Chronotropic, Inotropic, and Vasodilator Actions of Diltiazem, Nifedipine, and Verapamil: A Comparative Study of Physiological Responses and Membrane Receptor Activity

• Published in: Circulation research 1983-02, Vol.52 (2 Suppl I), p.I-29-I-39
• Main Authors: Millard, R W, Grupp, G, Grupp, I L, DiSalvo, J, DePover, A, Schwart, A
• Format: Article
• Language: English
• Subjects: Animals; Benzazepines - pharmacology; Blood Pressure - drug effects; Calcium Channel Blockers - metabolism; Calcium Channel Blockers - pharmacology; Coronary Circulation - drug effects; Diltiazem - pharmacology; Dogs; Guinea Pigs; Heart Rate - drug effects; In Vitro Techniques; Myocardial Contraction - drug effects; Nicotinic Acids - metabolism; Nifedipine - pharmacology; Nimodipine; Potassium - pharmacology; Pyridines - pharmacology; Receptors, Drug - metabolism; Vasodilation - drug effects; Verapamil - pharmacology
• ISSN: 0009-7330; 1524-4571

The three major, chemically distinct calcium channel-blocking drugs, diltiazem, nifedipine, and verapamil, produce coronary vasodilation in the conscious dog. Coronary vascular resistance was reduced by 50% with an intravenous dose of 3 μg/kg nifedipine, 30 μg/kg verapamil, and 100 μg/kg diltiazem. In conscious dogs, nifedipine and verapamil increased heart rate, whereas diltiazem produced a smaller increase in heart rate. The rate of left ventricular pressure development in conscious dogs was unaffected by diltiazem, increased by nifedipine, and decreased by verapamil. Tachycardia was reversed to bradycardia and consistent negative inotropic effects were demonstrated by all three drugs only after combined autonomic blockade with atropine and propranolol in conscious dogs. In isolated dog coronary artery strips contracted ex vivo with 50 ITIM potassium chloride, the ID50 for relaxation was 0.01 μM for nifedipine, 0.02 μM for verapamil, and 0.30 μM for diltiazem. In isolated ex vivo hearts, all agents produced dose-dependent negative chronotropy with a 25% reduction in spontaneous heart rate achieved by 0.09 μM nifedipine, 0.20 μM verapamil, and 0.40 JUM diltiazem. Similarly, the rate of force development in isolated myocardial strips was 50% depressed by nifedipine, 0.03 μM; verapamil, 0.10 μM; and diltiazem, 0.40 μM. On a membrane level, nifedepine, verapamil, and diltiazem interacted with a putative receptor or site associated with a calcium channel specifically labelled with [Hlnimodipine. The specific binding to cardiac sarcolemma was competitively inhibited by nifedipine, only partly inhibited by verapamil, and was stimulated by diltiazem. The effects of verapamil and diltiazem, but not the effect of nifedepine, occurred at pharmacologically active concentrations. Considerable nonspecific binding of dihydropyridines to sarcolemma may account, at least in part, for discrepancies between their dissociation constants on purified sarcolemma and their ED50 in pharmacological effects. Diltiazem and verapamil (1 μM) did not alter [H]nimodipine nonspecific binding. These results strongly suggest that calcium channel-blocking drugs may have different sites of action.