N-0861 SELECTIVELY ANTAGONIZES ADENOSINE-A1-RECEPTORS INVIVO

Experiments were performed to determine the antagonistic actions of (+/-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) at A1 and A2 adenosine receptors in vivo, and to evaluate the pharmacodynamics of the observed responses. The selectivity of antagonism of A1 vs. A2 receptors by N-0861 was evaluated by generating dose-response curves to adenosine-induced bradycardia (A1 effect), and vasodilation in the in situ constant-flow perfused rat hindquarter vasculature (A2 effect). N-0861, at doses greater-than-or-equal-to 1-mu-mol/kg + 0.04-mu-mol/kg per min, i.v. produced dose-related rightward shifts of the A1 dose-response curve, but had no effect on the A2 dose-response curve at doses as high as 100-mu-mol/kg, i.v. In contrast, the non-selective A1/A2 adenosine receptor antagonist 8-phenyltheophylline antagonized both A1 and A2 receptor-mediated responses to adenosine. The minimum effective i.v. dose and the duration of action of N-0861 were determined by evoking bradycardic responses to i.v. adenosine (A1 effect) in anesthetized, vagotomized, beta-blocked rats before and after single bolus doses of vehicle or N-0861 (0.3, 0.6, 1.0, 3.0 or 10.0-mu-mol/kg). The lowest i.v. dose of N-0861 to antagonize A, receptor-mediated bradycardia was 0.3-mu-mol/kg i.v.; the duration of effect ranged from 1 min (following 0.3-mu-mol/kg) to approximately 2.5 h (following 10-mu-mol/kg). N-0861 is a selective (by greater-than-or-equal-to 333-fold) antagonist of adenosine Al receptors.