Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemia-induced arrhythmias.
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.
Department of Pharmacology, State-Province Key Laboratories of Biomedicine and Pharmaceutics, Harbin Medical University, Baojian Road 157, Harbin 150081, China.
Shu
S
Wang
Hong-Mei
HM
Han
Ya-Nan
YN
Jiang
Chao
C
Wang
Hao-Xin
HX
Song
Zhen-Yu
ZY
Pan
Kai
K
Fan
Juan
J
Du
Yu-Hua
YH
Fan
Zhi-Min
ZM
Du
Yan
Y
Liu
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002794:Choline / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3 / Q000819:agonists* / Q000378:metabolism*; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D043587:Receptor, Muscarinic M3; D002794:Choline