To clarify the relative roles of A(2) adenosine receptor subtypes in the regulation of coronary flow and myocardial contractility, coronary vascular and functional responses to adenosine and its analogs were examined in isolated wild-type (WT) and A(2A) receptor knockout (A(2A)KO) mouse hearts. Nonselective agonists adenosine and 5'-N-ethyl-carboxamido-adenosine (NECA) increased coronary flow in A(2A)KO hearts, albeit with a rightward shift of concentration-response curves and decreased maximal vasodilation compared with WT hearts. 2-p-(2-Carboxy-ethyl)phenethylamino-5'-N-ethyl-carboxamidoadenosine (CGS-21680, a selective A(2A) receptor agonist) increased coronary flow in WT hearts but did not affect A(2A)KO hearts. Adenosine and NECA each elicited equal maximal increases in developed pressure in WT and A(2A)KO hearts, whereas CGS-21680 did not affect developed pressure in A(2A)KO hearts. Alloxazine, a selective A(2B) receptor antagonist, attenuated NECA-induced coronary vasodilation (from 202 +/- 14% to 128 +/- 9% of baseline, P < 0.05) and NECA-induced increases in developed pressure (from 133 +/- 8% to 112 +/- 7% of baseline, P < 0.05) in A(2A)KO hearts. Together, these findings support the conclusion that A(2B) adenosine receptor activation increases coronary flow and developed pressure in isolated murine hearts.