Role of A2A-adenosine receptor activation for ATP-mediated coronary vasodilation in guinea-pig isolated heart

1 Adenosine-5'-triphosphate (ATP) and adenosine are potent coronary vasodilators. ATP is rapidly converted to adenosine by ectonucleotidases. We examined whether coronary vasodilation caused by exogenous ATP is mediated by P-2 receptor activation or by A(2A)-adenosine receptor activation. 2 Effects of interventions on coronary conductance were determined by measuring coronary perfusion pressure in guinea-pig isolated hearts perfused at a constant flow of 10 ml min(-1). 3 ATP and adenosine both caused sustained, concentration-dependent increases of coronary conductance. Maximal responses to both agonists were equivalent. The values of pot (+/-s.e.mean) For ATP and adenosine were 6.68 +/- 0.04 and 7.06 +/- 0.05, respectively. Adenosine was significantly more potent than ATP (P < 0.0001, n = 10). 4 The values of pIC(50) for the selective A(2A)-adenosine receptor antagonist SCH58261 to antagonize equivalent responses to ATP and adenosine were 8.28 +/- 0.08 and 8.25 +/- 0.06 (P = 0.99, n = 6), respectively. 5 The non-selective adenosine receptor antagonists xanthine amine congener (XAC) and CGS15943 antagonized similarly the equivalent vasodilations caused by ATP (pIC(50) values 7.48 +/- 0.04 and 7.45 +/- 0.06, respectively) and adenosine (pIC(50) values 7.37 +/- 0.13 and 7.56 +/- 0.11). 6 In contrast to ATP and adenosine, the two P-2 agonists 2-methylthio-ATP and uridine-5'-triphosphate failed to cause stable increases of coronary conductance, caused desensitization of vasodilator responses, and were not antagonized by SCH 58261, s-parasulphophenyltheophylline, or XAC. 7 Glibenclamide attenuated coronary vasodilations caused by ATP and adenosine by 88 and 89%, respectively, but failed to attenuate those caused by 2-methylthio-ATP. 8 These results strongly suggest that sustained, submaximal coronary vasodilation caused by exogenous ATP is entirely mediated by adenosine acting upon A(2)A-adenosine receptors.