The effect of inhibitors of endogenous opioid degradation, bacitracin, bestatin, captopril, and D-phenylalanine, on digoxin-induced arrhythmias in guinea pigs

The purpose of this study was to investigate the effect of inhibition of endogenous opioid degradation on digitalis-induced arrhythmias, utilizing the inhibitors bacitracin, bestatin, captopril, and D-phenylalanine. Guinea pigs, anesthetized with pentobarbital, 50 mg/kg i.p., and breathing spontaneously received intracerebroventricular (i.c.v.) injection of bacitracin (6.8 mg/kg), bestatin (1 mg/kg), captopril (2 mg/kg), D-phenylalanine (1.2 mg/kg) or the diluent, saline. Digitalis arrhythmias were induced by a 50 μg/kg i.v. bolus of digoxin followed by 500 μg∙kg−1∙h−1 i.v. Bacitracin and bestatin, but not captopril or D-phenylalanine, significantly (p < 0.05) altered the relationship between the digoxin dose and the first occurrence of arrhythmias, i.e., digoxin-induced ventricular arrhythmias became manifest at lower digoxin doses. The mean digoxin dose and ED50s, at which arrhythmias first occurred, were significantly (p < 0.05) reduced by bacitracin and bestatin. The findings were similar for fatal arrhythmias, although D-phenylalanine appeared to decrease the digoxin dose at the development of fatal arrhythmias. The opioid antagonist naloxone, in a 50 μg/kg bolus and 50 μg∙kg−1∙h−1 i.c.v., completely prevented these effects of bacitracin and reduced the effect of bestatin. The relationship to arrhythmias could not be ascribed to an effect on blood pressure, as the blood pressure response to digoxin was the same in bestatin, D-phenylalanine, and control groups. To examine whether systemic administration of an inhibitor of opioid degradation had similar effects, a second protocol was selected with systemic administration of bacitracin because it altered the dose effect relationship after i.c.v. administration and systemic concentrations could be readily attained. Bacitracin, in a 13.5 mg/kg i.v. bolus and 135 mg∙kg−1∙h−1 i.v., was followed by 100 μg/kg digoxin i.v. every 15 min. Bacitracin significantly (p < 0.05) reduced the digoxin dose at the development of arrhythmias. This was reversed by naloxone, given as 2 mg/kg i.v. plus 10 mg∙kg−1∙h−1. Thus, these data indicate that inhibitors of degradation of some opioid potentiate digitalis arrhythmias in a manner that is inhibited by naloxone, and provide evidence that implicates a role for endogenous opioids in digitalis arrhythmias.Key words: digitalis arrhythmias, aminopeptidase inhibitors.