Download - Calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with particular reference to verapamil and propranolol

Calcium Antagonists and Beta Blockers in the Control of Mild to Moderate Systemic Hypertension,

with Particular Reference to Verapamil and Propranolol

BRAMAH N. SINGH, MD, PhD, PERLITA REBANAL, RN, MARTHA PIONTEK, RN, and KOONLAWEE NADEMANEE, MD

The antianginal and antiarrhythmic role of calcium antagonists is well established. Recent preliminary studies have indicated that, like /3 blockers, calcium antagonists may produce short- and long-term hypotensive effects in patients with mild to moderate essential hypertension. The pharmacologic properties of calcium antagonists provide a clear rationale for their use in the control of essential hypertension. The comparative hypotensive effects of verapamil (80 to 160 mg 3 times a day) and propranolol (40 to 120 mg 3 times a day) were evaluated over 4 weeks, preceded by a 4-week placebo phase, in a double-blind protocol in 17 patients with mild to moderate hypertension. Verapamil (n = 10) reduced the mean sitting systolic blood pressure by 10.7% (p <O.Ol) and standing by 7.6% (p <0.04). The corresponding data for propranolol (n

= 7) were 4.8% (not significant) and 5% (p = 0.04). Verapamil reduced the sitting diastolic blood pressure by 10.8% (p <O.Ol), propranolol by 7.5% (p = 0.01); the standing diastolic blood pressure was reduced by 10.7% with verapamil (p <O.Ol) and by 8.6% (p = 0.01) with propranolol. With verapamil the mean heart rate fell from 77.60 f 8.42 to 70.20 f 4.85 beats/min (p = 0.03); with propranolol it fell from 76.85 f 6.91 to 66.29 f 4.54 beats/min (p <O.Ol). Although a trend to- wards a slightly greater hypotensive effect was ap- parent with verapamil compared with propranolol, the difference was not statistically significant. It is concluded that verapamil and propranolol exert comparable hypotensive potency in patients with mild to moderate hypertension.

(Am J Cardiol 1986;57:99D-105D)

A lthough it has been recognized for some time that the overall spectrum of therapeutic activity of calcium antagonists is at least as wide as that of p blockers1 it is only in the past several years that the controlled evaluation of calcium antagonists as hypotensive agents has begun.2-G Beta blockers and calcium antagonists are potent antianginal and antiischemic agents; both classes of compounds exert somewhat similar effects in

From the Department of Cardiology, Wadsworth Veterans Ad- ministration Hospital, and the Department of Medicine, UCLA School of Medicine, Los Angeles, California. This study was supported in part by the Medical Research Service of the Veter- ans Administration, the American Heart Association, Greater Los Angeles Affiliate, and a grant-in-aid from the Knoll Phar- maceutical Company, Whippany, New Jersey.

Address for reprints: Bramah N. Singh, MD, Section of Cardi- ology 691/111E, Wadsworth Veterans Administration Hospital, Wilshire and Sawtelle Boulevards, Los Angeles, California 90073.

supraventricular and ventricular tachyarrhythmias7F8 From experimental studies it also appears that calcium antagonists and p blockers exert a comparable degree of cardioprotective effects in terms of the magnitude of myocardial enzyme release and tissue histochemistry, structural and ultrastructural disorganization, gross anatomic infarct size and incidence of ventricular fi- brillation after acute coronary artery ligation9 Because P-adrenergic blocking agents have been found to reduce the incidence of reinfarction and sudden death, presumably as a result of their cardioprotective actions, in the survivors of acute myocardial infarction, they are being increasingly used in patients with coronary artery disease and systemic hypertension.

The question has therefore arisen as to whether calcium antagonists as a class of compounds may also be used as monotherapy for the control of hypertension and myocardial ischemia in patients with ischemic heart disease and high arterial pressure. The purpose of this article is three-fold. The first is to discuss the

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1OOD A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL

pharmacologic similarities and differences between ,6 blockers and calcium antagonists. The second is to provide further evidence from a controlled double- blind study for the comparative efficacy of verapamil and propranolol in patients with mild to moderate hypertension. The third is to discuss the overall advantages and disadvantages of calcium antagonists and /3 blockers as hypotensive agents.

