Role of A₁ adenosine receptor in the regulation of coronary flow

To determine whether A₁ adenosine receptors (AR) participate in adenosine-induced changes of coronary flow, isolated hearts from A ₁AR^-/- and A₁AR^+/+ mice were perfused under constant pressure, and the effects of nonselective and selective agonists were examined. Adenosine, 5′-N-ethylcarboxamidoadenosine (NECA, nonselective), and the selective A_2AAR agonist 2-2- carboxyethylphenethylamino-5′-N-ethylcarboxamidoadenosine (CGS-21680) augmented maximal coronary vasodilation in A₁AR^-/- hearts compared with A₁AR^+/+ hearts. Basal coronary flow was increased (P < 0.05) in A₁AR^-/- hearts compared with A₁AR^+/+ hearts: 2.548 ± 0.1 vs. 2.059 ± 0.17 ml/min. In addition, selective activation of A₁AR with 2-chloro-N⁶-cyclopentyladenosine (CCPA) at nanomolar concentrations (1-100 nM) did not significantly change coronary flow; at higher concentrations, CCPA increased coronary flow in A₁AR^-/- and A ₁AR^+/+ hearts. Because deletion of A₁AR increased basal coronary flow, it is speculated that this effect is due to removal of an inhibitory influence associated with A₁AR. Adenosine and NECA at approximately EC₅₀ (100 and 50 nM, respectively) increased coronary flow in A₁AR^+/+ hearts to 177.86 > 8.75 and 172.72 ± 17% of baseline, respectively. In the presence of the selective A₁AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), the adenosine- and NECA-induced increase in coronary flow in A ₁AR^+/+ hearts was significantly augmented to 216.106 ± 8.35 and 201.61 ± 21.89% of normalized baseline values, respectively. The adenosine- and NECA-induced increase in coronary flow in A₁AR^-/- hearts was not altered by DPCPX. These data indicate that A₁AR may inhibit or negatively modulate coronary flow mediated by other AR subtypes (A_2A and A_2B).