EurJ Clin Pharmacol (1990) 38: S 125-S 128 @be@cerle@ @ Springer-Verlag 1990

Clinical efficacy and safety Are different hemodynamic patterns of antihypertensive drugs clinically important?

S. Julius Division of Hypertension,Department of Internal Medicine, Universityof MichiganMedical Center, Ann Arbor, Michigan, USA

Summary. Since vascular resistance is elevated in hy- sure through a fall in cardiac output have a physiologically pertension, it is suggested that vasodilators lower the undesirable effect. blood pressure by a physiologic mechanism and there- Such reasoning, logical as it may be, is a great fore must be more useful than cardiac output-lowering oversimplification; much depends on the circumstan- drugs. This is not entirely correct. Drugs that lower car- ces. The notion that decreased cardiac output and diac output are also relative vasodilators, but the vasodi- increased vascular resistance is unhealthy will be a lation occurs at a lower level of cardiac output. It is also surprise to anybody vaguely familiar with the hemody- not necessarily true that all vasodilators are good anti- namic adjustment to upright posture. Cardiac output is hypertensive agents. The clinical profile of a vasodilator much lower than in recumbency and the resistance is depends on its effect on the venous return, cardiac out- high, but reports on specific cardiovascular morbidity of put, regional blood flow, renin-angiotensin system, and upright posture are nonexistent. Similarly, a decrease in sympathetic reflexes. From the viewpoint of hemody- vascular resistance is not always good; hypertensive namics, an ideal antihypertensive drug is a vasodilator encephalopathy is associated with a great increase in that does not excessively increase cardiac output, causes cerebral blood flow [3]. Before endorsing vasodilators or no fluid retention, does not induce a great deal of venodi- condemning drugs that reduce the cardiac output, one lation, and does not elicit substantial neurohumoral must know much more about each of these compounds counterregulation. Angiotensin-converting-enzyme in- and about the prevailing conditions under which they are hibitors, some calcium antagonists, and some combined given. alpha/beta-blocking agents come close to satisfying the hemodynamic definition of an ideal antihypertensive drug. Vasodilation: at which level of cardiac output?

Key words: cardiac output, vascular resistance, blood The distinction between vasodilating and cardiac out- pressure put lowering drugs becomes even more moot when one takes into account that the simple formula (blood pres- sure=cardiac output xvascular resistance), while de- A general scheme of hemodynamics is given in Fig. 1 [1], scribing the physical components of the hemodynamic Blood pressure is a product of cardiac output and vascular relationship, is not directly applicable to the living organ- resistance, shown on the vertical and horizontal lines. The ism. Under a wide range of circumstances (upright vascular resistance, shown with diagonal isoresistance posture, bleeding, acute intravenous beta-blockade), the lines, can be calculated by dividing the mean blood pres- fall in cardiac output is met with an increase in vascular sure by the cardiac output. It follows from the graph that resistance while the blood pressure remains unchanged. the blood pressure can be decreased either by a fall in car- A pharmacologic decrease in cardiac output leads diac output or by a decrease in the vascular resistance. In to lower pressures only if the compensatory increase established hypertension, high pressure is due to an in- in resistance fails to materialize. An example is given in crease in vascular resistance [2]. Since vasodilators dimin- Fig.2, adapted from a study by Hansson et al. [4]. ish the high resistance, it is hypothesized that they reduce Treatment with propranolol did not decrease every- the pressure through a physiologic mechanism. Within the body's blood pressure but, regardless of their blood context of such thinking, drugs that decrease blood pres- pressure responses, all patients showed a decrease in car- S 126 S. Julius: Hemodynamics of antihypertensive drugs Pressure 130 - Resistance: Flow 5 4 3 j Vessel / / / I / 120 - "~-- [ / / / ,soresistance el 110 - t.-

