Calcium Channel Antagonists: Pharmacologic and Radioligand Binding Approaches to Mechanisms of Action

Abstract

The chemical heterogeneity of the group of agents known as the Ca²⁺ channel blockers or Ca²⁺ channel antagonists (Figure 1) has long suggested that these agents impair Ca²⁺ channel function by different mechanisms (for reviews see references 1 and 2). Accordingly, these agents exhibit important differences in their pharmacologic properties including variations in cardiac:smooth muscle selectivity (3,4) and differences in the extent to which they exhibit frequency- or use-dependence. Thus, verapamil/D600 and diltiazem are approximately equieffective in smooth and cardiac muscle, whereas nifedipine, and other 1,4-dihydropyridines, are significantly more selective for smooth muscle, both vascular and nonvascular (3–5). Similarly, verapamil/D600 and diltiazem exhibit to a significant degree the phenomena of use- and voltage-dependence whereby activity increases with increasing frequency of stimulation and with increasing membrane depolarization. This suggests that verapami1/D600 and diltiazem, unlike nifedipine, have a marked preference for interaction with channels in the open or depolarized state (6). Additionally, verapami1/D600 and diltiazem interact with a number of receptor systems, including muscarinic, adrenergic α₁ and α₂ and opiate, as well as with K⁺ channels, at concentrations (10^-6M) that are similar to those achieved clinically (for reviews see references 1,2,7). In contrast nifedipine is relatively free from such additional actions.