R 56 865, a Na+/Ca(2+)-overload inhibitor, protects against aconitine-induced cardiac arrhythmias in vivo.
Disturbances in cellular Na+/Ca2+ homeostasis may play a central role in the pathogenesis of ventricular arrhythmias and cell damage induced by the alkaloids veratridine and aconitine in vitro. To test this hypothesis in vivo, the effects on aconitine-induced arrhythmias of intravenous (i.v.) pretreatment with R 56 865 (a Na(+)- and Ca(2+)-overload inhibitor) were compared with those of lidocaine, verapamil, and tetrodotoxin (TTX) in anesthetized rats (n = 10 for each compound). The i.v. bolus injection of aconitine (6.2, 12.5, or 25 micrograms/kg) induced ventricular premature beats (VPBs), ventricular tachycardia (VT), ventricular fibrillation (VF), and mortality in a dose-dependent manner. Because aconitine at a dose of 12.5 micrograms/kg i.v. resulted in a high incidence of ventricular arrhythmias as well as mortality, this dose was used in further tests. Pretreatment of rats with R 56 865 (1.25 mg/kg) significantly reduced the incidences of aconitine-induced VT and VF, as well as mortality, relative to the saline control group. Pretreatment with verapamil (0.32 mg/kg), was ineffective against aconitine-induced ventricular arrhythmias and mortality. Pretreatment with lidocaine (10 mg/kg) significantly reduced the incidence of VT and caused low but not significant reductions in the incidences of VF and mortality induced by aconitine. Pretreatment with a selective sodium channel blocker TTX (4 micrograms/kg) also significantly reduced the incidences of VT, VF, and mortality elicited by aconitine. These results suggest that intracellular Na+ loading plays an important role in aconitine-induced ventricular arrhythmias; the Ca(2+)-overload after Na+ loading elicited by aconitine is not likely to be mediated by increased Ca2+ influx through a slow channel.
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Janssen Research Foundation, Department of Cardiovascular Pharmacology, Beerse, Belgium.
De Clerck
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D000157:Aconitine / Q000037:antagonists & inhibitors*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D052160:Benzothiazoles; D010880:Piperidines; D015222:Sodium Channels; D013844:Thiazoles; D013779:Tetrodotoxin; C054551:R 56865; D008012:Lidocaine; D012964:Sodium; D014700:Verapamil; D002118:Calcium; D000157:Aconitine