2 o #. ,.. 100- ro

90-

80 i 2 2.5 3 3.5 4 Cardiac index Fig.2. Hemodynamic effect of chronic beta-adrenergic blockade with propranolo]. (Data adapted from Hansson et al. [4]). The pa- F LOW tients are divided into responders (solid line) and nonresponders (broken line). The full circle at the base of the arrow presents the Fig. 1. The pressure-flow-resistance relationship. The diagonal lines hemodynamic state before the treatment and the head of the arrow, are lines of isoresistance, with the lowest representing low resistance the hemodynamics after 4 weeks of treatment with 160-320 mg pro- and the highest, high resistance. Note that the vascular caliber at low pranolol. Note that the non-responder group actually showed a resistance is larger and that small increases in pressure cause a large larger decrease in the cardiac index, but this was met by an increase increase in flow. At the high resistance line, the vascular caliber is in vascular resistance and the blood pressure did not change. In re- narrow and a large increase in pressure causes only a small increase spenders, the fall of the cardiac index did not elicit an increase of re- in flow. The horizontal vector represents a decrease in flow, associ- sistance and the blood pressure fell. Note that on propranolol both ated with an increase in resistance and no change in pressure. The di- groups had low cardiac indexes, but the responder group had sub- agonal, downwardly pointing vector represents a decrease in flow, stantially lower vascular resistance. with an unchanged resistance and a fall in blood pressure - Responders; ..... non-responders diac output. When responders and nonresponders are not given to patients who regularly engage in endurance compared, the real difference is that responders had exercise. much lower levels of vascular resistance, which means The hemodynamic picture at the opposite pole, when that they were relatively more vasodilated than the non- the cardiac output is high, can be equally disturbing. In responders. It follows that all antihypertensive agents are spite of the lower afterload, the large increase in cardiac vasodilators, but the dilation occurs at different levels of output increases the overall cardiac work and patients cardiac output. with decreased coronary reserve may develop a variety of The low cardiac output-low vascular resistance state ischemic syndromes. seen with beta-adrenergic blockade is not intrinsically deleterious, but some of its clinical consequences can be disturbing. At rest and at moderate levels of exercise, the What is being vasodilated? tissues continue to receive adequate oxygen supplies through increased oxygen extraction from the blood. Vasoconstrictive or vasodilating stimuli elicit very diverse During more strenuous exercise, beta-blocked patients responses along different segments of the vascular tree. cannot increase their cardiac output and experience the Veins are different from arteries in regard to both the vas- onset of fatigue. Good clinicians take into account this cular geometry and the contractile properties of the hemodynamic limitation and beta-blocking agents are smooth muscles. The wall-to-lumen ratio in the resistance

