Pharmacology and mechanisms of action of calcium-channel blockers

Abstract

The calcium-channel blockers represent a group of organic chemical structures that share the ability to inhibit Ca2+ entry into excitable cells. In coronary and peripheral arterial smooth muscle and the heart, inhibition of Ca2+ entry blunts the ability of Ca2+ to serve as an intracellular messenger. Thus, calcium-channel blockers are smooth-muscle dilators and have a negative inotropic effect on the working myocardial cells of the atria and ventricles. Calcium-channel blockers also have effects on impulse formation and conduction in some regions of the heart. A fast, Na+-dependent ionic current is responsible for the upstroke of the action potential in the working cells of the atria and ventricles and in the rapidly conducting cells of the His-Purkinje system, so that the calcium-channel blockers do not inhibit conduction in these cells. In the sinoatrial and atrioventricular nodes, where depolarization is due primarily to a Ca2+-dependent slow inward current, the calcium-channel blockers slow the sinus pacemaker and inhibit atrioventricular conduction. The actions of different calcium-channel blockers are not always similar; for example, nifedipine is much more potent as an inhibitor of calcium channels in smooth muscle than in the heart, whereas verapamil and diltiazem are approximately equipotent in heart and vascular smooth muscle. It is likely that the calcium-channel blockers reach their specific binding sites in membranes by first dissolving in the phospholipid bilayer, after which they may interact with hydrophobic regions of proteins that make up, or regulate, these channels. Further knowledge of these molecular properties should facilitate the development of new calcium-channel blockers with improved specificity.