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

Abstract

Increasing evidence indicates the important roles of M(3) muscarinic acetylcholine receptors (M(3) mAChR) in the regulation and maintenance of cardiac function and heart disease. In the present study, we investigated whether the M(3) 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 M(3) 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 Ca(2+) channels and the Na(+) /Ca(2+) 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 Ca(2+) overload was confirmed and this was decreased by choline. Furthermore, choline reduced the L-type Ca(2+) current (I(C) (a,) (L) ) compared with cardiomyocytes incubated in Tyrode's solution (pH 6.8) alone. Choline reduced the 'ischaemia'-induced upregulated expression of L-type Ca(2+) 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 M(3) mAChR, which reduces Ca(2+) overload mediated by L-type Ca(2+) channels and the NCX.

Reduction of Mitochondria–Endoplasmic Reticulum Interactions by Acetylcholine Protects Human Umbilical Vein Endothelial Cells From Hypoxia/Reoxygenation Injury

“…29 Moreover, previous studies have demonstrated that choline, an agonist of M3AChR, reduces intracellular Ca 2+ overload in cardiomyocytes. [30][31][32] However, additional studies are required to identify the link between M3AChR and attenuation of Ca 2+ overload. We further explored the signaling pathway mediated by acetylcholine in endothelial cells.…”

Choline Inhibits Ischemia-Reperfusion-Induced Cardiomyocyte Autophagy in Rat Myocardium by Activating Akt/mTOR Signaling

“…As a precursor molecule of neurotransmitter acetylcholine, studies have clarified that choline exhibited beneficial effects on several cardiac diseases including myocardial infarction [18], ischemic arrhythmias [19], IR injury [20] and cardiac hypertrophy [21]. Meanwhile, previous studies have revealed that choline reduced infarct size and prevented ischemic arrhythmias by inhibiting cardiomyocyte apoptosis as well as preserving phosphorylated connexin43 and regulating ion channels including L-type Ca 2+ channel and Na + /Ca 2+ exchanger [18-20].…”

Overexpression of M3 Muscarinic Receptor Suppressed Adverse Electrical Remodeling in Hypertrophic Myocardium Via Increasing Repolarizing K+ Currents

“…M 3 -mAChR protects the heart against hypertrophy by downregulating the expression of AT1 receptor [38], normalizing the deregulated expression of miR-133a [14], and upregulating the expression of phospho-p38 and calcineurin [39]. Probably, the most pertinent to the present study is the finding that M 3 -mAChR can produce anti-arrhythmic effects in ischemic hearts through downregulating miR-1 expression along with upregulation of Kir2.1 levels and reducing Ca 2+ overload mediated by enhanced L-type Ca 2+ channels and NCX [13]. Here our findings add to the beneficial profile of M 3 -mAChR with its anti-arrhythmic properties in the setting of CH.…”

“…Among these various regulators, the M 3 subtype of muscarinic acetylcholine receptors (M 3 -mAChR) has been noticed in recent years for its role in modulating cardiac function under physiological and pathological conditions [13-15]. M 3 -mAChR, which was once believed to be absent in myocardium, has not long ago been identified for its existence in the heart of various species, including man [16, 17].…”