EFFECTS OF A LEUKOTRIENE-D(4) 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 digitali s-induced arrhythmias in guinea-pigs, utilizing a dual inhibitor of ly poxygenase 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 intra venous injection of BW-755C (5, 10 and 20 mg/kg) or L-648,051 (5 and 1 0 mg/kg) 15 min prior to digoxin. Digitalis arrhythmias were induced b y a 50 mug/kg intravenous bolus injection, followed, 15 min later, by a 400 mug/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 no t 20 mg/kg) significantly increased the digoxin dose causing mortality . Both L-648,051 (5 mg/kg) and BW-755C (10 mg/kg) significantly preven ted the incidence of ventricular fibrillation. At a higher dose (20 mg /kg), BW-755C caused a more rapid development of ventricular fibrillat ion and mortality than in other doses. These data suggest that inhibit ors of lypoxygenase and leukotriene receptor antagonists may have prot ective effects and that endogenously released leukotrienes may play an important role in digoxin-induced arrhythmias in guinea-pigs.