Pharmacologic Considerations The bulk of the pharmacologic effects of P-adrener-

gic blocking drugs can be attributed to the ability of these compounds to competitively block p adrenoceptors. Structurally, these compounds are almost homo- geneous; minor structural differences have produced compounds of variable ,&blocking potency, varied pharmacokinetics and different associated features such as intrinsic sympathomimetic activity, cardiose- lectivity and membrane-depressant propensities. Al- though such features may influence the overall adverse effects profile of an individual agent, they have little or no effect on their therapeutic efficacy, which results essentially from blockade of ,6 adrenoceptors. In contrast, calcium antagonists constitute a structurally heterogeneous group of compoundslO that share 2 significant properties: the ability to block the slow calcium channel in cardiac muscle and the ability to inhibit transmembrane fluxes of calcium in smooth muscle especially in the coronary and peripheral circulations.10

Because of their often striking structural differences, individual calcium compounds may exhibit other pharmacologic actions (e.g., verapamil and diltiazem have noncompetitive sympatholytic actions], which may lead to a complex interplay with their intrinsic properties demonstrable in isolated tissues and the reflex changes they may produce as a result of sympathetic activation caused by peripheral vasodilatation.1° Because of the reflex effects and the varying potencies

of different calcium antagonists to induce peripheral vasodilatation, the in vitro and in vivo actions of calcium antagonists may differ markedly. This is particularly striking in atrioventricular (AV) nodal conduction and refractoriness. For example, as with 0 blockers, calcium antagonists such as verapamil, diltiazem, tia- pamil or gallopamil predictably lengthen AV conduction and refractoriness both in vivo and in vitro. By contrast, the dihydropyridines (e.g., nifedipine and ni- cardipine) are potent depressants of AV nodal conduction in isolated hearts, but this effect is nullified or even reversed by their reflex effectslo

It must be emphasized that while calcium antagonists alter AV nodal conduction by blocking the slow- channel potentials in this structure, p blockers produce their negative dromotropic effects by altering the sympathetic impulse traffic in the AV node. Thus, the AV nodal effects of the 2 classes of compounds are likely to summate if they have similar effects individually (e.g., propranolol compared with verapamil or diltiazem). With dihydropyridines, concomitant fi blockade is likely to convert a potentially facilitatory action on the AV node to a depressant one. These electrophysiologic features of the various compounds are of therapeutic significance in the choice of an agent for the control of hypertension or ischemic syndromes in patients who may have preexisting conduction system disease. From the standpoint of control of hypertension, however, the comparative cardiocirculatory effects of calcium antagonists and fi antagonists are the most rele- vant pharmacologic effects.

It is now well established that most /3 antagonists when administered intravenously or orally depress heart rate, cardiac output and indexes of ventricular contractility and increase the filling pressures of the ventricle. The characteristic hemodynamic effects of

25 20 “R PA PiW no C.I. LVEF CSF MVO, SVA PVR SW,

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+ 50, + 45% TIMOLOL : 1.0 mg paou

FIGURE 1. Hemodynamic effects of intravenously administered timolol in patients with coronary artery disease undergoing diagnos- tic cardiac catheterization. Note that p blockade induces an increase in mean pulmonary artery pressure (PA), systemic vascular resistance (SVR), left ventricular end-diastolic pressure (LVEDP), but a decrease in heart rate (HR), cardiac index (Cl), left ventrlcu- lar work index (LV WI) and left ventricular dP/dt (an index of contractility). Although not shown here, fi blockade produces a decrease in coronary sinus flow and in coronary arteriolar resistance.

FIGURE 2. Effects of intravenous verapamil (10 mg) on systemic and coronary hemodynamic indexes and left ventricular ejection fraction (LVEF) in patients with coronary artery disease. The most striking effect is a decrease in systemic vascular resistance (SVR) and mean aortic pressure (Ao) with the preservation of cardiac index (Cl). The increase in the mean pulmonary capillary wedge pressure (PCW) denotes some reduction in contractility but LVEF is unaffected. The increase in coronary sinus flow (CSF) is consistent with the coronary vasodilator effects of the calcium antagonist. Based on data in reference 11.

