Sarcoplasmic reticulum Ca2+ release channel ryanodine receptor (RyR2) plays a crucial role in aconitine-induced arrhythmias.

Abstract

The present study established a model of RyR(2) knockdown cardiomyocytes and elucidated the role of RyR(2) in aconitine-induced arrhythmia. Cardiomyocytes were obtained from hearts of neonatal Sprague-Dawley rats. siRNAs were used to down-regulate RyR(2) expression. Reduction of RyR(2) expression was documented by RT-PCR, western blot, and immunofluorescence. Ca(2+) signals were investigated by measuring the relative intracellular Ca(2+) concentration, spontaneous Ca(2+) oscillations, caffeine-induced Ca(2+) release, and L-type Ca(2+) currents. In normal cardiomyocytes, steady and periodic spontaneous Ca(2+) oscillations were observed, and the baseline [Ca(2+)](i) remained at the low level. Exposure to 3 microM aconitine increased the frequency and decreased the amplitude of Ca(2+) oscillations; the baseline [Ca(2+)](i) and the level of caffeine-induced Ca(2+) release were increased but the L-type Ca(2+) currents were inhibited after application of 3 microM aconitine for 5 min. In RyR(2) knockdown cardiomyocytes, the steady and periodic spontaneous Ca(2+) oscillations almost disappeared, but were re-induced by aconitine without affecting the baseline [Ca(2+)](i) level; the level of caffeine-induced Ca(2+) release was increased but L-type Ca(2+) currents were inhibited. Alterations of RyR(2) are important consequences of aconitine-stimulation and activation of RyR(2) appear to have a direct relationship with aconitine-induced arrhythmias. The present study demonstrates a potential method for preventing aconitine-induced arrhythmias by inhibiting Ca(2+) leakage through the sarcoplasmic reticulum RyR(2) channel.

• Authors: Min Fu, Ru-Xin Li, Li Fan, Guo-Wei He, Kent L Thornburg, Zhao Wang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 75 Issue 11 Pg. 2147-56 (Jun 01 2008) ISSN: 1873-2968 [Electronic] England
• PMID: 18439986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• RNA, Messenger
• RNA, Small Interfering
• Ryanodine Receptor Calcium Release Channel
• Caffeine
• Aconitine

Topics

• Aconitine (toxicity)
• Animals
• Arrhythmias, Cardiac (chemically induced, metabolism)
• Caffeine (pharmacology)
• Calcium Channels, L-Type (metabolism)
• Calcium Signaling (drug effects, physiology)
• Cells, Cultured
• Gene Expression (drug effects)
• Gene Silencing
• Membrane Potentials (physiology)
• Myocytes, Cardiac (drug effects, metabolism)
• RNA, Messenger (drug effects, metabolism)
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Sprague-Dawley
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
• Sarcoplasmic Reticulum (drug effects, metabolism)
• Transfection