Differential cardiovascular effects of calcium channel blocking agents: Potential mechanisms

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine > diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil > nifedipine > diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine > verapamil > diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.