacol. 74
(1981) 111 – 112.
240. K. Aoki, S. Kondo, A. Mochizuki, T. Yoshida
et al., Am. Heart J. 96 (1978) 218 – 226.
241. M. T. Olivari, C. Bartorelli, A. Polese, C.
Fiorentini et al., Circulation 59 (1979)
1056 – 1062.
242. M. D. Guazzi, C. Fiorentini, M. T. Olivari, A.
Bartorelli et al., Circulation 61 (1980)
913 – 919.
243. M. D. Guazzi, A. Polese, C. Fiorentini, A.
Bartorelli et al. Hypertension 5 (1983)
Suppl. 2, I 85 – I 90.
244. O. Lederballe Pedersen, N. J. Christensen,
K. D. Rämsch, J. Cardiovasc. Pharmacol. 2
(1980) 357 – 366.
245. M. Guazzi, M. T. Olivari, A. Polese, C.
Fiorentini et al., Clin. Pharmacol. Ther. 22
(1977) 528 – 532.
246. O. Lederballe Pedersen, Arch. Int.
Pharmacodyn. Ther. 239 (1979) 208 – 220.
247. M. J. Mulvany, N. Nyborg, Br. J. Pharmacol.
71 (1980) 585 – 596.
248. W. Vater, G. Kroneberg, F. Hoffmeister, H.
Saller et al., Arzneim.-Forsch. 22 (1972)
1 – 14.
249. B. F. Robinson, R. J. Dobbs, C. R. Kelsey, Br.
J. Clin. Pharmacol. 10 (1980) 433 – 438.
250. S. Kazda, B. Garthoff, G. Luckhaus, Postgrad.
Med. J. 59 (1983) Suppl. 2, 78 – 83.

251. Y. C. Streifler, C. Wittenberg, J. Rosenfeld in
M. Kaltenbach, H. N. Neufeld (ed.): Fifth
International Adalat Symposium, Excerpta
Medica, Amsterdam-Oxford-Princeton 1983,
pp. 164 – 174.
252. S. Kazda, B. Garthoff, G. Thomas, Drug
Develop. Res. 2 (1982) 313 – 323.
253. S. Kazda, A. Knorr, R. Towart, Prog.
Pharmacol. 5 (1983) 83 – 116.
254. R. A. B. McLeay, T. J. Stallard, R. D. Watson,
W. A. Littler, Circulation 67 (1983)
1084 – 1090.
255. L.-G. Ekelund, C. Ekelund, S. Rössner, Acta.
Med. Scand. 212 (1982) 71 – 75.
256. W. Kiowski, O. Bertel, P. Erne, P. Bolli et al.,
Hypertension 5 (1983) Suppl. 1, I 70 – I 74.
257. A. Zanchetti, in A. Zanchetti, D. M. Krikler
(ed.): Calcium Antagonism in Cardiovascular
Therapy: Experience with Verapamil,
Excerpta Medica,
Amsterdam-Oxford-Princeton 1981,
pp. 292 – 297.
258. G. Leonetti, C. Cuspidi, L. Sampieri, L.
Terzoli et al. J. Cardiovasc. Pharmacol. 4
(1982) Suppl. 3, S 319 –S 324.
259. F. A. Horster in W. Lochner, W. Braasch, G.
Kroneberg (ed.): Second International Adalat
Symposium, Springer-Verlag, New York 1975,
pp. 124 – 127.
260. K. Schlossmann, H. H. Medenwald, H.
Rosenkranz in W. Lochner, W. Braasch, G.
Kroneberg (ed.): Second International Adalat
Symposium, Springer-Verlag, New York 1975,
pp. 33 – 39.
261. S. R. Hamann, R. G. McAllister, J.
Cardiovasc. Pharmacol. 5 (1983) 920 – 927.
262. C. H. Kleinbloesem, P. van Brummelen, J. A.
van de Linde, P. J. Voogd et al., Clin.
Pharmacol. Ther. 35 (1984) 742 – 749.
263. K. D. Rämsch, J. Sommer, Hypertension 5
(1983) Suppl. 2, I 18 – I 24.
264. R. Krebs, Hypertension 5 (1983) Suppl. 2,
I 125 –I 129.
