Ability of CP-532,903 to protect mouse hearts from ischemia/reperfusion injury is dependent on expression of A adenosine receptors in cardiomyoyctes.

A adenosine receptor (AAR) agonists are effective at limiting injury caused by ischemia/reperfusion injury of the heart in experimental animal models. However, understanding of their mechanism of action, which is likely multifactorial, remains incomplete. In prior studies, it has been demonstrated that AAR-mediated ischemic protection is blocked by glibenclamide and is absent in Kir6.2 gene ablated mice that lack the pore-forming subunit of the ATP-sensitive potassium (K) channel, suggesting one contributing mechanism may involve accelerated activation of K channels. However, presence of AARs in the myocardium has yet to be established. Utilizing a whole-cell recording technique, in this study we confirm functional expression of the AAR in adult mouse ventricular cardiomyocytes, coupled to activation of ATP-dependent potassium (K) channels via G inhibitory proteins. We further show that ischemic protection provided by the selective AAR agonist CP-532,903 in an isolated, buffer-perfused heart model is lost completely in Adora3 mice, which is a newly developed model developed and comprehensively described herein whereby the AAR gene (Adora3) is deleted exclusively in cardiomyocytes. Our findings, taken together with previously published work, are consistent with the hypothesis that AAR agonists provide ischemic tolerance, at least in part, by facilitating opening of myocardial K channels.