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Activation of cardiac muscarinic M 3 receptors induces delayed cardioprotection by preserving phosphorylated connexin43 and up‐regulating cyclooxygenase‐2 expression
Author(s) -
Zhao Jinlong,
Su Yue,
Zhang Yong,
Pan Zhenwei,
Yang Lili,
Chen Xichuang,
Liu Yan,
Lu Yanjie,
Du Zhimin,
Yang Baofeng
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00606.x
Subject(s) - cardioprotection , methoctramine , muscarinic acetylcholine receptor , medicine , agonist , ischemia , pharmacology , endocrinology , muscarinic acetylcholine receptor m3 , receptor
Background and purpose: Activation of muscarinic M 3 mucarinic acetylcholine receptors (M 3 ‐mAChRs) has been previously shown to confer short‐term cardioprotection against ischaemic injuries. However, it is not known whether activation of these receptors can provide delayed cardioprotection. Consequently, the present study was undertaken to investigate whether stimulation of M 3 ‐mAChRs can induce delayed preconditioning in rats, and to characterize the potential mechanism. Experimental approach: Rats were pretreated (24 h), respectively, with M 3 ‐mAChRs agonist choline, M 3 ‐mAChRs antagonist 4‐DAMP or M 2 ‐mAChRs antagonist methoctramine followed by the administration of choline. This was followed by 30 min of ischaemia and then 3 h of reperfusion. Ischaemia‐induced arrhythmias and ischaemia–reperfusion (I/R)‐induced infarction were determined. The phosphorylation status of connexin43 (Cx43) after 30 min ischaemia, and the expression level of Hsp70, cyclooxygenase‐2 (COX‐2) and iNOS effected by administration of choline were also measured. Key results: Compared to the control group, pretreatment with choline significantly decreased ischaemia‐induced arrhythmias, reduced the total number of ventricular premature beats, the duration of ventricular tachycardia episodes and markedly reduced I/R‐induced infarct size. Furthermore, choline attenuated ischaemia‐induced dephosphorylation of Cx43, and up‐regulated the expression of Hsp70 and COX‐2. Administration of 4‐DAMP abolished these changes, while methoctramine had no effect. Conclusions and implications: Our results suggest that stimulation of M 3 ‐mAChRs with choline elicits delayed preconditioning, which we propose is the result of up‐regulation of the expression of COX‐2 and inhibition of the ischaemia‐induced dephosphorylation of Cx43. Therefore, M 3 ‐mAChRs represent a promising target for rendering cardiomyocytes tolerant to ischaemic injury.