Several studies have suggested a central role for Na+/Ca2+ 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 Ca2+ 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 micrograms/kg per min). All nine guinea-pigs pretreated with saline developed ventricular premature beats at an ouabain dose of 159 +/- 9 micrograms/kg (mean +/- S.E.M.), ventricular tachycardia at a dose of 190 +/- 10 micrograms/kg, ventricular fibrillation at a dose of 253 +/- 18 micrograms/kg and died at a dose of 269 +/- 16 micrograms/kg; none of the animals developed heart block or asystole. 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 Ca2+ 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 micrograms/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular premature beats, ventricular tachycardia, ventricular fibrillation, and death.(ABSTRACT TRUNCATED AT 250 WORDS)