P-blocking compounds as exemplified by the proper- cular resistance and reflex sympathetic effects. The ties of timolol are shown in Figure 1. These drugs may currently available data suggest that the most signifi- also reduce coronary blood flow commensurate with cant mechanism mediating the hypotensive effect of the reduction in myocardial oxygen demand. When calcium antagonists is peripheral dilatation. However, given intravenously, they may increase systemic vas- experience is limited with the hemodynamic actions of cular resistance, which, however, decreases during calcium antagonists after prolonged oral therapy. long-term oral administration of these agents owing to We investigated the comparative effects of long- the sustained reduction in cardiac output. The latter term administration of verapamil and propranolol on may contribute significantly to the hypotensive action ventricular function in patients with known coronary of the p antagonists. artery disease.14 The effects of the 2 compounds on

In contrast to the action of /3 blockers, the most strik- heart rate, blood pressure and left ventricular ejection ing hemodynamic effects of calcium antagonists con- fraction determined by radionuclide ventriculography sist of a predictable and consistent reduction in sys- at rest and during exercise on a bicycle ergometer temic vascular resistance accompanied by either no were compared. The mean data are summarized in change or an increase in cardiac output.lO Further, Figures 3 and 4. In patients with relatively well-pre- unlike fi blockers, calcium antagonists reduce coro- served ventricular function, neither drug had a signifi- nary vascular resistance with a tendency for the coro- cant effect on left ventricular ejection fraction at rest. nary sinus flow to increase. Some of the agents may Both drugs prevented the decrease in the ejection frac- produce a slight increase in the filling pressures of the tion induced by exercise, undoubtedly owing to their ventricle presumably owing to impairment of contrac- antiischemic actions. However, the @blockade caused tility, but this is of little hemodynamic consequence by propranolol led to a significant attenuation of the unless the overall ventricular performance is severely heart rate and systolic blood pressure induced by exer- impaired.ll The typical hemodynamic changes pro- cise, while the corresponding changes induced by cal- duced by calcium antagonism as exemplified by intra- cium antagonism with verapamil were modest. Similar venous verapamil are illustrated in Figure 2. The alter- differences have also been found between other p ations produced by diltiazem are very similar.lzJ3 blockers and calcium antagonists. They are of clinical With dihydropyridines, the hemodynamic response is relevance in so far as patients other than those with dominated by a greater reduction in the systemic vas- coronary artery disease [e.g., those with hypertension]

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n FIGURE 3. Effects of long-term oral administration of propranolol PLACEBO PLACEBO (80 mg 3 times a day) and verapamil(l20 mg 3 times a day) on left PROPRANOLOL MRAWvtIL ventricular ejection fraction, determined by radionuclide ventriculo- FIGURE 4. Changes in heart rate, systolic blood pressure and their graphy, at rest and after bicycle exercise. At rest, neither drug had product induced by the long-term oral administration of propranolol a significant effect. During pacing, the decrease was prevented and verapamil. Both agents attenuate the exercise-induced incre- by both propranolol and verapamil. Based on data from Josephson ments in these parameters but the p blocker was more potent. et al.l4 Based on data from Josephson et aLT4

102D, A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL

treated with these 2 classes of drugs are likely to re- spond to physical exercise somewhat differently. For example, with p blockade, exercise capacity is likely to be more severely limited than it is with calcium antagonists.

Comparative Hypotensive Effects of Verapamil and Propranolol

The data presented here are based on a double- blind, placebo-controlled comparative evaluation of the hypotensive potency of verapamil and propranolol in patients with mild to moderate systemic hypertension (140/90 to 180 to 200/110 to 115 mm Hg].

Methods Patient selection and protocol design: The criteria

for entry into the study included a diastolic pressure between 95 and 114 mm Hg determined from 3 consec- utive recordings. Patients with a history of diabetes mellitus, heart failure, AV block or bronchial asthma were excluded. Patients in whom withdrawal from monoamine oxidase inhibitors, antiarrhythmic agents and psychotropic drugs was not possible were also excluded. All subjects were men, mean age 56 years (range 35 to 74).

