Targeted deletion of adenosine A₃ receptors augments adenosine-induced coronary flow in isolated mouse heart

Abstract

To determine whether adenosine A3 receptors participate in adenosine-induced changes in coronary flow, isolated hearts from wild-type (WT) and A3 receptor knockout (A3KO) mice were perfused under constant pressure and effects of nonselective and selective agonists were examined. Adenosine and the selective A2A agonist 2-[p-(2-carboxyethyl)]phenylethylamino-5Ј-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A 3KO hearts compared with WT hearts. Selective activation of A 3 receptors with 2-chloro-N 6 -(3-iodobenzyl)-adenosine-5Ј-N-methyluronamide (Cl-IB-MECA) at nanomolar concentrations did not effect coronary flow, but at higher concentrations it produced coronary vasodilation both in WT and A 3KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A2A receptors. Because deletion or blockade of adenosine A3 receptors augmented coronary flow induced by nonselective adenosine and the selective A2A receptor agonist CGS-21680, we speculate that this is due to removal of an inhibitory influence associated with the A3 receptor subtype. These data indicate that the presence of adenosine A3 receptors may either inhibit or negatively modulate coronary flow mediated by other adenosine receptor subtypes. coronary vasodilation; knockout mice; A 2A receptor knockout mice ADENOSINE PRODUCES potent coronary vasodilation in different mammalian species including bovine, canine, porcine, rat, guinea pig, mouse, and humans (1,2,8,18,19,27,34). The cardiovascular effects of adenosine are mediated by activation of four known cell surface adenosine receptors (A 1 , A 2A , A 2B , and A 3 ); however, the relative contribution of each adenosine receptor subtype in modulating coronary flow is not yet fully understood (11,21,23,32). Whereas it is well established that coronary vasodilation is primarily mediated through A 2A receptor activation, it has been demonstrated that A 2B receptor activation plays a role in coronary flow regulation in humans and mice (14,20,34). The physiological significance of A 3 receptors in vascular responses is not yet characterized, although its role in myocardial ischemia and reperfusion is beginning to be understood (4,7,12). Recently, it has been reported (4, 7) that A 3 receptors play an injurious role during myocardial ischemia-reperfusion, because targeted deletion of the A 3 receptor confers resistance to myocardial ischemic injury. In isolated rat and rabbit hearts, selective activation of A 3 receptors did not change coronary flow (16), yet infusion of adenosine in A 3 KO mice has been shown to cause a significant decrease in blood pressure compared with wild-type (WT) mice (36), suggesting that A 3 receptors affect vascular tone in this species. However, there are no reports demonstrating whether and to what extent A 3 receptors are involved in the modulation of coronary flow in mice.With recent reports (20, 34) in murine hearts indicating a predominant role of A 2A over A 2B recep...

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