Entity

Time filter

Source Type


Wang S.,State Province Key Laboratories of Biomedicine and Pharmaceutics | Wang S.,Harbin Medical University | Han H.-M.,State Province Key Laboratories of Biomedicine and Pharmaceutics | Han H.-M.,Harbin Medical University | And 9 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2012

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 Ca,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. © 2012 Blackwell Publishing Asia Pty Ltd.


Liu Y.,State Province Key Laboratories of Biomedicine and Pharmaceutics | Sun L.,State Province Key Laboratories of Biomedicine and Pharmaceutics | Pan Z.,State Province Key Laboratories of Biomedicine and Pharmaceutics | Bai Y.,State Province Key Laboratories of Biomedicine and Pharmaceutics | And 9 more authors.
Molecular Medicine | Year: 2011

The present study was designed to investigate the cardiac benefits of M 3 muscarinic receptor (M 3-mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K+ channel by microRNA-1 (miR-1) in a conditional overexpression mouse model. A cardiac-specific M 3-mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M 3-mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia-reperfusion (I/R). By using whole-cell patch techniques, M 3-mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K+ current. By using Western blot techniques, M 3-mAChR overexpression also rescued the expression of the inward rectifying K+ channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M 3-mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K+ current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death. © 2011 The Feinstein Institute for Medical Research.

Discover hidden collaborations