Mechanism of action of calcium antagonists on myocardial and smooth muscle membranes

Although calcium channel blockers vary considerably in their chemical structure and pharmacologic profile, the widely accepted mechanism of their action is an inhibition of Ca2+ influx - via voltage-activated slow channels - into smooth and cardiac muscle. Other ways of Ca2+ entry, such as passive diffusion and Na+/Ca2+ and K+/Ca2+ exchange, are not affected by these compounds. However, various blockers exert a slightly different inhibitory action on the slow channels, which indicates that various binding sites in the cell membranes, or even in intracellular sites, may be involved. Potential sites of action of calcium channel blockers in the myocardium include: the slow calcium channels; Na+/Ca2+ channels; mitochondria; sarcoplasmic reticulum; myofilaments; and calcium efflux. However, experimental evidence has been given for only the first site, and the third and fourth sites are still controversial. In the vascular smooth muscles, calcium channel blockers could possibly block the potential-dependent or receptor-operated channels, or bind to calmodulin. Again, only the first site of action has been experimentally proven. An important feature of calcium channel blockers is their different affinities for various tissues. For instance, cinnarizine and its difluorinated derivative flunarizine are 1000 times more effective in blocking slow channels in vascular smooth muscles than those in the myocardium. Even within the same system, such as the cardiovascular system, differences in tissue specificity are encountered. Thus, while nimodipine acts preferentially on cerebral vessels, diltiazem has more affinity for the coronary vasculature. Tissue specificity is exhibited even for different myocardial structures; thus, while verapamil affects the nodal and conductive tissues in the myocardium (hence its use as an antiarrhythmic agent), nifedipine is almost devoid of such activity. Organ selectivity of calcium channel blockers is one of the attractive features of this group of compounds; hence their use in a variety of cardiovascular conditions.