Comparative elfects of verapamil , diltiazem , and nifedipine on hemodynamics and left ventricular function during acute myocardial ischemia in dogs

The calcium channel-blocking drugs verapamil, diltiazem, and nifedipine are being used with increasing frequency in patients with angina pectoris due to coronary artery disease. Although each of these agents possesses negative inotropic potential, their relative effects on myocardial function in relation to their vasodilator potencies are unknown. We undertook to study this in 20 conscious dogs that had partial occlusions of their circumflex coronary arteries during therapy with placebo, verapamil, nifedipine, or diltiazem. Myocardial blood flow was measured by use of microspheres, and left ventricular function was measured by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure and coronary vascular resistance of nonischemic myocardium. Global ejection fraction and ejection fraction of the ischemic region were significantly decreased by verapamil (p < .01) and increased by nifedipine (p < .001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p < .001); nifedipine also increased diastolic filling rate, but only at doses that markedly decreased mean arterial pressure and coronary vascular resistance. The effect of diltiazem on diastolic filling rate was not significantly different than placebo. For doses causing an equal decrease in mean arterial pressure, verapamil decreased heart rate (p < .001 ), and diltiazem and nifedipine increased heart rate (p < .001 ). We conclude that the relative potencies of these three calcium channel-blocking agents on left ventricular systolic and diastolic function during myocardial ischemia are different when compared with their relative vasodilator potencies. These differences may have important clinical implications. Circulation 69, No. 2, 382-390, 1984. THE ANTIANGINAL POTENTIAL of calcium channel-blocking agents is currently under active investigation. Of the several calcium channel-blocking agents available, the most commonly studied have been verapamil, diltiazem, and nifedipine. These agents have several hemodynamic and electrical effects: they are potent coronary and systemic vasodilators,' they possess negative inotropic potential,2 and verapamil and diltiazem can decrease sinus node automaticity and thereby decrease heart rate.3-' As a result of these effects, angina due to coronary artery disease might be improved. Thus, any negative inotropic actions and slowing actions of the sinus node, as well as From the Cardiology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda. Address for correspondence: Joann Urquhart, M.D., Cardiology Branch, NHLBI, Building 10. Room 7B15, National Institutes of Health, Bethesda, Maryland 20205. Received June 10, 1982; revision accepted Oct. 20, 1983. 382 any hypotensive effects, may improve angina pectoris by decreasing myocardial oxygen demands. In addition, the capacity of the calcium antagonists to dilate coronary arteries and thereby increase myocardial blood flow2 may play an important therapeutic role even in patients without frank coronary spasm.6 On the other hand, if the negative inotropic effects of these drugs were marked, congestive heart failure could be precipitated. While each of these agents has been shown to possess the capacity for decreasing myocardial contractility, there is considerable controversy concerning the relative magnitude of their myocardial depressant potential.7-10 One of the reasons for such controversy is that although each drug has been assessed in intact dogs without ischemia'0 or in isolated muscle preparation s, 'I 12 there have been no studies that have used dose-response curves in conscious animals in which reflex mechanisms remain intact and that have investi-