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Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemia‐induced arrhythmias

Increasing evidence indicates the important roles of M3 muscarinic acetylcholine receptors (M3 mAChR) in the regulation and maintenance of cardiac function and heart disease. In the present study, we investigated whether the M3 mAChR mediates the cardioprotection against ischaemia‐induced arrhythmias and the mechanisms involved. Myocardial ischaemia was established in Wistar rats by occlusion of the left anterior descending coronary artery. Rats were treated with choline chloride (an M3 mAChR agonist; 10 mg/kg, i.v.) 10 min before occlusion. In addition, 4‐diphenylacetoxy‐N‐methylpiperidine‐methiodide (4‐DAMP; 0.12 μg/kg, i.v.) was administered 5 min before choline in the 4‐DAMP‐treated group. Ischaemia‐induced arrhythmias were evaluated in each group for a period of 1 h after occlusion. After 24 h occlusion, protein and mRNA levels of L‐type Ca2+ channels and the Na+/Ca2+ exchanger (NCX) were determined. Ischaemia‐induced arrhythmias following coronary artery occlusion were diminished by choline and this effect was reversed in the 4‐DAMP‐treated group. In vitro, the effects of myocardial ischaemia were simulated by incubating isolated ventricular cardiomyocytes with Tyrode's solution (pH 6.8). Intracellular Ca2+ overload was confirmed and this was decreased by choline. Furthermore, choline reduced the L‐type Ca2+ current (ICa,L) compared with cardiomyocytes incubated in Tyrode's solution (pH 6.8) alone. Choline reduced the ‘ischaemia’‐induced upregulated expression of L‐type Ca2+ channels and NCX at both the protein and mRNA level. Based on these results, choline has an obvious protective effect against ischaemia‐induced arrhythmias that is mediated via activation of cardiac M3 mAChR, which reduces Ca2+ overload mediated by L‐type Ca2+ channels and the NCX.