265. A. Scriabine, B. Garthoff, S. Kazda, K.
Rämsch et al. in A. Scriabine (ed.): New Drugs
Annual: Cardiovascular Drugs, vol. 2, Raven
Press, New York 1984, pp. 37 – 39.
266. R. Towart, J. Cardiovasc. Pharmacol. 4
(1982) 895 – 902.
267. S. Kazda, B. Garthoff, A. Knorr, Fed. Proc. 42
(1983) 196 – 200.
268. H. Meyer, F. Bossert, E. Wehinger, K. Stoepel
et al., Arzneim.-Forsch. 31 (1981) 407 – 409.
269. K. Stoepel, A. Heise, S. Kazda,
Arzneim.-Forsch. 31 (1981) 2056 – 2061.
Antihypertensives 29
270. A. Knorr, K. Stoepel, Arzneim.-Forsch. 31
(1981) 2062 – 2064.
271. B. F. Johnson, L. Romero, R. Marwaha in A.
Scriabine, S. Vanov, K. Deck (ed.):
Nitrendipine, Urban & Schwarzenberg,
Baltimore 1984, pp. 535 – 541.
272. K. Kobayashi, R. C. Tarazi, Hypertension 5
(1983) Suppl. 2, I 45 – I 51.
273. C. E. Hall, S. Hungerford, Clin. Exp.
Hypertens. 5 (1983) 721 – 728.
274. D. G. Taylor, S. Shoemaker, T. E. Kowalski in
A. Scriabine, S. Vanov, K. Deck (ed.):
Nitrendipine, Urban & Schwarzenberg,
Baltimore 1984, pp. 311 – 326.
275. D. C. Warltier, K. A. Lamping, M. G.
Zyvoloski, G. J. Gross et al., J. Cardiovasc.
Pharmacol. 5 (1983) 272 – 277.
276. H. R. Black, N. Vlachakis in A. Scriabine, S.
Vanov, K. Deck (ed.): Nitrendipine, Urban &
Schwarzenberg, Baltimore 1984,
pp. 509 – 518.
277. J. F. Burris, A. V. Notargiacomo, V.
Papademetriou, E. D. Freis, Hypertension 4
(1982) Suppl. 2, I 32 – I 35.
278. L. Hansson, L. Andrén, L. Oro, T. Ryman,
Hypertension 5 (1983) Suppl. 2, I 25 – I 28.
279. H. O. Ventura, F. H. Messerli, W. Oigman,
F. G. Dunn et al., Am. J. Cardiol. 51 (1983)
783 – 786.
280. F. M. Fouad, R. Pedrinelli, E. L. Bravo, F.
Abi-Samra et al., Clin. Pharmacol. Ther. 35
(1984) 768 – 775.
281. H. Haas, E. Busch, Arzneim.-Forsch. 17
(1967) 257 – 272.
282. R. Mannhold, P. Zierden, R. Bayer, R.
Rodenkirchen et al., Arzneim.-Forsch. 31
(1981) 773 – 780.
283. S. Baky, E. B. Kirsten in M. E. Goldberg (ed.):
Pharmacological and Biochemical Properties
of Drug Substances, Academy of
Pharmaceutical Sciences, Washington, D.C.
1981, pp. 226 – 261.
284. S. Baky in A. Scriabine (ed.): New Drugs
Annual: Cardiovascular Drugs, vol. 2, Raven
Press, New York 1984, pp. 71 – 102.
285. B. N. Singh, J. T. Collett, C. Y. Chew, Prog.
Cardiovasc. Dis. 22 (1980) 243 – 301.
286. R. A. Walsh, F. R. Badke, R. A. O’Rourke, Am.
Heart J. 102 (1981) 341 – 350.
287. S. F. Flaim, K. Kanda in S. F. Flaim, R. Zelis
(ed.): Calcium Blockers: Mechanisms of
Action and Clinical Applications, Urban &
Schwarzenberg, Baltimore 1982,
pp. 155 – 178.
30 Antihypertensives
288. B. A. Gould, R. S. Hornung, S. Mann, V. B.
Subramanian et al., Hypertension 5 (1983)
Suppl. 2, I 91 – I 96.
289. K. Midtbo, O. Hals, J. van der Meer, J.
Cardiovasc. Pharmacol. 4 (1982) Suppl. 3,
S 363 – S 368.
