CIRCULATORY ACTIONS AND SECONDARY EFFECTS

Transcription

1 Br. J. clin. Pharmac. (1981),12, 5s-9S DRUGS ACTING DIRECTLY ON VASCULAR SMOOTH MUSCLE: CIRCULATORY ACTIONS AND SECONDARY EFFECTS 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 predominantly upon the venous reservoir include sodium nitroprusside, 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 /81/ $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 contractile behaviour. Like muscle of this type elsewhere, its activation depends predominantly on the entry of calcium through potential operated channels. 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 mechanisms that are selectively inhibited by sodium nitroprusside 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

2 6S zyme inhibitor, captopril, is not strictly speaking a directly acting dilator, but it is conveniently considered 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 sensitive 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 situations 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 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 dimensions, cardiac output and arterial pressure. Since these effects depend on venous pooling, they are more pronounced in the upright position and postural 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. Venodilatation 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 sympathetic 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 reduced cardiac output both before and after administration 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 following administration of a dilator can be reduced by P-adrenoceptor antagonists, the increase in output induced by the dilator does not depend on sympathetic 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 venodilatation 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 assessed 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 activated 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 exception of converting enzyme inhibitors such as captopril, 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 sometimes seen when intravenous infusions of sodium

3 DRUGS ACTING ON VASCULAR SMOOTH MUSCLE 7S 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 (Cottrell 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 vasculature and there is evidence suggesting that it depends 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 consequent 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 usually 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 mellitus 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 hydralazine even when the dose has been kept within the recommended limits; granulocytopenia and nephrotic syndrome which have been reported during treatment with captopril although the incidence and relation 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 antagonists that induce dilatation by interfering with sympathetic constrictor tone. When given locally, a- adrenoceptor antagonists are more effective in dilating 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 antagonists 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 phentolamine cause the rate to increase, but this effect is not usually seen with prazosin or indoramin. The effect on renin secretion also varies: phenoxybenzamine 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 antagonists 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 include 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

4 8S resistance vessels equally and its importance in the clinical use of this group of compounds has not been adequately investigated. The possibility that tolerance 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 administration of a compound are often much less pronounced than those of a single dose. A high degree of tolerance to the dilator action of hydralazine has been demonstrated in the forearm vessels 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 continued 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 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 circumstances it would appear rational to introduce a second dilator agent that would overcome this unwanted compensation. A waning of the dilator response observed 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 inhibited 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 resistance vessels may result, in part at least, from increased sympathetic constrictor tone; in these circumstances 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 results from such studies, coupled with a growing understanding 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. References COLLIER, J.G., LORGE, R.E. & ROBINSON, B.F. (1978). Comparison of effects of tolmesoxide, diazoxide, hydralazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of man. Br. J. clin. Pharmac., 5, COLLIER, J.G., NACHEV, C. & ROBINSON, B.F. (1972a). Effect of catecholamines and other vasoactive substances on superficial hand veins in man. Clin. Sci., 43, COLLIER, J.G., NACHEV, C. & ROBINSON, B.F. (1972b). Comparison of blockade at a-adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man. Br. J. Pharmac., 44, 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, 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, KOSHY, M.C., MICKLEY, D., BOURGOIGNIE, J. & BLAUFOX, M.D. (1977). Physiologic evaluation of a new antihypertensive agent: prazosin HCI. Circulation, 55, KOCHEL, 0. (1967). Effect of diazoxide on plasma renin activity in hypertensive patients. Ann. internalmed., 67, 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 patients with arterial hypertension. Acta med. scand., suppl. 625, LOWE, R.D. & ROBINSON, B.F. (1967). 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