Cardioprotective Actions of Adenosine in the Heart: New Strategy for the Treatment of Ischemic Heart Diseases

Abstract

Adenosine is recognized as an important chemical mediator for myocardial and vascular functions, which may assist cardioprotection during ischemia and reperfusion. Adenosine receptors can be divided into two types; A1 and A2 receptors, coupled with Gi and Gs proteins, respectively. Stimulations of A1 and A2 adenosine receptors decrease or increase adenylate cyclase activity, respectively. In ischemic hearts, the major role of endogenous adenosine is to relax coronary smooth muscles and increase blood flow through A2 receptors. The vasodilatory effects of adenosine are enhanced by alpha2-adrenoceptor stimulation due to sympathetic activation, H+, and ATP sensitive K+ channels, all of which occur in ischemic hearts. In the cardiovascular system, coronary vasodilation is not the only effect of adenosine. Stimulation of adenosine A2 receptors also attenuates both free radical generation by activated leukocytes and aggregation of platelets. On the other hand, adenosine A1 receptors activation attenuates beta-adrenoceptor-mediated increases in myocardial contractility, Ca2+ influx into myocytes, and norepinephrine release from presynaptic vesicles. Any of these effects may attenuate ischemic and reperfusion injury. Indeed, endogenous adenosine potentially attenuates contractile dysfunction during ischemia and reperfusion through activations of both adenosine A1 and A2 receptors. Furthermore, adenosine substantially limits the infarct size following sustained ischemia. Endogenous adenosine has been hypothesized as an essential mediator of ischemic preconditioning, which is generally accepted to limit infarct size. We elucidated that ischemic preconditioning increases 5’-nucleotidase activity and adenosine release, which may contribute to the reduction of infarct size. Taken together, we postulate the hypothesis that adenosine is a potential modulator for attenuation of ischemic and reperfusion injury.