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

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 A_2A agonist 2-[p-(2-carboxyethyl)]phenylethylamino-5′-N-ethylcarboxamidoadenosine (CGS-21680) produced augmented maximal coronary vasodilation in A₃KO hearts compared with WT hearts. Selective activation of A₃ receptors with 2-chloro-N⁶(3-iodobenzyl)-adenosine-5′-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 A₃KO hearts. Cl-IB-MECA-induced increases in coronary flow were susceptible to both pharmacological blockade and genetic deletion of A_2A receptors. Because deletion or blockade of adenosine A₃ receptors augmented coronary flow induced by nonselective adenosine and the selective A_2A 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.