Drugs 25 (Suppl. 2): 100-102 (1983) 0012-6667/83/0300-0100/$01.50/0 cADIS Press Australasia Ply Ltd (Inc. NSW). All rights reserved.
Haemodynamic Effects of
~-Blockers
Jay N. Cohn Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis
Summary
1. Introduction
The pharmacological effects of ;i-blockers have been well documented but there is still no clear picture of the integrated systemic haemodynamic response to adrenoceptor blockade. This response is reviewed and the changes in systemic vascular resistance in hypertensive patients and during exercise are analysed.
groups of drugs suggests that peripheral {3-receptors playa minor role in resting haemodynamics. Drugs Although the pharmacological effects of {3- with partial agonist activity tend to support heart adrenoceptor blockade are well known, and the dif- rate and cardiac output and thus result in a lesser ferential effects of {31- and ,B2-receptors have been rise in systemic vascular resistance. thoroughly explored, the integrated systemic The mechanism of the increased systemic vashaem adynamic response to receptor blockade re- cular resistance after acute {3-blockade is not well mains surprisingly poorly understood. In the pres- understood. Increased a-agonist activity has been ent review we shall explore the acute haemodyn- suggested and a modest rise in circulating plasma amic response to {3-blockade and analyse the noradrenaline has been reported in some studies. mechanism of the changes in systemic vascular re- An increased hypotensive effect to a-receptor sistance which occur in hypertensive subjects. Fur- blockade and to systemic autonomic inhibition thermore, we shall examine the haemodynamic re- during this phase has also been reported (Simon et sponse to exercise in the presence of {3-blockade aI., 1979). It is thus likely that some increase in and examine the effects of ,B-blockers with varying sympathetic vasoconstrictor activity plays a role in partial agonist effect on left ventricular perform- the rise in systemic vascular resistance. Another mechanism that has often been neance. glected is the passive change in vascular resistance that may result in a reduction in cardiac output. In recent studies in our laboratory an acute reduc2. Acute Haemodynamic Response tion in stroke volume with no change in heart rate Cardiac {3-blockade results in slowing of heart was induced in paced dogs by changing the pacing rate and reduction in cardiac output with little sequence from A-V sequential to A-V simultanechange in stroke volume. Arterial pressure is little ous. This sudden change in atrial contribution to affected by acute blockade and thus calculated sys- ventricular filling led to a sudden reduction in temic vascular resistance is increased. The overall stroke volume averaging about 20%. Arterial preshaemodynamic response is similar with non-selec- sure stabilised within 2 beats after this stroke voltive {3-blockers which also inhibit peripheral recep- ume change but the reduction in pressure averaged tors. The similarity of acute response to these 2 only 9%. Therefore, calculated systemic vascular
Haemodynamic Effects of jj-Blockers
resistance rose approximately 10%. Although it has been well recognised that arterial pressure reduction may result in a passive increase in resistance by a reduction of transmural pressure in the resistance vessels, the magnitude of this response has not been well defined. The significant increase which occurred in these dog studies despite only a modest fall in arterial pressure makes it apparent that this mechanism cannot be disregarded as a factor in the rise in systemic resistance following any intervention which reduces cardiac output.
3. Subacute and Chronic Haemodynamic Response The temporal sequence of arterial pressure changes after institution of therapy with ,8-blockers has been somewhat controversial. An antihypertensive effect has been reported to occur anywhere from hours to weeks after start of therapy. In studies from our laboratory a remarkably telescoped course was demonstrated (Simon et aI., 1981). After the first dose of atenolol, arterial pressure was unchanged and cardiac output reduced, as would be expected. By the following day, however, arterial pressure had already fallen and, although cardiac output fluctuated somewhat during succeeding days, the overall haemodynamic response accounting for the delayed fall in blood pressure appeared to be a delayed reduction in systemic vascular resistance. Similar findings have been reported from other laboratories which have described persistence of a reduced cardiac output for as long as 5 years after institution of therapy with j1-blockers. Thus, the sustained antihypertensive effect of ,8blockers can be attributed to reversal of the acute increase in systemic vascular resistance which normally accompanies initiation of therapy. The mechanism for this vasoconstrictor reversal is not known, but a number of mechanisms are available to account for it. Sympathetic outflow could be reduced by virtue of a central action of ,8-blockers; noradrenaline release could be inhibited by virtue of /1-blocker-induced decrease in circulating angiotensin; a-receptor sensitivity could be reduced, perhaps by virtue of down-regulation' inhibition of renin release could reduce the vaso~ constrictor effect of angiotensin; increases in prostaglandin or other vasodilator substances could counteract vasoconstrictor mechanisms. Guyton et al. (1974) had introduced the term 'whole body autoregulation' to account for changes in resistance which appeared to be unrelated to any known neural or humoral mechanism. Their thesis would
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suggest that a reduction in cardiac output leads to underperfusion of vascular beds that respond by relaxing arteriolar tone in order to encourage an increase in flow. Since cardiac output remains at reduced levels during long term administration of P-blockers, however, the so-called whole body autoregulation in this context must lead to a reduction in pressure rather than an increase in flow. The mechanism for this intrinsic vasodilator response is not known.
