Effects of a leukotriene D4 receptor antagonist, L-648,051, and a dual inhibitor lypoxygenase and cyclooxygenase, BW-755C, on digoxin-induced arrhythmias in guinea-pigs

In this study, we investigated the effects of leukotrienes on digitalis-induced arrhythmias in guinea-pigs, utilizing a dual inhibitor of lypoxygenase and cyclooxygenase, BW-755C, and a leukotriene D4 receptor antagonist, L-648,051. Guinea-pigs, anaesthetized with urethane (1.5 g/kg, intraperitoneally) and breathing spontaneously, received an intravenous injection of BW-755C (5, 10 and 20 mg/kg) or L-648,051 (5 and 10 mg/kg) 15 min prior to digoxin. Digitalis arrhythmias were induced by a 50 micrograms/kg intravenous bolus injection, followed, 15 min later, by a 400 micrograms/kg/hr intravenous infusion. Compared with the control group, L-648,051 (5 mg/kg) significantly increased the digoxin dose causing ventricular tachycardia and mortality. BW-755C (5 and 10 mg/kg, but not 20 mg/kg) significantly increased the digoxin dose causing mortality. Both L-648,051 (5 mg/kg) and BW-755C (10 mg/kg) significantly prevented the incidence of ventricular fibrillation. At a higher dose (20 mg/kg), BW-755C caused a more rapid development of ventricular fibrillation and mortality than in other doses. These data suggest that inhibitors of lypoxygenase and Leukotriene Receptor antagonists may have protective effects and that endogenously released leukotrienes may play an important role in digoxin-induced arrhythmias in guinea-pigs.