DISCRIMINATION OF A(1) VERSES A(2) RECEPTOR SUBTYPE SELECTIVITY OF ADENOSINE RECEPTOR AGONISTS IN-VIVO

Previous attempts to discern and quantify the selectivity of agonists for A(1) versus A(2) adenosine receptors in vivo have been confounded by the activation of baroreceptor reflexes and/or simultaneous express ion of responses to both A(1) and A(2) receptor activation. In anesthe tized, vagotomized rats with isolated in situ constant-flow perfused h indquarters (HQ), bradycardic responses to i.v. agonist injections mea sured A(1) receptor activation and HQ vasodilation elicited by i.a. ag onist injections measured the stimulation of A(2) receptors. Adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) produced A(2) receptor-medi ated HQ vasodilation at doses 8- and 4-fold lower (-log ED(50) values, 7.3 +/- 0.04 mol and 8.7 +/- 0.06 mol, respectively) than those requi red to evoke A(1) receptor-mediated bradycardia (-log ED(50) values, 6 .4 +/- 0.01 mol and 8.1 +/- 0.07 mol, respectively). N-6-cyclopentylad enosine (CPA) was approximately 8-fold selective for A(1) receptors (- log ED(50) values, A(1), 8.5 +/- 0.05 mol; A(2), 7.6 +/- 0.16 mol). 2- (Phenylamino)adenosine (CV-1808) and 2[2(4-fluorophenyl)ethoxy]adenosi ne (FPEA) were at least 125- and 200-fold more potent agonists at A(2) receptors (-log ED(50) values, 7.7 +/- 0.10 mol and 8.0 +/- 0.24 mol, respectively) than at A(1) receptors (-log ED(50) values, 5.6 +/- 0.0 8 mol and 5.7 +/- 0.01 mol, respectively). These studies demonstrated that stimulation of A(1) and A(2) receptors may be discriminated in vi vo and that such responses are selective, reproducible, dose-dependent and quantifiable. A comparison of these in vivo measures with known i n vitro data suggests that the A(2a) adenosine receptor mediates vasod ilation in the rat HQ and that in vitro assays may predict the orders of potency of adenosine A(1) and A(2a) receptor agonists in vivo but t hey are less reliable predictors of the absolute potency and, hence, t he A(1)/A(2) receptor selectivity of agonists.