The antiarrhythmic and antifibrillatory effects of calcium antagonists.
Calcium-channel antagonists are widely used in the treatment of supraventricular tachyarrhythmias. The potential benefits of these agents in the management of ventricular arrhythmias, however, are not widely appreciated. Ventricular arrhythmias result from abnormalities of impulse generation and/or impulse conduction. The calcium ion has been implicated in both mechanisms. Myocardial cytosolic calcium increases during ischemia and sympathetic nervous system activation. Elevations in cytosolic calcium provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Myocardial ischemia also results in a dispersion of refractory period, producing random re-entrant circuits and ventricular fibrillation. Alterations in action potential duration that produce this dispersion of refractory period are associated with spatial and temporal nonuniformities of intracellular calcium transients. Calcium-channel antagonists have been shown to prevent afterdepolarizations and to reduce the endocardial to epicardial dispersion of the refractory period during myocardial ischemia, and therefore could prevent malignant arrhythmias. A slow inward calcium current may, in fact, be required for the initiation and maintenance of ventricular fibrillation. Calcium antagonists reduce, whereas calcium agonists enhance, the susceptibility to ventricular fibrillation induced by the combination of exercise and acute myocardial ischemia. The cardioprotection occurs independently of actions on vascular smooth muscle. Thus, calcium antagonists that exert direct myocardial actions may prove to be particularly effective in the prevention of sudden cardiac death in patients. The challenge remains to develop calcium antagonists that selectively modulate myocardial calcium entry without compromising cardiac mechanical function.
Billman
G E
GE
Department of Physiology, Ohio State University, Columbus 43210.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D014693:Ventricular Fibrillation / Q000188:drug therapy*
D002121:Calcium Channel Blockers; D002118:Calcium