4. Haemodynamic Response to Exercise Although a distinct pattern of haemodynamic change in response to /1-blockade can be demonstrated with a subject at rest, it is clear that a greater haemodynamic response should be demonstrable during exercise when the sympathetic nervous system is usually activated. Indeed, the modest heart rate attenuation at rest is greatly accentuated during exercise and the cardiac output response of exercise is also strikingly inhibited. Arterial pressure remains at lower levels throughout exercise and the systemic vascular response to exercise appears to be essentially normal. Since maximum cardiac output is strikingly reduced, it is not surprising that patients receiving {1-blockers may experience some reduction of maximal exercise capacity. The most striking therapeutic effect of /1-blockade therefore is a reduction of heart rate and blood pressure during exercise. This response has a salutary effect on myocardial oxygen consumption and thus provides the basis for use of /1-blockers in the management of angina. The reduction in myocardial oxygen consumption consequent to the reduced heart rate/blood pressure product may be slightly counterbalanced by an increase in left ventricular volume. This effect apparently is very modest, however, and may even be counterbalanced by some increase in subendocardial perfusion, possibly resulting from the longer diastolic filling interval.
5. Effects on Left Ventricular Function Because of the known negative inotropic effect of /1-blockade, concern about the development of congestive heart failure as a complication of /1blocker therapy has long been expressed. A shift of the Frank-Starling curve downward and to the right is the expected physiological response to /1-block-
Haemodynamic Effects of (j·Blockers
ade. Despite this shift ofthe curve, however, clinical congestive heart failure is a relatively rare complication of such therapy. Even in hypertensive subjects with early evidence of congestive heart failure, ~-blockers often improve the performance of the heart by virtue of their reduction of arterial pressure. Nonetheless, reports of congestive heart failure complicating such drug therapy have led to concern that patients with impaired left ventricular function cannot be allowed to take the drug. More recent studies suggest that ~-blockers may be surprisingly well tolerated even in the presence of relatively severe heart disease. In patients with acute myocardial infarction, short term administration of /3-blockers results in a modest fall in cardiac output with little change in left ventricular filling pressure. Although this fall in cardiac output might be viewed as an ominous sign, most patients apparently tolerate the therapy without significant side effects, and a rise in left ventricular filling pressure appears not to be a problem. It is possible that the shift of the function curve downward and to the right in patients with heart disease is less than that observed in normal subjects. Another possibility is that left ventricular diastolic compliance is changed by P-blockade such that the left ventricle becomes more distensible and changes in left ventricular filling pressure therefore no longer reflect changes in left ventricular end-diastolic volume. If this were the case, then the left ventricle might be dilating after administation of /3-blockers in the presence of acute myocardial infarction even though the left ventricular filling pressure remains essentially unchanged. If diastolic stiffness plays a role in the natural history in ischaemic heart disease, then (j-blockers might be viewed as therapeutically effective agents in the setting of acute myocardial infarction. Several studies in both the United States and Sweden have suggested that short term administration of P-b!ockers might have a salutary effect on the course of acute myocardial infarction, but the results of these studies are not yet persuasive. Similar studies have recently been undertaken in patients with congestive cardiomyopathy presenting with low cardiac output and high left ventricular filling pressure accompanied by tachycardia. In a group of such patients treated in Goteborg, a remarkable remission in the symptoms and progressive reduction in heart size after institution of It-blocker therapy has been reported (Swedberg et aI., 1980). These authors have suggested that the beneficial effects of the drug may be related to its actions on diastolic compliance. Although the role of p-blockers in the management of these forms of
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acute and chronic heart disease remains controversial, these studies have made it apparent that acute and chronic responses to these drugs may not be the same and that long term benefits of therapy must be assessed by observing the chronic haemodynamic and clinical responses.
6. Partial iJ-Agonists Because of the negative inotropic effect of ~ blockers an effort has been made by the phannaceutical industry to develop It-blockers that have partial agonist activity. These drugs exert intrinsic activity of their own when interacting with a preceptor, but at the same time may block the ~ receptor from the action of released or circulating noradrenaline. A large number of partial agonists with It-agonistic activity have been synthesised and studied. Those with only modest intrinsic activity have proved to be effective in the management of hypertension, whereas those with a more potent sympathomimetic effect have been advocated for use in the management of congestive heart failure. These drugs exhibit a strikingly different haemodynamic profile than the pure It-blockers. Heart rate usually is not slowed and cardiac output is not reduced and may actually be considerably increased. Indeed, a dissociation between inotropic and chronotropic properties of the drugs may be demonstrated with a strikingly different balance than is observed after administration of isoprenaline. How long teon stimulation of ~-receptors can continue to be effective for inotropic support of a failing heart remains to be established in carefully controlled trials.
References Guyton, A.C.; Coleman, T.G.; Cowley, A.W.; Manning, R.O.; Norman , R.A. and Ferguson, J.D.: A systems analysis approach to understanding long-range arterial blood pressure control. Circulation Research 35: 159-176 (1974). Simon. G. ; Kiowski , W. and Julian, S.: Effect of systemic autonomic inhibilion on the haemodynamic response to anti· hypertensive therapy with timolol. International Journal of Clinical Pharmacology and Biophannacy 12: 507-510 (1979). Simon, G. ; Franciosa, J.A.; Gimenez, H.J. and Cohn, J.N.: Shortterm systemic hemodynamic adaptation to beta·adrenergic inhibition with atenolol in hypertensive patients. Hypertension 3: 262·268 (1981). Swedberg, K ; Hjalmarson, A.; Waagstein, F. and Wallentin, I.: Beneficial effects of long-term beta·blockade in congestive cardiomyopathy. British Heart Journal 44: 117-133 (1980). Author's address: Dr IN. Cohn. Cardiovascular Division, University of Minnesota Hospital, Minneapolis. Minn. (USA).
