Abstract

The coronary vasodilation caused by adenosine is due to activation of A₂ adenosine receptors (A₂AdoRs), but the subtype or subtypes of A₂AdoR (A_2A and/or A_2B) that mediate this action are uncertain. The purpose of this study was to test the hypothesis that A_2AAdoRs mediate coronary vasodilation caused by exogenous or endogenous adenosine in the guinea pig isolated perfused heart. The newly described A_2AAdoR antagonist SCH58261 was used to selectively block A_2AAdoRs. Attenuations by SCH58261 of increases in coronary conductance (A₂ response) and of atrioventricular nodal conduction time (A₁ response) caused by exogenous and endogenous adenosine and by agonists with relative selectivity for A_2A and A₁AdoRs were measured. The CGS21680-induced increase of coronary conductance was antagonized by SCH58261 in a concentration-dependent and competitive manner with aK_B value of 5.01 nm. Also reversed by SCH58261 (60 nmol/L) were the increases in coronary conductance caused by the relatively selective A₁AdoR agonists CCPA (70 nM), and (R)-(−)N^b-(2-phenyl-isopropyl)adenosine (60 nM) but not those caused by sodium nitroprusside (1.2 μM) and diltiazem (0.4 μM). SCH58261 (≤100 nM) did not attenuate the A₁AdoR-mediated prolongations of S-H interval caused by either adenosine or CCPA. SCH58261 attenuated the coronary vasodilation caused by 50 nM adenosine with an IC₅₀ value of 6.8 ± 0.6 nM. The coronary vasodilations caused by the nucleoside uptake inhibitor draflazine and the adenosine kinase inhibitor iodotubercidin were completely reversed by 60 nM SCH58261 or adenosine deaminase (7 U/ml). Thus, the A_2AAdoR plays a major role as mediator of coronary vasodilation caused by exogenous and endogenous adenosine and by AdoR agonists.