Hemodynamic responses to adenosine, the A₁ receptor agonists N⁶-cyclopentyladenosine (CPA) and adenosine amine congener (ADAC), and the A₂ receptor agonist 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA) were investigated in the hindquarter vascular bed of the cat under constant-flow conditions. Injections of adenosine, CPA, ADAC, CPCA, ATP, and adenosine 5'-O-(3-thiotriphosphate) (ATPS) into the perfusion circuit induced dose-related decreases in perfusion pressure. Vasodilator responses to the A₁ agonists were reduced by the A₁ receptor antagonists KW-3902 and CGS-15943, whereas responses to CPCA were reduced by the A₂ antagonist KF-17837. Vasodilator responses to adenosine were reduced by KW-3902, CGS-15943, and by KF-17837, suggesting a role for both A₁ and A₂ receptors. Vasodilator responses to ATP and the nonhydrolyzable ATP analog ATPS were not attenuated by CGS-15943 or KF-17837. After treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester, the cyclooxygenase inhibitor sodium meclofenamate, or the ATP-dependent K⁺ (K) channel antagonists U-37883A or glibenclamide, responses to adenosine and ATP were not altered. Responses to adenosine, CPA, and CPCA were increased in duration by rolipram, a type 4 cAMP phosphodiesterase inhibitor, but were not altered by zaprinast, a type 5 cGMP phosphodiesterase inhibitor. When blood flow was interrupted for a 30-s period, the magnitude and duration of the reactive vasodilator response were reduced by A₁ and A₂ receptor antagonists. These data suggest that vasodilator responses to adenosine and the A₁ and A₂ agonists studied are not dependent on the release of cyclooxygenase products, nitric oxide, or the opening of K channels in the regional vascular bed of the cat. The present data suggest a role for cAMP in mediating responses to adenosine and suggest that vasodilator responses to adenosine and to reactive hyperemia are mediated in part by A₁ and A₂ receptors in the hindquarter vascular bed of the cat.