科研之友
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摘要
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.
