Article date: March 2010
By: Jinlong Zhao, Yue Su, Yong Zhang, Zhenwei Pan, Lili Yang, Xichuang Chen, Yan Liu, Yanjie Lu, Zhimin Du, Baofeng Yang in Volume 159, Issue 6, pages 1217-1225
Background and purpose: Activation of muscarinic M3 mucarinic acetylcholine receptors (M3‐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 M3‐mAChRs can induce delayed preconditioning in rats, and to characterize the potential mechanism.
Experimental approach: Rats were pretreated (24 h), respectively, with M3‐mAChRs agonist choline, M3‐mAChRs antagonist 4‐DAMP or M2‐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 M3‐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, M3‐mAChRs represent a promising target for rendering cardiomyocytes tolerant to ischaemic injury.
DOI: 10.1111/j.1476-5381.2009.00606.x
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