290. P. Erne, P. Bolli, O. Bertel, U. L. Hulthén et al.,
Hypertension 5 (1983) Suppl. 2, I 97 – I 102.
291. U. L. Hulthen, P. Bolli, F. W. Amann, W.
Kiowski, F. R. Bühler, J. Cardiovasc.
Pharmacol. 4 (1982) Suppl. 3, S 313 – S 318.
292. G. Muiesan, E. Agabiti-Rosei, C. L. Alicandri
in A. Zanchetti, D. M. Krikler (ed.): Calcium
Antagonism in Cardiovascular Therapy:
Experience with Verapamil, Excerpta Medica,
Amsterdam 1981, pp. 238 – 249.
293. A. Chaudhry, M. M. Vohra, Eur. J. Pharmacol.
97 (1984) 156 – 158.
294. G. Haeusler, J. Pharmacol. Exp. Ther. 180
(1972) 672 – 682.
295. D. G. Taylor, T. E. Kowalski, J. Pharmacol.
Exp. Ther. 228 (1984) 491 – 499.
296. L. H. Opie, Lancet 1 (1980) 806 – 810.
297. H. Kugita, H. Inoue, M. Ikezaki, M. Konda et
al., Chem. Pharm. Bull. (Tokyo) 19 (1971)
595 – 602.
298. H. Kugita, H. Inoue, H. Ikezaki, S. Takeo,
Chem. Pharm. Bull. (Tokyo) 18 (1970)
2028 – 2037.
299. T. Nagao, M. Sato, H. Nakajima, A. Kijomoto,
Jpn. J. Pharmacol. 22 (1972) 1 – 10.
300. M. Sato, T. Nagao, I. Yamaguchi, H. Nakajima
et al., Arzneim.-Forsch. 21 (1971)
1338 – 1343.
301. R. P. Hof, Br. J. Pharmacol. 78 (1983)
375 – 394.
302. H. Narita, T. Nagao, H. Yabana, I. Yamaguchi,
J. Pharmacol. Exp. Ther. 227 (1983)
472 – 477.
303. M. Sato, S. Murata, H. Narita, M. Tomita et
al., Jpn. J. Pharmacol. 75 (1979) 99 – 106.
304. I. Yamaguchi, K. Ikezawa, S. Murata, H. Narita
et al., Jpn. J. Pharmacol. 24 (1974) 511 – 522.
305. S. F. Flaim in A. Scriabine (ed.): New Drugs
Annual: Cardiovascular Drugs, vol. 2, Raven
Press, New York 1984, pp. 123 – 156.
306. N. Nakaya, A. Schwartz, R. W. Millard, Circ.
Res. 52 (1983) 302 – 311.
307. M. Matsuzaki, K. P. Gallagher, J. Patritti, T.
Tajimi et al., Circulation 69 (1984) 801 – 814.
308. W. Klein, D. Brandt, K. Vrecko, M. Härringer,
Circ. Res. 52 (1983) Suppl. 1, I 74 – I 173.
309. M. E. Safar, A. Ch. Simon, J. A. Levenson,
J. L. Cazor, Circ. Res. 52 (1983) Suppl. 1,
I 169 – I 173.
310. T. Meshi, J. Sugihara, Y. Sato, Chem. Pharm.
Bull. (Tokyo) 19 (1971) 1546 – 1556.
311. J. E. Francis, ACS Symp. Ser. 27 (1976)
55 – 79.
312. H. A. J. Struyker-Boudier, H. Van Essen,
J. F. M. Smits, Eur. J. Pharmacol. 95 (1983)
151 – 159.
313. E. G. Spokas, H.-H. Wang, J. Pharmacol. Exp.
Ther. 212 (1980) 294 – 303.
314. I. Khatri, N. Uemura, A. Notargiacomo, E. D.
Freis, Am. J. Cardiol. 40 (1977) 38 – 42.
315. S. Sen, R. C. Tarazi, Am. J. Physiol. 244
(1983) H 97 – H 101.
316. M. J. M. C. Thoolen, J. C. A. Van Meel, B.
Wilffert, P. B. M. W. M. Timmermans et al.,
Pharmacology 27 (1983) 245 – 254.
