Inhibition of Na +/Ca 2+ overload with R 56 865 protects against cardiac arrhythmias elicited by ouabain in vivo in guinea-pigs

Abstract

Several studies have suggested a central role for Na +/Ca 2+ in the pathogenesis of ouabain-induced cardiac arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmias of i.v. pretreatment with R 56 865, a Na + and Ca 2+ overload inhibitor, were compared with those of lidocaine, verapamil and tetrodotoxin in anesthetized guinea-pigs. Cardiac arrhythmias were induced by i.v. infusion of ouabain (10 μg/kg per min). All nine guinea-pigs pretreated with saline developed ventricular premature beats at an ouabain dose of 159 ± 9 μg/kg (mean ± S.E.M.), ventricular tachycardia at a dose of 190 ± 10 μg/kg, ventricular fibrillation at a dose of 253 ± 18 μg/kg and died at a dose of 269 ± 16 μg/kg; none of the animals developed heart block or asytole. Pretreatment with R 56 865 (1.25 mg/kg, n = 6) significantly increased the ouabain doses required to induce ventricular premature beats, ventricular tachycardia, ventricular fibrillation and death relative to those for the saline group. Pretreatment with a Ca 2+ entry blocker verapamil (0.32 mg/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular arrhythmias and death; this medication was associated with second or third degree heart block during ouabain infusion in four out of six animals. Pretreatment with lidocaine ((10 mg/kg, n = 6) caused a significant increase in the dose of ouabain needed to initiate cardiac arrhythmias and to cause death. Pretreatment with a selective Na + channel blocker tetrodotoxin (4 μg/kg, n = 6) also significantly increased the ouabain does required to provoke ventricular premature beats, ventricular tachycardia, ventricular fibrillation, and death. The present results suggest that intracellular Na + and Ca 2+ loading plays an important role in the ouabain-induced cardiac arrhythmias and demonstrate the capacity of R 56 865 to reduce the ventricular arrhythmias and death caused by ouabain toxicity in vivo.