Br. J. clin. Pharmac.

(1981),12, 5s-9S

DRUGS ACTING DIRECTLY ON VASCULAR SMOOTH MUSCLE:

CIRCULATORY ACTIONS AND SECONDARY EFFECTS
B.F. ROBINSON
Department of Medicine, St George's Hospital Medical School, London

1 The circulatory actions of dilator substances reflect their relative effectiveness in dilating
resistance vessels as compared to the vessels making up the systemic venous reservoir.
2 The ability of dilator substances to act selectively on blood vessels of different types depends on
functional differences in the smooth muscle. The smooth muscle of the resistance vessels, for
example, depends for its activation on the entry of calcium through potential operated channels and
is, in consequence, particularly sensitive to the dilator action of drugs such as verapamil and
nifedipine.
3 Drugs which act predominantly upon the resistance vessels cause an increase in heart rate and
cardiac output, but this is not, as is commonly supposed, dependent on an increase in sympathetic
activity.
4 All directly-acting dilator substances give rise to an increase in plasma renin activity, but their
ability to cause sodium retention varies greatly.
5 a-Adrenoceptor antagonists show circulatory effects suggesting a predominant effect upon the
venous system after single doses, but their effects are more balanced during chronic administration.
They vary in their effect on plasma renin activity, but all tend to cause sodium retention.
6 Tolerance has been demonstrated to the dilator action of the organic nitrates and also of
hydralazine.

Introduction
DRUGS that induce vascular relaxation by acting
directly upon the smooth muscle in the vessel wall
have proved useful in the treatment of a variety of
disorders including hypertension, angina pectoris
and severe cardiac failure. The circulatory actions of
each dilator agent, and hence the clinical conditions
in which it may be of use, are determined by the
relative effects of the drug upon the resistance vessels
on the one hand and the vessels making up the
systemic venous reservoir on the other. Drugs acting
predominantly or solely upon the resistance vessels
include verapamil, nifedipine, captopril, diazoxide,
hydralazine and minoxidil. Drugs acting predomin-
antly upon the venous reservoir include sodium nit-
roprusside, glyceryl trinitrate and the other organic
nitrates.
Selective action of dilator agents on resistance vessels
and veins
The ability of drugs to act selectively on blood vessels
of different types reflects differences in the functional
properties of the smooth muscle in the vessel wall
(Robinson & Collier, 1979). The effects of several
0306-5251/81/130005-05 $01.00
important dilator agents are dependent on the
mechanism by which the smooth muscle is activated
and stimulated to contract. The smooth muscle in the
resistance vessels possesses intrinsic tone and, in
some circumstances at least, exhibits rhythmic con-
tractile behaviour. Like muscle of this type else-
where, its activation depends predominantly on the
entry of calcium through potential operated chan-
nels. It is this aspect of their function that confers on
the resistance vessels their sensitivity to the dilator
action of drugs such as verapamil and nifedipine that
act by inhibiting this mode of calcium flux. The
smooth muscle in the limb veins has little capacity for
spontaneous activity and depends for activation on
stimulation by agonists such as noradrenaline to
which it responds with graded contractions that can
be sustained for long periods. Contractile activity of
this type is mediated by receptor operated mechan-
isms that are selectively inhibited by sodium nitro-
prusside and glyceryl trinitrate; it is not dependent on
the entry of calcium through potential operated
channels, and is, in consequence, relatively resistant
to verapamil and nifedipine.