317. C. Chevillard, M. N. Mathieu, B. Saiag, M.
Worcel, Br. J. Pharmacol. 69 (1980)
415 – 420.
318. V. S. R. Krishnamurty, Can. J. Physiol.
Pharmacol. 59 (1981) 1159 – 1169.
319. M. B. Murphy, A. J. Scriven, M. J. Brown, R.
Causon et al., Eur. J. Clin. Pharmacol. 23
(1982) 479 – 482.
320. O. Kohlmann, M. Bresnahan, H. Gavras,
Hypertension 6 (1984) Suppl. 1, I 1 – I 6.
321. E. G. Spokas, G. Folco, J. Quilley, P. Chander,
J. C. McGiff, Hypertension 5 (1983) Suppl. 1,
I 107 – I 111.
322. G. Haeusler, M. Gerold,
Naunyn-Schmiedebergs Arch. Pharmacol. 310
(1979) 155 – 167.
323. K. Hermsmeyer, A. Trapani, P. W. Abel, M.
Worcel, J. Pharmacol. Exp. Ther. 227 (1983)
322 – 326.
324. C. Chevillard, B. Saiag, M. Worcel, Br. J.
Pharmacol. 73 (1981) 811 – 817.
325. A. J. McLean, P. DuSouish, K. W. Barron,
A. H. Briggs, J. Pharmacol. Exp. Ther. 207
(1978) 40 – 48.
326. M. Khayyal, F. Gross, V. A. W. Kreye, J.
Pharmacol. Exp. Ther. 216 (1981) 390 – 394.
327. J. L. Freslon, J. F. Guidicelli, Br. J. Pharmacol.
80 (1983) 533 – 543.
328. S. Greenberg, J. Pharmacol. Exp. Ther. 215
(1980) 279 – 286.
329. L. Hansson, R. Olander, H. Aberg, R.
Malmcrona et al., Acta Med. Scand. 190
(1971) 531 – 534.
330. C. K. Newsome, Southwest Med. 42 (1961)
558 – 567.
331. J. A. Franciosa, G. Pierpont, J. N. Cohn, Ann.
Intern. Med. 86 (1977) 388 – 393.

332. A. A. Rubin, F. E. Roth, R. M. Taylor, H.
Rosenkilde, J. Pharmacol. Exp. Ther. 136
(1962) 344 – 352.
333. T. C. Hamilton, D. Robson, Eur. J. Pharmacol.
32 (1975) 273 – 278.
334. W. G. Nayler, I. McInnes, J. B. Swann, D.
Race et al. Am. Heart J. 75 (1968) 223 – 232.
335. P. Limbourg, P. Figel, H. Justin, K. F. Lang,
Eur. J. Clin. Pharmacol. 8 (1975) 387 – 392.
336. J. Taylor, R. D. Green, Eur. J. Pharmacol. 12
(1970) 385 – 387.
337. J. C. A. van Meel, P. B. M. W. M. Timmermans,
P. A. van Zwieten, Eur. J. Pharmacol. 92
(1983) 27 – 34.
338. A. J. Wohl, L. M. Hausler, F. E. Roth, J.
Pharmacol. Exp. Ther. 162 (1968) 109 – 114.
339. N. Winer, D. S. Chokshi, M. S. Yoon, A. D.
Freedman, J. Clin. Endocrinol. 29 (1969)
1168 – 1175.
340. R. Vandongen, D. M. Greenwood, Eur. J.
Pharmacol. 33 (1975) 197 – 200.
341. G. Sponer, P. Schelling, D. Ganten, F. Gross,
Naunyn-Schmiedebergs Arch. Pharmacol. 303
(1978) 15 – 20.
342. I. I. A. Tabachnick, A. Gulbenkian, F.
Seidman, J. Pharmacol. Exp. Ther. 150 (1965)
455 – 462.
343. A. McNair, F. Andreasen, P. E. Nielsen, Eur. J.
Clin. Pharmacol. 24 (1983) 151 – 156.
344. D. W. DuCharme, W. A. Freyburger, B. E.
Graham, R. G. Carlson, J. Pharmacol. Exp.
Ther. 184 (1973) 662 – 670.
345. W. A. Pettinger, N. Engl. J. Med. 303 (1980)
922 – 926.