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FIGURE 5. Effects of verapamil and propranolol on the mean sitting systolic blood pressure. Data represent mean f standard deviation.

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FIGURE 6. Effects of long-term administration of verapamil and FIGURE 7. Changes in the mean sitting diastolic blood pressures propranolol on the mean standing systolic blood pressure. induced by long-term administration of verapamil and propranolol.

The study design was such that during the first phase of 4 weeks, placebo was given in a single-blind fashion and blood pressure was recorded weekly. During the second phase, which was double-blind, verapamil or propranolol was given in an incremental dose sched- ule over 4 weeks. Patients randomized to verapamil received 80 mg 3 times a day during the first week, 120 mg 3 times a day during the second week and 160 mg 3 times a day during the third and fourth weeks. In the propranolol series, the corresponding dosages were 40 mg 3 times a day during the first week, 80 mg 3 times a day in the second week and 120 mg 3 times a day during the third and fourth weeks. During the fifth week the drugs were tapered off. If the control of blood pressure was deemed adequate, long-term therapy was instituted (data presented elsewhere).

Results Eight of the 25 patients who entered the study were

not included in the analysis of data because of various unavoidable deviations from the protocol.

Data analysis: The comparison of the data was based on the blood pressure and heart rate readings at baseline (the last observation of the placebo run-in phase) and the posttreatment recording at the end of the double-blind phase. The parameters analyzed were: average sitting systolic blood pressure, average standing systolic blood pressure, average sitting diastolic blood pressure, average standing diastolic blood pressure and heart rate. At baseline, an analysis of variance was used on each parameter with respect to age, race, treatment and their interactions as effects in the model. None of the interactions was statistically significant.

There were also no significant between-treatment differences at baseline with any parameter. At posttreatment and change from baseline, an analysis of covariance, with the baseline value of each parameter as the covariate, was used. Again, there were no significant interactions and so a reduced model was used with baseline, age, race and treatment as effects. There were no statistically significant between-treatment differences for the first 4 parameters; for heart rate,

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February 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 lQJ0

propranolol had a significantly lower mean posttreatment (p <O.Ol] and a significantly greater reduction from baseline (p <O.Ol).

For each of the 5 parameters under consideration, the (normalized] raw data were used with the follow- ing exception: if the residuals from the first fitted model were not normally distributed, as determined by the Shapiro-Wilk W-statistic at 0.05 level of significance, then the raw data were transformed using the transfor- mation y = In(x). If the residuals from the fitted model using log-transformed data were not normally distributed, then the raw data were ranked.

If the residuals of the fitted model (for either the raw data or the log transformed data) were found to be normally distributed, then a paired t test was used as the within-drug test. Otherwise, the Wilcoxon signed rank test for paired data was used.

Using these methods, raw data were used at baseline, posttreatment and change from baseline for each of the 4 parameters. For heart rate, log-transformed data were used at baseline and ranked data at posttreatment and change from baseline.

The mean data (& standard deviation) with respect to the 5 parameters analyzed are shown in Figures 5 through 9.

Average sitting and standing systolic pressures (Fig. 5 and 6): At baseline, the sitting systolic pressure was 162.73 f 14.31 (mean f standard deviation] and decreased to 145.33 f 12.80 mm Hg on verapamil (n = 10). The change was statistically significant (-10.7%; p <O.Ol]. The corresponding sitting systolic pressures for the propranolol series (n = 7] were 154.10 f 17.18 (baseline) and 146.76 f 22.22 mm Hg (propranolol], a reduction of 4.8% that did not reach statistical significance.

With verapamil, the average standing systolic pressure was 158.00 f 18.65 at baseline and 146.20 f 20.28 mm Hg with the drug. This reduction of 7.6% was statistically significant (p <O.O4). Propranolol reduced the standing systolic pressure from 152.57 f 15.67 to 144.86 f 20.28 mm Hg (5.0%, p = 0.04).

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FIGURE 8. Changes in the mean standing diastolic pressures during FIGURE 9. Changes in heart rate induced by long-term administra- long-term administration of verapamil and propranolol. tion of verapamil and propranolol.

