Arrhythmogenesis toxicity of aconitine is related to intracellular ca(2+) 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 Ca(2+) signals were previously unknown. We investigated the effects of aconitine on intracellular Ca(2+) signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca(2+) signals were evaluated by measuring L-type Ca(2+) currents, caffeine-induced Ca(2+) 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 Ca(2+) 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 [Ca(2+)]i by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca(2+)]i induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca(2+) signals.
Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Yu-hong
YH
Zhou
Xian-mei
XM
Piao
Xue
X
Liu
Hai-hai
HH
Liang
Lei-min
LM
Wang
Xue-hui
XH
Xiong
Lu
L
Wang
Yan-jie
YJ
Lu
Hong-li
HL
Shan
D000157:Aconitine / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D002110:Caffeine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D000157:Aconitine
Aconitine; L-type Ca2+ current; NCX; SERCA2a; arrhythmias; caffeine-induced Ca2+ release