Inhibition of Na+/Ca2+ overload with R 56,865 protects against cardiac arrhythmias elicited by ouabain in vivo in guinea-pigs.
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)
Janssen Research Foundation, Department of Cardiovascular Pharmacology, Beerse, Belgium.
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D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D052160:Benzothiazoles; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D010042:Ouabain / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D012964:Sodium / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014700:Verapamil / Q000494:pharmacology
D052160:Benzothiazoles; D010880:Piperidines; D013844:Thiazoles; D013779:Tetrodotoxin; D010042:Ouabain; C054551:R 56865; D008012:Lidocaine; D012964:Sodium; D014700:Verapamil; D002118:Calcium