Calcium channel antagonists, Part I: Fundamental properties: mechanisms, classification, sites of action.

Ca2+ channel antagonists are agents that interact with the voltage-dependent Ca2+ channel in a highly specific way. The prototype agents of cardiovascular importance are verapamil, nifedipine, and diltiazem, in historical order of appearance. These agents all have different molecular structures and bind separately with receptor sites located in or near the calcium channel, at molecular sites still to be fully identified. There are probably three distinct receptor sites (V, N, D) which stand in relation to the "gate" of the long-acting "L" calcium channel. There is probably overlap among the receptor sites, especially between the V and D sites to explain their common properties. All three agents inhibit the voltage-dependent calcium channel in vascular smooth muscle and also myocardial slow calcium channels. The ratio of the arterial to the myocardial effect is an index of the arterial selectivity, generally held to be a desirable property because the negative inotropic effect is usually a liability. The general clinical impression that nifedipine is the agent most active in vascular tissue in relation to the myocardial effect is supported by data on the relative potencies of these three agents on blood perfused dog preparations and by a comparison of the potency on rat vascular (portal vein) versus myocardial effects. Nonetheless all three agents are highly active in the inhibition of K(+)-induced vascular contractions (nifedipine 10(-9) M to 10(-8) M; verapamil 10(-7) M to 10(-6) M; and diltiazem 5 x 10(-7) M to 10(-6) M; concentrations for 50% inhibition of K(+)-induced vascular contractions in rat or rabbit aorta; comparative data for resistance vessels not available). The clinical impression that verapamil and diltiazem are more active on nodal tissue is also supported by a comparison of potencies on blood perfused dog nodal preparations in comparison with effects on coronary flow, with verapamil and diltiazem being approximately 10x more potent on the AV node than increasing coronary blood flow, so that the nodal effect is first detected. These basic pharmacological properties explain why all these three agents have clinical effects relevant to inhibition of vascular contraction (antihypertensive and antianginal effects) and only verapamil and diltiazem have clinically relevant inhibitory effects on the AV node (inhibition of supraventricular tachycardias). The comparative potencies of verapamil, diltiazem, and nifedipine in angina and hypertension will be examined in Parts II and III of this review.