Disruption of the intracellular Ca2+ homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes.
Aconitine is an effective ingredient in Aconite tuber, an important traditional Chinese medicine. Aconitine is also known to be a highly toxic diterpenoid alkaloid with arrhythmogenic effects. In the present study, we have characterized the properties of arrhythmic cytotoxicity and explored the possible mechanisms of aconitine-induced cardiomyocytes. Results show that aconitine induces significant abnormity in the spontaneous beating rate, amplitude of spontaneous oscillations and the relative intracellular Ca(2+) concentration. Also, mRNA transcription levels and protein expressions of SR Ca(2+) release channel RyR(2) and sarcolemmal NCX were elevated in aconitine-induced cardiomyocytes. However, co-treatment with ruthenium red (RR), a RyR channel inhibitor, could reverse the aconitine-induced abnormity in intracellular Ca(2+) signals. These results demonstrate that disruption of intracellular Ca(2+) homeostasis in the cardiac excitation-contraction coupling (EC coupling) is a crucial mechanism of arrhythmic cytotoxicity in aconitine-induced cardiomyocytes. Moreover, certain inhibitors appear to play an important role in the detoxification of aconitine-induced Ca(2+)-dependent arrhythmias.
Fu
Min
M
School of Medicine, Tsinghua University, Beijing, PR China.
Wu
Meng
M
Wang
Ji-Feng
JF
Qiao
Yan-Jiang
YJ
Wang
Zhao
Z
D000157:Aconitine / Q000633:toxicity*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006339:Heart Rate / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis; D019284:Thapsigargin / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; C503872:caisequestrin 2, rat; D012430:Ruthenium Red; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium; D000157:Aconitine