Role of A2A Receptor in the Modulation of Myocardial Reperfusion Damage

Abstract

Adenosine protects myocardium from ischemia and reperfusion damage; however, the mechanism of action is still under discussion. We investigated whether (a) adenosine protects isolated crystalloid-perfused rabbit heart from ischemia/ reperfusion injury; (b) this action is receptor mediated and what receptor subtypes are involved, and (c) this action is dependent on an enhanced nitric oxide production. Our results showed a cardioprotective effect of adenosine (10(-4) M), of nonselective adenosine-receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA; 5 x 10(-6) M), and of A2A agonists CGS 21680 (10(-8) and 10(-6) M), 2-hexynylNECA (10(-7) M). On the contrary, A1 agonist CCPA (10(-8) and 10(-6) M) does not provide any protection. The effect has been achieved in terms of significant reduction in contracture development 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) M 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, 22.2 +/- 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 [adenosine triphosphate (ATP) content is 9.9 +/- 0.5, 10.4 +/- 0.6, 9.8 +/- 0.5, and 10.5 +/- 0.5 micromol/gdw in treated hearts vs. 7.6 +/- 0.2 micromol/gdw; p < 0.05]. Moreover, our data indirectly show a functional presence of A2A receptors on cardiomyocytes as the protection is A2A mediated and exerted only during reperfusion, although in the absence of blood and coronary flow changes. These activities appear independent of nitric oxide pathways, as adenosine and 2-hexynylNECA effects are not affected by the presence of a nitric oxide-synthase inhibitor (10(-4) M L-NNA).

Infarct-Sparing Effect of A 2A -Adenosine Receptor Activation Is Due Primarily to Its Action on Lymphocytes

“…2,23 Similar cardioprotective effects also have been reported in exsanguinous isolated heart models. [11][12][13] Hence, the attenuation of postischemic myocardial injury by A 2A AR agonists has been attributed to their actions on the vasculature (or myocytes) under certain conditions. 13,24 Several other studies using isolated heart models revealed that A 2A AR activation does not alter ventricular myocyte cAMP levels and exerts no protective effect against myocardial ischemia-reperfusion injury, 14,15,21 suggesting that A 2A ARs either were expressed at low levels or were not functionally significant in cardiomyocytes.…”

“…3,6,11 The salutary effect of A 2A AR activation against myocardial ischemia-reperfusion injury has been reported in intact animal models 2,3 and in several ex vivo experiments. [11][12][13] However, other ex vivo studies showed that activation of A 2A ARs exerts no protective effects to the myocardium during postischemic reperfusion. 14,15 The conflicting findings in these experiments may be attributed to an important role for blood-borne leukocytes that are absent in exsanguinous hearts and/or variations in A 2A AR distribution or function in different animal species.…”

Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes

“…Recently, 0008 Yang et al demonstrated that the protective effect of NECA, an agonist of adenosine, on reperfusion injury was abolished by l-NAME in intact rabbit hearts, suggesting a possible involvement of NO in the action of NECA [5]. Nonetheless, there has also been evidence that NO is not responsible for adenosine-induced early preconditioning [6] or adenosineinduced protective effect on reperfusion injury [7]. Although the reason for this discrepancy is not clear, the role of NO was determined by either suppressing NOS activity or detecting NOS expression, without direct evidence of whether adenosine verily altered intracellular NO concentration in cardiomyocytes or not.…”

Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist

“…On the other hand, there have also been reports showing both anti-inflammatory (8,26) and anti-infarct (1) effects of A 3 adenosine receptor activation. Nevertheless, the cardioprotective effects of adenosine during reperfusion injury appear to be mediated at least in part by A 2A receptor activation (2,13,15,18). Activation of A 2A receptors results in increased intracellular adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) concentration, resulting in activation of protein kinase A and inhibition of multiple steps in the inflammatory cascade.…”