Comparative antiarrhythmic and electrophysiological effects of drugs known to inhibit calmodulin (TFP, W7 and bepridil)

Abstract

The potential antiarrhythmic and electrophysiological actions of drugs known to inhibit calmodulin, i.e. trifluoperazine (TFP) and N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W7) have been compared with bepridil, whose antiarrhythmic actions have previously been ascribed to blockade of the fast inward sodium current in cardiac tissue. Like bepridil, both TFP and W7 reduced the severity of arrhythmias evoked by 30 min of coronary artery occlusion in the anaesthetized rat. TFP (2.5-10 mg kg-1, i.v.), W7 (2.5-10 mg kg-1, i.v.) and bepridil (1-5 mg kg-1, i.v.) also antagonized the development of ventricular fibrillation induced by 5 min of occlusion followed by reperfusion. All three drugs also reduced mortality. TFP and bepridil also reduced the incidence of reperfusion-induced ventricular tachycardia whilst all 3 drugs reduced its duration. Although TFP was shown to possess alpha-adrenoceptor blocking properties, the classical alpha-blocker, phentolamine, failed to reduce significantly the incidence or severity of reperfusion arrhythmias. In contrast to bepridil (2-20 microM), which markedly reduced the maximum rate of depolarization (Vmax) of guinea-pig isolated papillary muscle, W7(5-50 microM) showed only weak effects on Vmax and was at least 10 times less potent than bepridil whilst TFP only reduced Vmax in high concentrations (40-100 microM) which lowered resting membrane potential. Unlike bepridil, neither TFP (4-40 microM) nor W7 prolonged the absolute refractory period. The results suggest that drugs which inhibit calmodulin confer protection against both ischaemia-and reperfusion-induced arrhythmias in the rat. Although the electrophysiological actions of bepridil would adequately account for its antiarrhythmic activity, the same cannot be said of W7 and especially TFP. In conclusion, calmodulin antagonism may constitute a mechanism of antiarrhythmic activity.