Average sitting and standing diastolic blood pressures: The mean sitting diastolic pressure at baseline with verapamil was 101.53 f 4.49 and decreased to 90.53 f 9.25 mm Hg with the drug (-10.8%, p <O.Ol]. The corresponding pressures with propranolol were 103.43 f 6.08 at baseline and 95.71 f 9.25 mm Hg with the drug (-7.5%, p = O.Ol]. A similar trend of difference was evident for the average standing diastolic blood pressure. With verapamil, the standing diastolic pressure was 102.60 f 6.28 at baseline and decreased to 91.60 f 9.41 mm Hg with drug (of 10.7%, p <O.Ol). Propranolol induced a decrease of 8.6% (p = 0.01) from 105.14 f 6.28 to 96.14 f 9.41 mm Hg. Although there was a trend for the diastolic pressure to be reduced somewhat more by verapamil, the difference did not reach statistical significance.

Effects of verapamil and propranolol on heart rate: The differences between the 2 drugs are shown in Figure 9. With verapamil the heart rate decreased from 77.6 f 8.42 to 70.2 f 4.85 beats/min (-9.5%, p = 0.03). The corresponding data for propranolol were 76.86 f 6.91 at baseline and 66.29 f 4.54 beats/min with drug. The decrease in heart rate with propranolol was highly significant I-13.8%, p <O.Ol). Although the reduction in heart rate with propranolol was clearly greater than that with verapamil, the difference did not reach statistical significance.

Discussion The data from our randomized, double-blind, pla-

cebo-controlled study has provided further evidence of the efficacy of verapamil in the control of mild to moderate hypertension. There was a tendency for a slightly greater effect with verapamil when compared with propranolol, particularly with respect to the sitting and standing diastolic blood pressures, but the difference did not reach statistical significance at the largest dosages of the 2 drugs used in the study. Al- though the number of the patients in our series was small, unlike the findings of ‘Biihler et al,15 our data did not indicate a trend for a greater hypotensive effect for verapamil as a function of advancing age. Thus, further work is needed to define the possible relation between age and hypotensive effectiveness of verapamil and other calcium antagonists.

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104D A SYMPOSIUM: CALCIUM ANTAGONISTS IN HYPERTENSION-FOCUS ON VERAPAMIL

There have been a number of open-label studies that have suggested that verapamil might have significant hypotensive effects in patients with mild to moderate hypertension. 5,~ Of particular interest have been the findings of Gould et a1,17 who analyzed the effects of verapamil by ambulatory blood pressure monitor- ing after 6 weeks of drug therapy at a dosage of 120 to 160 mg 3 times a day. A consistent reduction in blood pressure was found over 24 hours but especially during the daytime, with the preservation of the shape of the circadian pattern of blood pressure variation. The drug was also found to produce an overall reduction in blood pressure with dynamic and isometric exercise, with a reduction in heart rate but without the develop- ment of postural hypotension. In recent years several studies have suggested that verapamil has hypotensive potency that compares favorably with that of many other commonly used antihypertensive compounds such as /3 blockers,15J8-21 a-methyldopa,2z reserpinez3 and diuretics.15

Verapamil versus ,6 blockers in hypertension: Our data indicate that verapamil and propranolol in a blinded study exerted approximately equipotent effects in patients with mild to moderate hypertension, although there appeared to be a trend for a slightly greater potency with the calcium antagonist. In this respect, our experience is similar to that of Leonetti et alazO They compared the effects of 120 and then 160 mg 3 times a day of verapamil to propranolol60 and then 80 mg 3 times a day (each drug regimen lasting for 6 weeks) in 31 patients with moderate essential hypertension. Both the drugs produced a significant reduction in systolic and diastolic blood pressures, both in the supine and the upright positions. As in our current study, the fall in the blood pressure induced by verapamil was slightly but not significantly greater than that produced by propranolol, and there was a greater bradycardic effect with the p blocker than with the calcium antagonist. Doyle et aPgJ1 have reported a similar double-blind crossover of verapamil(l20 mg 3 times a day for 6 weeks] and pindolol(7.5 mg 2 times a day for 6 weeks] and of verapamil(160 mg 2 times a day for 6 weeks) and labetalol (200 mg 2 times a day for 6 weeks]. They found that verapamil was equally as effective as pindolol and labetolol in lowering the high systolic and diastolic pressures. It was of interest that the echocardiographic assessment of cardiac output revealed that the salutary effects of verapamil were accompanied by a slight increase in cardiac output. This indicated that, unlike the ,8 blockers, the hypotensive effect of verapamil was due entirely to a decrease in peripheral vascular resistance in line with the drug’s peripheral vasodilator actions. The differing mechanisms of action of p blockers and calcium antagonists clearly raises the possibility of their combined use in the control of essential hypertension, a therapeutic concept that is well established in the control of chronic stable angina.Z4J5

