Arrhythmogenesis Toxicity of Aconitine Is Related to Intracellular Ca2+ Signals

Aconitine is a well-known arrhythmogenic toxin and induces triggered activities through cardiac voltage-gated Na+ channels. However, the effects of aconitine on intracellular Ca2+ signals were previously unknown. We investigated the effects of aconitine on intracellular Ca2+ signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca2+ signals were evaluated by measuring L-type Ca2+ currents, caffeine-induced Ca2+ release and the expression of NCX and SERCA2a. Action potential and triggered activities were recorded by whole-cell patch-clamp techniques. In rat ventricular myocytes, the action potential duration was significantly prolonged by 1 mu M aconitine. At higher concentrations (5 mu M and 10 mu M), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 mu M) significantly increased the ICa-L density from 12.77 +/- 3.12 pA/pF to 18.98 +/- 3.89 pA/pF (n=10, p<0.01). The activation curve was shifted towards more negative potential, while the inactivation curve was shifted towards more positive potential by 1 mu M aconitine. The level of Ca2+ release induced by 10 mM caffeine was markedly increased. Aconitine (1 mu M) increased the expression of NCX, while SERCA2a expression was reduced. In conclusion, aconitine increased the cytosolic [Ca2+](i) by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca2+](i) induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca2+ signals.