Differences in responsiveness to other groups of
drugs are less well understood. The converting en-
)Macmillan Publishers Ltd 1981
6S B.F. ROBINSON
zyme inhibitor, captopril, is not strictly speaking a
directly acting dilator, but it is conveniently consi-
dered with this group. The selectivity of captopril for
the resistance vessels probably reflects the fact that
they are very sensitive to the constrictor action of
angiotensin II whereas the veins are much less sensi-
tive and rapidly develop tachyphylaxis (Collier,
Nachev & Robinson, 1972a). The extent to which
resistance vessel tone is dependent upon the action of
angiotensin II varies greatly in different clinical situa-
tions and it is therefore to be expected that captopril
will show a corresponding variation in its dilator
action in different patients. Diazoxide shows little
selectivity and is approximately equally effective in
resistance vessels and veins; its mechanism of action
is not understood (Collier, Lorge & Robinson,
1978). Hydralazine, by contrast, is highly selective
for the resistance vessels; its action is characterized
by a very slow onset so that the maximum effect after
local arterial infusion may be delayed for as long as
30-40 min (Collier, Lorge & Robinson, 1978); it is
firmly bound to the vessel wall, but the way in which it
induces relaxation and the reasons for its selectivity
still need to be clarified. Minoxidil is inactive when
given locally and must first be metabolized to some
other substance, as yet unknown, before dilatation is
induced; the mechanism of action and the reason for
its selectivity for the resistance vessels are unknown.
Circulatory effects of dilator drugs
Dilatation of the venous reservoir causes a fall in
central venous pressure with a consequent reduction
in pulmonary venous pressure, left ventricular di-
mensions, cardiac output and arterial pressure. Since
these effects depend on venous pooling, they are
more pronounced in the upright position and postur-
al hypotension may occur. This pattern of action,
which is the principal effect of the organic nitrates,
can cause a large reduction in the work and oxygen
needs of the left ventricle and is thus of particular
value in the management of angina pectoris. Ven-
odilatation may also be of value in the treatment of
cardiac failure when elevation of pulmonary venous
pressure is a conspicuous clinical feature.
Dilatation of the resistance vessels leads directly to
a fall in arterial pressure. The effects of the reduced
peripheral resistance are, however, offset to some
extent by a compensatory increase in cardiac output.
It is often assumed that the increase in cardiac output
induced by dilators, and the associated tachycardia,
are both dependent upon a reflex increase in sym-
pathetic activity. This simple view is almost certainly
incorrect. The opening of an arterio-venous shunt
results in circulatory changes very similar to those
imposed by administration of an arteriolar dilator,
but the increase in cardiac output induced in dogs by
this manoeuvre is not reduced by prior P-
adrenoceptor blockade (Lowe & Robinson, 1967).
More recently, in a study of the effect of intravenous
diazoxide in man, it was observed that although prior
administration of a 1-adrenoceptor antagonist re-
duced cardiac output both before and after adminis-
tration of the dilator, the magnitude of the increase in
output and heart rate were not reduced (Man In 'T
Veld et al., 1980). The additional administration of
atropine eliminated the increase in heart rate induced
by the dilator and the now elevated control output
showed only a small further increase. These findings
indicate that even though the cardiac output follow-
ing administration of a dilator can be reduced by
P-adrenoceptor antagonists, the increase in output
induced by the dilator does not depend on sympathe-
tic stimulation of the heart; the increase may result in
part from withdrawal of parasympathetic tone, but it
may also partially reflect the intrinsic properties of
the myocardium.
Dilatation of the resistance vessels is of value
clinically in the treatment of raised arterial pressure
and may also be useful in severe cardiac failure when
left ventricular emptying is limited by the pressure
against which it must eject. Most dilator drugs do not
act solely on vessels of one type but act to some extent
both on veins and resistance vessels. The pattern of
their circulatory effects will thus depend upon their
relative effects on venous capacitance and peripheral
resistance. When left ventricular function is severely
impaired, the effect of simultaneous dilatation of
both veins and resistance vessels may be such as to
mimic a direct effect on the myocardium: reduction
in left ventricular diastolic pressure induced by veno-
dilatation may be associated with an increase in
stroke volume resulting from the lowered peripheral
resistance. If no account is taken of the change in
systolic pressure, and ventricular performance is as-
sessed solely in terms of filling pressure and stroke
volume, it may be erroneously concluded that the
function of the myocardium itself has been improved.
