Arrhythmogenesis Toxicity of Aconitine Is Related to Intracellular Ca²⁺ Signals

Abstract

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 µM aconitine. At higher concentrations (5 µM and 10 µM), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 µM) 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 μM aconitine. The level of Ca2+ release induced by 10 mM caffeine was markedly increased. Aconitine (1 µM) 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.

Research progress of aconitine toxicity and forensic analysis of aconitine poisoning

“…Previous publications have described that aconitine could damage myocardial cells, increase the expression of RyR2 and decrease the expression of NCX1, DHPR-a1 significantly, thus leading to the unbalance of intracellular calcium homeostasis [60]. The results of current research provided strong evidences that aconitineinduced arrhythmia was associated with intracellular Ca 2þ signals and pre-treatment with aconitine reduced the sarcoplasmic reticulum Ca 2þ -ATPase expression, increased the expression of Na þ /Ca 2þ exchange in rat ventricular myocytes, which is consistent with the previous studies [61,62].…”

Icariin, a Novel Blocker of Sodium and Calcium Channels, Eliminates Early and Delayed Afterdepolarizations, As Well As Triggered Activity, in Rabbit Cardiomyocytes

“…Moreover, icariin can augment I CaL directly causing intracellular Ca 2+ overload, which may eventually result in arrhythmias (Zhou et al, 2013). In the present study, we found that icariin increased the onset time and onset dosage of aconitine-induced VPC, VT and VF in whole rabbits.…”

Antitoxic effect of baicalin and glycyrrhetic acid on PC12 cells induced by Aconitum brachypodum Diel

“…Arrhythmogenic toxicity of aconitine is related to intracellular Ca 2+ signals (Zhou et al, 2013). Neuronal cells rely heavily on strict regulation of their intracellular calcium concentration ([Ca 2+ ] i ).…”