Molecular basis of calcium channel blockade

Calcium plays a central role in cellular regulation, where its major function is activation. In the sinoatrial node, the entry of positively charged calcium ions through calcium channels in the plasma membrane generates an inward (depolarizing) current that contributes to pacemaker activity, whereas calcium entry in the atrioventricular (AV) node provides the major depolarizing current during AV conduction. In the working myocardial cells of the atria and ventricles, calcium entry through plasma membrane channels triggers calcium release from intracellular stores in the sarcoplasmic reticulum, and so plays a central role in excitation-contraction coupling. Calcium also serves as an intracellular messenger that binds to members of a family of intracellular calcium-binding proteins that include troponin and calmodulin. In the heart, calcium binding to troponin initiates systole, and formation of the calcium-calmodulin complex in vascular smooth muscle initiates a cascade of reactions that leads to vasoconstriction. Calcium channel blockers, by inhibiting the opening of calcium channels, attenuate all of these reactions; in the heart, they slow the sinus pacemaker and AV conduction and depress myocardial contractility. In smooth muscle, these drugs are vasodilators. Different members of the diverse group of chemical structures that block calcium channels have different specificities for different channels, and so differ in their effects on the cardiovascular system.