Hemodynamic effects of vasodilators

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Arterioles only Arterioles + veins Arteriolar dilatation + $ symp. resp. Cardiac output 1"1"1` Cardiac output 1" or 4- --> Cardiac output 4- --> Hydralazine Nitroprusside ACE Diazoxide Prazosin Verapamil-like Ca antagonists Minoxidil Nitroglycerin Combined c~ + 13 blockers Nifedipine-like Ca antagonists Fig.& See text S. Julius: Hemodynamicsof antihypertensivedrugs S 127 vessels is much larger, and vasodilation causes a large regulated through alpha-adrenergic adrenoreceptors. change in the vascular resistance. A similar decrease in Left ventricular hypertrophy is a strong risk factor for fu- venous smooth-muscle contraction does not affect the re- ture blood-pressure-related mortality and morbidity. sistance; the response is a large increase in vascular capac- Since reflex-inducing vasodilators favor ventricular ity. The balance between hemodynamic changes in the hypertrophy, they are not the preferred treatment of resistance and capacitance vessels determines the level of choice for hypertension. cardiac output. Fluid retention is another potent counterregulatory A drug causing only arteriolar dilatation, with no in- mechanism to offset the hypotensive effect of vasodila- crease in venous capacity, reduces the blood pressure but tors. This is due in part to the redistribution of the simultaneously increases the cardiac output. As men- intrarenal blood flow, but activation of the renin-an- tioned above, an excessive cardiac output may have nega- giotensin system also plays a major role. If the fluid tive clinical effects. A predominant venodilator decreases retention is not prevented, a vasodilator will lose its in- the preload and thereby reduces the cardiac output. This itial efficacy. Drugs that directly antagonize the renin- is particularly bothersome in the upright posture, since ex- angiotensin system (converting enzyme inhibitors) or cessive gravitational pooling of blood frequently causes prevent the reflex increase in renin (combined vaso- orthostatic hypotension. A schematic overview of the ef- dilators-beta-blockers) greatly obviate the problem. Cal- fect of various classes of vasodilators on cardiac output is cium antagonists also cause little fluid retention as, in ad- given in Fig. 3. dition to causing vasodilation, they also directly increase Veins and arterioles are morphologically very differ- diuresis. ent, and it is easy to visualize why they would be function- ally different. The morphology of arterioles across the whole body is rather uniform. Nevertheless, arterioles What is an ideal vasodilator? show a great range of functional differences and their re- sponse to vasodilators varies from organ to organ. These Vasodilators are not a homogeneous group of compounds differences in regional vasodilation must be taken into with uniformly advantageous features. To be efficacious consideration when one evaluates the clinical profile of a and useful, a vasodilator must fulfill certain criteria: vasodilator. Unpleasant flushing and peripheral edema 1. Vasodilation should occur at a normal level of cardiac with some calcium antagonists, as well as headaches with output; levels that are either too low or too high are unde- hydralazine, reflect the excessive regional vasodilation sirable. caused by these compounds. The substantial fluid reten- 2. The vasodilator should not cause excessive blood flow tion observed with minoxidil is in large part caused by un- in the skin or in other nonessential organs. favorable redistribution of the renal blood flow. 3. Renal blood flow should not be reduced. 4. There should be little or no fluid retention. 5. Vasodilators should either not elicit or be capable of Which compensatory responses are elicited? abolishing sympathetic counterregulatory responses. 6: The vasodilator should not cause excessive venodilation. Vasodilation triggers a number of counterregulatory re- Three major groups of contemporary vasodilators sponses; some of them directly oppose the vasodilation, meet most of these criteria: converting enzyme inhibi- whereas others strive to maintain an unchanged blood tors, some calcium antagonists, and combined pressure. The pressure-preserving mechanisms of particu- alpha/beta-adrenergic blocking agents. Converting lar interest are sympathetic cardiostimulation, fluid reten- enzyme inhibitors are not direct vasodilators; rather, they tion, and activation of the renin-angiotensin system. remove the angiotensin-mediated vasoconstriction. Acute vasodilation inevitably elicits reflex increases Nevertheless, the end result is a decrease in vascular re- in the heart rate and stroke volume. In addition to the sistance. This decrease is not associated with tachycardia aforementioned balance between dilatation of the veins or with an increase in plasma norepinephrine [9]. Con- and arterioles, this reflex cardiostimulation largely deter- verting enzyme inhibitors antagonize the