Sites of action of Ca2+ channel inhibitors.

Ca2+ channel inhibitors are viewed as a subgroup of Ca2+ antagonists. Most of the currently used Ca2+ channel inhibitors are thought to act by reducing Ca2+ entry into the cell through Ca2+ channels. There is substantial electrophysiological evidence that the major site of action of verapamil, nifedipine and diltiazem in cardiac cells is a sarcolemmal Ca2+ channel. Cytosolic sites of action may contribute to their effects but probably only at higher than therapeutic concentrations. The recent ligand binding studies also tend to support the view that the sarcolemma is the site of action of Ca2+ channel inhibitors in smooth muscle. High affinity binding sites for 1,4-dihydropyridines without any established function are found in fast skeletal muscle and some neuronal membranes. The binding of [3H]nitrendipine to membranes from cardiac, skeletal and smooth muscle, and from brain is saturable, reversible and of high affinity; it is sensitive to cations and other drugs that interact with Ca2+ channels. Inhibition of [3H]nitrendipine binding and blockade of K+ responses in guinea pig ileum by 1,4-dihydropyridines are well correlated, supporting the view that the observed binding is to Ca2+ channel. In contrast, blockade of Ca2+ channels in cardiac and skeletal muscle and in brain synaptosomes occurs only at higher concentrations than needed to saturate the high affinity binding sites. The therapeutic success of Ca2+ channel inhibitors in the treatment of angina pectoris, hypertension, peripheral vascular diseases, and many other disease entities is based on selective inhibition of Ca2+ entry into smooth muscle cells. The specificity of some of these drugs for Ca2+ channels in different cell types, organs, or vascular beds is probably determined by receptor modulation and the effect of reflex mechanisms, which in turn determine the indications for their therapeutic use.