Article: article from journal or magazin.
A key role of TRPC channels in the regulation of electromechanical activity of the developing heart.
Aims It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart.Methods and results TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting and co-immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6, and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the alpha 1C subunit of the L-type voltage-gated calcium channel (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first-and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity.Conclusions These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis.
Aminoquinolines/pharmacology, Aminoquinolines/toxicity, Animals, Atrioventricular Block/chemically induced, Atrioventricular Block/metabolism, Blotting, Western, Calcium Channel Blockers/pharmacology, Calcium Channels, L-Type/drug effects, Calcium Channels, L-Type/metabolism, Chick Embryo, Dose-Response Relationship, Drug, Electrocardiography, Electrophysiologic Techniques, Cardiac, Gene Expression Regulation, Developmental, Heart/drug effects, Heart/embryology, Heart Conduction System/drug effects, Heart Conduction System/embryology, Heart Rate, Myocardial Contraction, Nifedipine/pharmacology, Polymerase Chain Reaction, Pyrazoles/pharmacology, Pyrazoles/toxicity, RNA, Messenger/metabolism, TRPC Cation Channels/antagonists & inhibitors, TRPC Cation Channels/genetics, Time Factors, Ventricular Function
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