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

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Abstract
1 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. 2 Like bepridil, both TFP and W7 reduced the severity of arrhythmias evoked by 30 min of coronary artery occlusion in the anaesthetized rat. 3 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. 4 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. 5 In contrast to bepridil (2-20 .mu.M), which markedly reduced the maximum rate of depolarization (Vmax) of guinea-pig isolated papillary muscle, W7 (5-50 .mu.M) 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 .mu.M) which lowered resting membrane potential. 6 Unlike bepridil, neither TFP (4-40 .mu.M) nor W7 prolonged the absolute refractory period. 7 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. 8 In conclusion, calmodulin antagonism may constitute a mechanism of antiarrhythmic activity.