Therapeutic implications: Our data and those con- tained in the published reports on the effects of verapamil clearly establish the role of this reference calcium antagonist in the control of mild and moderate

essential hypertension. The results have indicated that as a single agent verapamil is at least as effective as propranolol in this setting. The question has therefore arisen as to the circumstances in which the agent might be preferable to p blockers. In our own studies, the adverse effect profile of the 2 classes of compounds could not be evaluated critically because of the small number of patients studied. However, from the experience that has accrued in the treatment of angina by propranolol and other /3 blockers on the one hand and verapamil on the other, it is clear that the latter has significant advantages in certain situations. For example, in hypertensive patients with diabetes, broncho- spastic disease and peripheral vascular disorders, verapamil and other calcium antagonists are preferable to /3 blockers, which are relatively contraindicated. It is also known that because verapamil and many other calcium antagonists interfere less with sympathetic re- flexes, they are less likely to reduce exercise capacity. For example, Atterhog and Ekelundz6 showed that although intravenously administered verapamil in- creased the pulmonary capillary wedge pressure in healthy men at rest, this effect disappeared with exercise. In contrast, it is known that ,6 blockade produces a significant impairment of exercise performance in normal subjectsz7

It should be emphasized that there is now convinc- ing evidence that the cardioprotective action of ,f3 blockers in the survivors of acute myocardial infarction is associated with a reduction in the incidence of sudden death and reinfarction during continuous prophylactic drug administration.28 An impressive body of experimental data has established that calcium antagonists also have a potent cardioprotective action in the ischemic myocardium. However, whether these agents will eventually be shown to exert a salutary effect on the incidence of sudden death and reinfarction in the survivors of acute myocardial infarction remains uncertain. The preliminary data are inconclu- sive.zg Because a significant number of hypertensive patients also have coronary artery disease, the role of calcium antagonists as hypotensive and cardioprotective agents in this context clearly merits critical ap- praisal. At present, the available data leave little doubt as to the role of verapamil as a hypotensive agent in patients with mild to moderate hypertension,

References 1. Ellrodt G, Chew CYC, Singh BN. Therapeutic implications of&w-channel blockade in cardiocirculatory disorders. Circulation 1980;62:669-679. 2. Anavekar SN, Christophidis N, Louis WJ, Doyle AE. VerapamiJ in the treatment of hypertension. f Cardiovasc Pharmacol 1981;3:287-293. 3. Biihler FR, Hulthen UL. Kiowski W, Muller FB. Bolli P. The place of calcium antagonist verapamil in antihypertensive therapy. 1 Cardiovasc Pharmacol 1982:4:suDoJ:S350-S357. 4. Leonetti G, Sala d,‘Bianchiri C, Terzoli L, Zanchetti A. Antihypertensive and renal effects of orally administered verapamil. Eur J Clin Pharmacol 1980;18:375-382. 5. Lewis GRJ. Verapamil in the management of the chronic hypertensive. Clin Invest Med 1980;3:175-177. 6. Klein W, Brandt W, Urecko K, Horringer M. Role of calcium antagonists in the treatment of essential hypertension. Circ Res 1983;suppI I, pt 11:174-181. 7. Singh BN, Nademanee K, Baky S. Calcium antagonists: clinical uses in treating arrhythmias. Drugs 1983:25:125-253. 8. Sineh BN. Collett IT. Chew CYC. New oersoectives in the Dharmacoloeic therapy of cardiac drrhythmias. Prog Card&ax Dis 1980;2;:243-301. v 9. Hamm CW, Opie LH. Protection of infarcting myocardiam by slow-chan-

