Role of A(2A) receptor in the modulation of myocardial reperfusion damage

Adenosine protects myocardium from ischemia and reperfusion damage; however , the mechanism of action is still under discussion. We investigated whethe r (a) adenosine protects isolated crystalloid-perfused rabbit heart from is chemia/ reperfusion injury; (b) this action is receptor mediated and what r eceptor subtypes are involved, and (c) this action is dependent on an enhan ced nitric oxide production. Our results showed a cardioprotective effect o f adenosine (10(-4) M), of nonselective adenosine-receptor agonist 5'-N-eth yl-carboxamidoadenosine (NECA; 5 x 10(-6) M), and of A(2A) agonists CGS 216 80 (10(-8) and 10(-6) M), 2-hexynylNECA (10(-7) M). On the contrary, A(1) a gonist CCPA (10(-8) and 10(-6) M) does not provide any protection. The effe ct has been achieved in terms of significant reduction in contracture devel opment during reperfusion [diastolic pressure was 46.8 +/- 7.1 mm Hg (p < 0 .01); 46.1 +/- 7.8 mm Hg (p < 0.01); 46.9 +/- 5.5 mm Hg (p < 0.01); and 59. 3 +/- 6.7 mm Hg (p < 0.05) with 10(-4) M adenosine, 5 x 10(-6) M NECA, 10(- 6) CGS 21680, and 10(-7) M 2-hexynylNECA, respectively, versus 77.6 +/- 5.0 mm Hg in control]; reduced creatine phosphokinase release (13.5 +/- 1.6, 2 2.2 +/- 7.9, 14.2 +/- 3.3, and 14.1 +/- 4.5 U/gww in treated hearts vs. 34. 6 +/- 7.2 U/gww in controls, p < 0.05); improved energy metabolism [adenosi ne triphosphate (ATP) content is 9.9 +/- 0.5, 10.4 +/- 0.6, 9.8 +/- 0.5, an d 10.5 +/- 0.5 mu mol/gdw in treated hearts vs. 7.6 +/- 0.2 mu mol/gdw; p < 0.05]. Moreover, our data indirectly show a functional presence of a,, rec eptors on cardiomyocytes as the protection is A,, mediated and exerted only during reperfusion, although in the absence of blood and coronary flow cha nges. These activities appear independent of nitric oxide pathways, as aden osine and 2-hexynylNECA effects are not affected by the presence of a nitri c oxide-synthase inhibitor (10(-4) M L-NNA).