346. D. W. DuCharme, G. R. Zins in A. Scriabine
(ed.): Pharmacology of Antihypertensive
Drugs, Raven Press, New York 1980,
pp. 415 – 421.
347. M. Velasco, K. O’Malley, N. W. Robie, J.
Wells et al., Clin. Pharmacol. Ther. 16 (1974)
1031 – 1038.
348. H. R. Brunner, P. Jaeger, R. K. Ferguson, E.
Jequier et al., Br. Med. J. 2 (1978) 385 – 388.
349. H. N. Sapru, A. J. Krieger, Am. J. Physiol. 236
(1979) H 174 – H 182.
350. S. Sen, R. C. Tarazi, F. M. Bumpus,
Cardiovasc. Res. 11 (1977) 427 – 433.
351. R. V. Jackson, M. M. Williamson, B.
Seneviratne, R. D. Gordon, Aust. N.Z. J. Med.
13 (1983) 39 – 44.
352. J. M. McCall, J. W. Aiken, C. G. Chidester,
D. W. DuCharme et al., J. Med. Chem. 26
(1983) 1791 – 1793.
Antihypertensives 31
353. C. J. Limas, J. N. Cohn, Circ. Res. 35 (1974)
609 – 617.
354. G. D. Nicholson, G. A. Alleyne, G. Valdes,
R. L. Westerman, J. Cardiovasc. Pharmacol. 2
(1980) Suppl., 242 – 246.
355. F. C. Luft, R. Bloch, J. J. Szwed, C. M. Grim et
al., JAMA 240 (1978) 1985 – 1987.
356. M. Valasco, A. Urbina-Quintana, E.
Hernández, A. Ramirez et al., Eur. J. Clin.
Pharmacol. 20 (1981) 259 – 262.
357. R. E. Mutterperl, F. B. Diamond, D. T.
Lowenthal, J. Clin. Pharmacol. 16 (1976)
498 – 509.
358. Y. K. Seedat, R. Rawat, Eur. J. Clin.
Pharmacol. 25 (1983) 9 – 11.
359. E. H. Herman, T. Balazs, R. Young, F. L. Earl
et al., Toxicol. Appl. Pharmacol. 47 (1979)
493 – 503.
360. R. L. Cohen, M. E. Alves, V. C. Weiss, D. P.
West et al., J. Invest. Dermatol. 82 (1984)
90 – 93.
361. V. A. W. Kreye, E. Marquard,
Naunyn-Schmiedebergs Arch. Pharmacol. 306
(1979) 203 – 207.
362. I. H. Tuzel, J. Clin. Pharmacol. 14 (1974)
494 – 503.
363. M. Pagani, S. F. Vatner, E. Braunwald,
Circulation 57 (1978) 144 – 151.
364. R. D. Bastron, G. J. Kaloyanides, J.
Pharmacol. Exp. Ther. 181 (1972) 244 – 249.
365. G. Ross, P. V. Cole, Anaesthesia 28 (1973)
400 – 406.
366. A. P. Adams, T. N. S. Clarke, J. Edmonds-Seal,
P. Föex et al., Br. J. Anaesth. 46 (1974)
807 – 817.
367. J. Kyncl, Naunyn-Schmiedebergs Arch.
Pharmacol. 269 (1971) 390 – 391.
368. V. A. W. Kreye in A. Scriabine (ed.):
Pharmacology of Antihypertensive Drugs,
Raven Press, New York 1980, pp. 373 – 396.
369. C. A. Gruetter, B. K. Barry, D. B. McNamara,
D. Y. Gruetter, P. J. Kadowitz, L. J. Ignarro, J.
Cyclic Nucleotide Res. 5 (1979) 211 – 224.
370. C. A. Gruetter, D. Y. Gruetter, J. E. Lyon, P. J.
Kadowitz et al., J. Pharmacol. Exp. Ther. 219
(1981) 181 – 186.
371. V. A. W. Kreye, Trends Pharmacol. Sci. 1
(1980) 384 – 388.
372. V. A. W. Kreye, G. D. Baron, J. B. Lüth, H.
Schmidt-Gayk, Naunyn-Schmiedebergs Arch.
Pharmacol. 288 (1975) 381 – 402.
373. D. H. Foley, Pharmacology 28 (1984)
95 – 103.