R-56-865, A NA+ CA2+-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 hyp othesis in vivo, the effects on aconitine-induced arrhythmias of intra venous (i.v.) pretreatment with R 56 865 (a Na+- and Ca+-overload inhi bitor) were compared with those of lidocaine, verapamil, and tetrodoto xin (TTX) in anesthetized rats (n = 10 for each compound). The i.v. bo lus injection of aconitine (6.2, 12.5, or 25 mug/kg) induced ventricul ar premature beats (VPBs), ventricular tachycardia (VT), ventricular f ibrillation (VF), and mortality in a dose-dependent manner. Because ac onitine at a dose of 12.5 mug/kg i.v. resulted in a high incidence of ventricular arrhythmias as well as mortality, this dose was used in fu rther tests. Pretreatment of rats with R 56 865 (1.25 mg/kg) significa ntly reduced the incidences of aconitine-induced VT and VF, as well as mortality, relative to the saline control group. Pretreatment with ve rapamil (0.32 mg/kg), was ineffective against aconitine-induced ventri cular arrhythmias and mortality. Pretreatment with lidocaine (10 mg/kg ) significantly reduced the incidence of VT and caused low but not sig nificant reductions in the incidences of VF and mortality induced by a conitine. Pretreatment with a selective sodium channel blocker TTX (4 mug/kg) also significantly reduced the incidences of VT, VF, and morta lity elicited by aconitine. These results suggest that intracellular N a+ loading plays an important role in aconitine-induced ventricular ar rhythmias; the Ca2+-overload after Na+ loading elicited by aconitine i s not likely to be mediated by increased Ca2+ influx through a slow ch annel.