Differential Actions on Rabbit Nodal, Atrial, Purkinje Cell and Ventricular Potentials of Melperone, a Bradycardic Agent Delaying Repolarization: Effects of Hypoxia

Abstract

1 Melperone, a butyrophenone tranquillizer, caused bradycardia in vivo and in vitro. 2 Although Melperone had ax-adrenoceptor antagonist activity in the pithed rat, it was not a P-adrenoceptor antagonist, nor was it a cholinoceptor agonist.3 The bradycardic action could be attributed almost entirely to a prolongation by Melperone of action potential duration (APD) in sinus node cells, with little effect on the slow diastolic depolarization. 4 APD was prolonged by Melperone in atrial and ventricular muscle, and most of all in the bundle of His, but only moderately in the terminal Purkinje cells. 5 In all cardiac tissues depolarized by fast inward current, Melperone caused a dose-related reduction in the maximum rate of depolarization and conduction velocity. On desheathed frog nerve Melperone had a local anaesthetic potency equal to that of procaine. 6 There was no negative inotropic effect in cardiac muscle, nor interference with A-V nodal conduction, from which it was inferred that Melperone did not restrict slow inward current. 7 Melperone did not reduce hypoxic shortening of APD relative to the initial value at the start of hypoxia, but because APD was already lengthened by Melperone in normoxic conditions, APD90 during hypoxia remained close to normal values. There was no protection against hypoxic depression of contractions. 8 It was concluded that Melperone had class 1 and class 3 antiarrythmic actions and merited trial as an antiarrhythmic drug.

Pharmacological mapping of regional effects in the rabbit heart of some new antiarrhythmic drugs

“…In vitro we found that melperone at 2.67 tIM had no effect on A-H conduction time; at higher concentrations, however, there was a small increase in A-H conduction time, which was attributed to depressed conduction in atrium and His bundle rather than in the A-V node itself (Millar & Vaughan Williams, 1982a). However, at the lower concentrations, below the threshold for class 1 action, it has been suggested that melperone may actually reduce inactivation of sodium channels.…”

Electrophysiological effects of melperone on isolated rabbit heart muscles

“…The effects of antiarrhythmic drugs in vivo are affected by their actions on the autonomic tone, the inotropic state of the heart, and the state of the central nervous system, as well as their direct antiarrhythmic actions. The postsynaptic aadrenoceptor antagonism (Petersen, 1981), the positive inotropism (Smiseth et al, 1981;Platou et al, 1982) and the bradycardic effect of melperone (Millar & Vaughan Williams, 1982) might favourably affect the direct antiarrhythmic actions of melperone, studied in our experiments.…”

“…Melperone was proposed as one of the promising class 3 antiarrhythmic drugs by Vaughan Williams (Millar & Vaughan Williams, 1982). The reported serum concentrations of melperone ranged from 0.2pm to 2.0Mm during clinical administration (Refsum et al, 1978).…”

“…It was reported that in mammalian cardiac muscles, melperone prolonged the action potential duration (APD) and the effective refractory period (ERP) without affecting the maximum rate of depolarization (J,,.,) and without depressing contractility (Millar & Vaughan Williams, 1982). These effects are typical of antiarrhythmic drugs of class 3, according to the classification of Vaughan Williams (Vaughan Williams, 1970).…”

“…(Millar & Vaughan Williams, 1982). A recent investigation (Campbell, 1983a) revealed that class 1 antiarrhythmic drugs have different kinetics of depression of P.. (resting block and rate-dependent block), and rate-dependent block (RDB) is considered to be essential for class 1 antiarrhythmic action.…”