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nel inhibitors. Circ Res 1983;suppi I,pt II:129-138. 10. Singh BN, Hecht HS, Nademanee K, Chew CYC. Efectrophysiologic and hemodynamic effects of slow channel blocking drugs. Prog Cardiovasc Dis 1982;23:103-132. 11. Chew CYC, Hecht HS, Collett JT, McAllister RG, Singh BN. Influence of the severity of ventricular dysfunction on hemodynomic responses to intravenously administered verapamil in ischemic heart disease. Am r Cardiol 19m;47:917-922. 12. Hossack KF, Brown BG, Stewart DK, Dodge HT. Diltiazem-induced effects on sympathetically mediated constriction of normal and diseased coronary arteries: lack of epicardial coronary dilatory effect in humans. Circuk- tion 1984;70:465-471. 13. Josephson MA, Bufkin-Coyle K, Singh BN. Effects of intravenous diltiazem on pacing-induced manifestations of myocardial ischemio and ventricular function in patients with coronary artery disease. Am \ Cardiol 1986, in review. 14. Josephson MA, Hecht HS, Hopkins HS, Guerrero J, Singh BN. Compara- tive effects of oral verapamil and propranofol on exercise-induced myocardial ischemia and energetics in patients with coronary artery disease: Single- blind placebo cross-over evaluation using radionuclide ventriculography. Am Heart T 1982;103:978-985. 15. Biihler FR, Erne P, Muller FB, H&hen UL, Kiowski W, Block LH, Bolli P. Calcium antagonists in hypertension-a new therapeutic concept. In: Althaus U, Burkhardt D, Vogt E. eds. Symposium on Calcium Antagonism. Frankfurt: Verlag Cublt, 1984:116-124. 16. Pedersen OLC. Does verapomil have a clinically significant antihypertensive effect? Eur J Cfin Pharmacol 1978;13:21-24.

placebo-controlled double-blind randomized cross-over trial. Am J Cardiol 1982;50:1164-1172. 19. Doyle AE. Comparison of beta-adrenoceptor blockers and calcium antagonists in hypertension. Hypertension 1983;2:103-108. 20. Leonetti G, Pasotti C, Ferrari GP, Zanchetti A. Double-blind comparison of the antihypertensive effects of verapamil and propranofof. In: Zanchetti A, Krikler D, eds. Calcium Antagonism in Cardiovascular Therapy: Experience with Verapamii. Amsterdam: Excerpta Medico, 1981:260-267. 21. Doyle AE, Anavekar SN, Oliver LE. A clinical trial of verapamil in the treatment of hypertension. In Ref 20:92-105. 22. Lewis GRJ, Marley MD, Maslowski AH, Bones PJ. Verapamil in the management of hypertensive patients. Aust NZ Med 1979;9:62-64. 23. Leary WP, Asmal AC. Treatment of hypertension with verapamil. Circ Ther Res 1979;25:747-752. 24. Singh BN, Chew CYC, losephson MA. Pharmacologic and hemodynamic mechanisms underlvine the antianeinal actions of veraoamil. Am T Cardiol 1982;50:886-892. ' y

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17. Gould BA, Man S, Kieso H, Subramanian VB, Raftery EB. The 24-hour 28. Singh BN, Venkatesh N. Prevention of myocardial reinfarction and sud- ambulatory blood pressure profile with verapomil. Circulation 1982;65:22-27. den death in survivors of acute myocardiaf infarction: role of prophylactic /3- 18. Frishman WH, Klein NA, Klein P, Strom JA, Tawil R, Strair R, Wong B, blockade. Am Heart r 1984;107:189-200. Roth S, LeJemtel T, Pollack S, Sonnenblick EH. A comparison of oral pro- 29. Danish Multicenter Study Group. Verapamil in acute myocardial infarc- pranolol and verapamil in patients with hypertension and angina pectoris: a tion. Eur Heart 1 1984;4:516-528.

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