effect of an- mines the degree of elevation of the cardiac output. This giotensin on aldosterone and thereby prevent sodium increased sympathetic drive may have a specific negative and fluid retention. effect on the heart. The issue evolves around the so- Dihydropiridine-type calcium antagonists are potent called trophic effect of the sympathetics. Whereas the in- peripheral vasodilators and elicit very strong sympathetic crease in blood pressure mechanically elicits cardiac and responses. The clinical side effects of headache, tachycar- vascular hypertrophy, the degree of hypertrophy depends dia, and flushing can limit their usefulness. Diltiazem and on various other "growth" factors. Denervated blood verapamil-like drugs, although generally less efficacious vessels fail to develop vascular hypertrophy [5, 6]. In as dilators, can prevent tachycardia; they are also spontaneously hypertensive rats, reflex-inducing vasodi- mild diuretics. When edema occurs, this is due to fluid re- lators (hydralazine and minoxidil) decrease the blood distribution from the intravascular to the interstitial pressure but fail to reduce the left ventricular hyper- space and not to generalized fluid retention. Absence of trophy [7]. Rats treated with a sympatholytic agent (cz- both fluid retention and tachycardia are desirable fea- methyldopa) showed significant reduction of the left ven- tures. tricular wall mass in spite of poorer blood pressure Combined alpha- and beta-adrenergic blocking agents control. Noradrenaline facilitates the growth of cardiac are a welcome addition to our antihypertensive armamen- myocytes in isolated culture [8]. This effect appears to be tarium. Their alpha-adrenergic blocking action is respon- s 128 S. Julius: Hemodynamics of antihypertensive drugs sible for vasodilation, whereas the beta-blocking compo- References nent adds other desirable features. Blockade of cardiac and renal beta-adrenergic receptors prevents tachycardia 1. Julius S (1988) The blood pressure seeking properties of the cen- and the renin-angiotensin-induced sodium retention. The tral nervous system. J Hypertension 6:177-185 2. Julius S, Egan B (1986) Hemodynamics of hypertension. In: Zan- clinical efficacy of these compounds depends on whether chetti A, Tarazi RC (eds) Handbook of hypertension, vol 7. Pa- the duration and potency of the alpha- and beta-adrener- thophysiology of hypertension - cardiovascular aspects. Elsevier, gic component at a given dose are well balanced. Other Amsterdam, pp 153-178 ancillary properties such as the magnitude of the venous 3. Strandgaards OJ, Skinhoj E, Lassen NA (1973) Autoregulation effect and the presence of intrinsic sympathomimetic ac- of brain circulation in severe arterial hypertension. Br Med J 1: tivity are also important. These differences require that 507-510 4. Hansson L, Zweifler AJ, Julius S, Hunyor SN (1974) Hemody- each new compound in this class be examined in its own namic effects of acute and prolonged [3-adrenergic blockade in es- right. The drug that is the subject of this symposium, car- sential hypertension. Acta Med Scand 196:27-34 vedilol, has a number of attractive properties. The vasodi- 5. Bevan RD (1975) Effect of sympathetic denervation on smooth lation in the skin and muscles is not excessive, the de- muscle cell proliferation in the growing rabbit ear artery. Circ Res crease in peripheral resistance occurs at normal levels of 37:14-19 cardiac output, and there is no evidence of excessive ve- 6. Hart MN, Heistad DD, Brody MJ (1980) Effect of chronic hyper- tension and sympathetic denervation on the wall/lumen ratio of nodilation or fluid retention. cerebral vessels. Hypertension 2:41%428 The efforts of the pharmaceutical industry to bring 7. Sen S, Tarazi RC, Bumpus FM (1977) Cardiac hypertrophy and new compounds to the market may confuse the practic- antihypertensive therapy. Cardiovasc Res 11:427433 ing physician with new names and doses to learn. 8. Simpson P (1983) Norepinephrine-stimulated hypertrophy of cul- However, many of these compounds offer a true advant- tured rat myocardial cells in an alphal-adrenergic response. J Clin age. Generally speaking, the more uniform a class Invest 72:732-738 9. Ibsen H, Egan B, Julius S (1983) Baroreflex sensitivity during of drugs (diuretics, converting enzyme inhibitors), converting enzyme inhibition with Enalapril (MK-421) in normal the less likely it is that a new compound will be truly man. J Hypertens 1 [Suppl 2]:222-224 different. However, within the class of combined beta- and alpha-blocking agents, much depends on the balance between various characteristics of these S. Julius, M.D., Sc.D. multiple-action compounds. The impressive dossier of Division of Hypertension Department of Internal Medicine clinical trials and some of the interesting features of car- University of Michigan Medical Center vedilol make it a compound well worth consideration in 3918 Taubman Center everyday practice. Ann Arbor, Michigan 48109-0356, USA