Apart from the changes in cardiac output induced
by dilator substances, other mechanisms may be acti-
vated which modify the final response to the drug. All
directly acting dilator agents may induce a rise in
plasma renin activity (Kuchel, 1967; Ueda, Yagi &
Kaneko, 1968; Kaneko et al., 1968); with the excep-
tion of converting enzyme inhibitors such as captop-
ril, the increase in renin activity will lead to increased
concentrations of angiotensin II which will oppose
the dilator effect. The extent to which this mechanism
is of importance in limiting the fall in arterial pressure
in response to a dilator is uncertain. The effect may
be larger than has been supposed, however, and it has
been suggested that the rebound hypertension some-
times seen when intravenous infusions of sodium
 DRUGS ACTING ON VASCULAR SMOOTH MUSCLE
nitroprusside are abruptly discontinued reflects the
effect of elevated plasma renin activity, unmasked in
these circumstances because the half-life of renin is
significantly longer than that of nitroprusside (Cot-
trell et al., 1980). The mechanism of the increase in
renin secretion induced by dilators is uncertain. The
effect of hydralazine on renin secretion has been
studied in some detail; it does not appear to result
from a direct effect of the drug upon the renal vascu-
lature and there is evidence suggesting that it de-
pends on a reflex response to the general circulatory
changes mediated through the renal sympathetic
nerves (Ueda et al., 1970). In accord with this view,
the increase in renin secretion induced by dilators can
usually be attenuated by prior administration of P-
adrenoceptor antagonists; the response to minoxidil,
however, is only partially antagonized by propranolol
and it has been suggested that the increase in renin
secretion induced by this drug is in part the result of
decreased renal perfusion pressure (O'Malley et al.,
1975).
Continued administration of dilator substances
may induce retention of salt and water with conse-
quent expansion of the blood volume. In contrast to
the effect on renin secretion, which appears to be a
consistent feature of the response to directly acting
dilators, the effect on sodium excretion varies widely
between drugs. The effect is most marked with
diazoxide and minoxidil, which may give rise to
sodium retention of such intensity that large doses of
loop diuretics are required to reverse it. Hydralazine
induces more moderate sodium retention that is usu-
ally easily controlled; nifedipine and captopril have
little effect on sodium balance. The mechanism by
which dilator substances induce retention of salt and
water and the reasons for the differences between
drugs are not fully understood.
Several of the dilator drugs in current use can give
rise to important non-circulatory side-effects that
limit their usefulness. These include: diabetes mel-
litus which is an almost invariable consequence of
treatment with diazoxide; hirsutism which occurs
with both diazoxide and minoxidil; the drug-induced
lupus syndrome which is seen occasionally with hyd-
ralazine even when the dose has been kept within the
recommended limits; granulocytopenia and nephro-
tic syndrome which have been reported during treat-
ment with captopril although the incidence and rela-
tion to dosage remain to be determined.
Comparison of directly acting dilators with
a-adrenoceptor antagonists
It is of interest to compare the effects of directly
acting dilators with those of a-adrenoceptor antagon-
ists that induce dilatation by interfering with sym-
7S
pathetic constrictor tone. When given locally, a-
adrenoceptor antagonists are more effective in dilat-
ing the noradrenaline constricted hand vein than they
are in dilating the forearm resistance vessels and in
this respect their pattern of action resembles that of
glyceryl trinitrate (Collier, Nachev & Robinson,
1972b; Collier, Lorge & Robinson, 1978). When
given intravenously in single doses, the a-
adrenoceptor antagonists have variable effects, but
the circulatory response is in general consistent with a
dominant effect upon the venous reservoir; prazosin,
for example, causes a fall in mean arterial pressure in
patients with hypertension which is associated with a
fall in cardiac output (Safar etaaL, 1974). This pattern
of action is not surprising as the veins are much more
dependent upon sympathetic stimulation for their
level of tone than are resistance vessels. During
long-term oral administration a-adrenoceptor an-
tagonists such as phentolamine and prazosin have
less effect upon the circulation than after single
doses, and the pattern of response suggests that the
effect upon the venous reservoir is reduced more
than that upon the resistance vessels (Lund-
Johansen, 1974; Safar et al., 1974).
