ATP-sensitive K+Channels Mediate the Delayed Cardioprotective Effect of Adenosine A1Receptor Activation

Adenosine A1receptor stimulation increases myocardial resilence to ischaemia many hours later but the mechanism of protection is unclear. We hypothesized that A1receptor-induced delayed cardioprotection is mediated by KATPchannel opening. Rabbits were pretreated with saline or the selective A1receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), 0.1 mg/kg i.v. After 24 h, they were anaesthetized and subjected to 30 min left coronary artery occlusion (CAO) and 120 min reperfusion. Twenty minutes before CAO, either glibenclamide 0.3 mg/kg, sodium 5-hydroxydecanoate (5-HD) 5 mg/kg, or a corresponding volume of vehicle solution were given i.v. Infarct size as a percentage of ischaemic risk volume (I/R%) was assessed by triphenyltetrazolium. In the absence of either glibenclamide or 5-HD, CCPA pretreatment resulted in significant limitation of infarction (I/R 23.4±3.3%vs39.6±2.6% in saline pretreated animals,P<0.01). Administration of glibenclamide before CAO abolished this delayed protective effect of CCPA (I/R 37.4±4.7%), as did 5-HD (I/R 48.8±3.7%). Neither glibenclamide nor 5-HD significantly modified I/R in saline pretreated animals. Risk volume was similar in all groups (0.8–1.1 cm3). Systemic haemodynamic variables were not markedly different between any of the groups immediately before or during the ischaemia-reperfusion protocol. Thus, delayed protection following transient A1receptor activation was abolished by pre-ischaemic treatment with either glibenclamide or 5-HD, providing pharmacological evidence that KATPchannel opening mediates A1agonist-induced delayed myocardial protection. The inhibitory effect of 5-HD suggests specific involvement of mitochondrial KATPbut the mechanisms of sub-acute regulation of KATPfunction following A1receptor stimulation remain to be determined.