The effect of a-adrenoceptor antagonists upon the
heart rate varies: phenoxybenzamine and phen-
tolamine cause the rate to increase, but this effect is
not usually seen with prazosin or indoramin. The
effect on renin secretion also varies: phenoxyben-
zamine induces an increase in both noradrenaline
and renin activity in the plasma at doses that do not
cause a fall in arterial pressure (Johnston et al.,
1973); prazosin, on the other hand, had little or no
effect on plasma renin activity when given over an
8 week period to patients with hypertension (Koshy
et al., 1977). These differences may relate to the
extent to which the different antagonists give rise to
an increase in the effective level of sympathetic
stimulation and this in turn may be related to the
selectivity of the agent for pre- and post- junctional
a-receptors.
All of the a-adrenoceptor antagonists tend to cause
sodium retention and in this respect resemble the
directly acting dilators. The a-adrenoceptor antagon-
ists may, of course, also give rise to other side-effects,
both circulatory and non-circulatory as a result of
interference with a-adrenergic function; these in-
clude postural hypotension, nasal stuffiness and
ejaculatory impotence.
Tachyphylaxis and use of dilators of different types in
combination
The development of tolerance is well recognized with
the organic nitrates (Schelling & Lasagna, 1967); it is
not known, however, if this affects both venous and
8S B.F. ROBINSON
resistance vessels equally and its importance in the
clinical use of this group of compounds has not been
adequately investigated. The possibility that toler-
ance also develops during continued administration
of other dilator substances has been largely ignored.
It is likely, however, that with some drugs at least,
tolerance is induced since the effects of chronic ad-
ministration of a compound are often much less
pronounced than those of a single dose. A high
degree of tolerance to the dilator action of hyd-
ralazine has been demonstrated in the forearm ves-
sels of some patients undergoing long-term oral
therapy with the drug (Robinson, Collier & Dobbs,
1980). The mechanism of this is unknown, but it is
likely that it accounts for the not infrequent failure of
hydralazine to induce the expected lowering of blood
pressure during long-term treatment. As has been
mentioned, the effects of x-adrenoceptor antagonists
may differ greatly in long-term treatment from those
observed after a single dose; it is not known to what
extent this reflects an altered response in the blood
vessels themselves and to what extent it results from
physiological adaptations, such as expansion of the
blood volume, which could compensate for con-
tinued venodilatation.
It is usual to prescribe dilator agents singly, but the
realization that they may act through different
mechanisms raises the possibility that they might
usefully be employed in combination. Failure to
maintain the initial response during long-term
References
COLLIER, J.G., LORGE, R.E. & ROBINSON, B.F. (1978).
Comparison of effects of tolmesoxide, diazoxide, hyd-
ralazine, prazosin, glyceryl trinitrate and sodium nitro-
prusside on forearm arteries and dorsal hand veins of
man. Br. J. clin. Pharmac., 5, 35-44.
COLLIER, J.G., NACHEV, C. & ROBINSON, B.F. (1972a).
Effect of catecholamines and other vasoactive sub-
stances on superficial hand veins in man. Clin. Sci., 43,
455-467.
COLLIER, J.G., NACHEV, C. & ROBINSON, B.F. (1972b).
Comparison of blockade at a-adrenoceptors by thymox-
amine and phentolamine in peripheral arteries and veins
of man. Br. J. Pharmac., 44,294-300.
COTTRELL, J.E., ILLNER, P., KITTAY, M.J., STEELE, J.M.,
LOWENSTEIN, J. & TURNDORF, H. (1980). Rebound
hypertension after sodium nitroprusside induced
hypotension. Clin. Pharmac. Ther., 27,32-36.
JOHNSTON, C.I., ANAVEKAR, N., CHUA, K.G. & LOUIS,
W.J. (1973). Plasma renin and angiotensin levels in
human hypertension following treatment. Clin. Sci. moL
Med., 45, 287s-290s.
KANEKO, Y., IKEDA, T., TAKEDA, T., INOUE, C.,
TAGAWA, H. & UEDA, H. (1968). Renin release in
patients with benign essential hypertension. Circulation,
38,353-362.
therapy with a single dilator agent may reflect a
compensatory change in the activity of a control
system in the vascular smooth muscle that is not
directly influenced by that drug; in these circum-
stances it would appear rational to introduce a second
dilator agent that would overcome this unwanted
compensation. A waning of the dilator response ob-
served in the resistance vessels during administration
of an a-adrenoceptor antagonist, for example, might
well be due in part to increased activity of the intrinsic
myogenic mechanism; this mechanism could be inhi-
bited by simultaneous administration of nifedipine or
verapamil. Conversely, the administration of
nifedipine is associated with evidence of increased
sympathetic activity (Lederballe et al., 1979) and
failure to achieve the expected response in the resis-
tance vessels may result, in part at least, from in-
creased sympathetic constrictor tone; in these cir-
cumstances it would seem reasonable to explore the
effect of simultaneous administration of an x-
adrenoceptor antagonist.
There is need for well planned studies to evaluate
the effect of combined therapy with dilator drugs
which have different mechanisms of action. The re-
sults from such studies, coupled with a growing un-
derstanding of the basic mechanisms by which dilator
agents act, should lead not only to more effective use
of existing substances, but also to a more rational
approach to the development of new dilator drugs.
KOSHY, M.C., MICKLEY, D., BOURGOIGNIE, J. &
BLAUFOX, M.D. (1977). Physiologic evaluation of a new
antihypertensive agent: prazosin HCI. Circulation, 55,
533-537.
KOCHEL, 0. (1967). Effect of diazoxide on plasma renin
activity in hypertensive patients. Ann. internalMed., 67,
791-799.
LEDERBALLE PEDERSEN, O., MIKKELSEN, E., KOR-
NERUP, H.J. & CHRISTENSEN, N.J. (1979). Effects of
nifedipine on blood pressure, regional hemodynamics,
plasma renin activity and plasma catecholamines in pa-
tients with arterial hypertension. Acta med. scand.,
suppl. 625,65-67.
LOWE, R.D. & ROBINSON, B.F. (1967). The unimportance
of autonomic control of the heart in mediating the
response of cardiac output to a fall in peripheral resis-
tance. J. Physiol., 189, 68-69P.
LUND-JOHANSEN, P. (1974). Hemodynamic changes at
rest and during exercise in longterm prazosin therapy of
essential hypertension. In: Prazosin-evaluation of a
new antihypertensive agent. Ed. Cotton, D.W.K. Ams-
terdam: Excerpta Med.
MAN IN 'T VELD, A.J., WENTING, G.J., BOOMSMA, F.,
VERHOEVEN, R.P. & SCHALEKAMP, M.A.D.H. (1980).
Sympathetic and parasympathetic components of reflex
 DRUGS ACTING ON VASCULAR SMOOTH MUSCLE
cardiostimulation during vasodilator treatment of
hypertension. Br. J. clin. Pharmnac., 9, 547-551.
O'MALLEY, K., VELASCO, M., WELLS, J. & MCKAY, J.L.
(1975). Control plasma renin activity and changes in
sympathetic tone as determinants of minoxidil-induced
increase in plasma renin activity. J. clin. Invest., 55,
230-235.
ROBINSON, B.F. & COLLIER, J.G. (1979). Vascular smooth
muscle: correlations between basic properties and re-
sponses of human blood vessels. Brit. med. Bull., 35,
305-312.
ROBINSON, B.F., COLLIER, J.G. & DOBBS, R.J. (1980).
Acquired tolerance to dilator action of hydralazine dur-
ing oral administration. Br. J. clin. Pharmac., 9,
407-412.
9S
SAFAR, M.E., WEISS, Y.A., LONDON, G.L. & MILLIEZ, P.L.
(1974). Short-term hemodynamic studies with prazosin.
In: Prazosin-evaluation of a new anti-hypertensive
agent. Ed. Cotton, D.W.K. Amsterdam: Excerpta Med.
SCHELLING, J.L. & LASAGNA, L. (1967). A study of cross-
tolerance to circulatory effects of organic nitrates. Clin.
PharmacoL Ther., 8, 256-260.
UEDA, H., KANEKO, Y., TAKEDA, T., IKEDA, T. & YAGI S.
(1970). Observations on the mechanism of renin release
by hydralazine in hypertensive patients. Circulat. Res.,
27, (suppl. 2), 201-206.
UEDA, H., YAGI., S. & KANEKO, Y. (1968). Hydralazine
and plasma renin activity. Arch. internal Med., 122,
387-391.