Effects of N6-endonorbornan-2-yl-9-methyladenine, N0861, on negative chronotropic and vasodilatory actions of adenosine in the canine heart in vivo.

The pharmacology of N6-endonorbornan-2-yl-9-methyladenine (N0861), a new selective antagonist of adenosine at the A1 adenosine receptor subtype (A1-AdoR), was studied in vivo using a canine model. First, the pharmacokinetics of N0861 were determined in anesthetized dogs. The time-dependent decay of plasma levels of N0861 fitted a two-compartment polyexponential model with alpha-phase t1/2 = 3.80 min and beta-phase t1/2 = 80.55 min. Secondly, the effect of N0861 on the negative chronotropic and vasodilatory actions of adenosine in the canine heart were determined. N0861 attenuated the negative chronotropic action of adenosine (1-6 mumol/kg; rapid bolus into the right atrium) on sinus node pacemaker activity in a dose-dependent manner (pA2 = 4.23). For example, the maximal prolongation of sinus cycle length induced by 6 mumol/kg adenosine was 82 +/- 13% under baseline conditions and 57 +/- 10, 34 +/- 5 and 34 +/- 6% during infusion of N0861 at incremental rates leading to plasma levels of 7.75 +/- 1.02, 14.15 +/- 0.87, and 19.71 +/- 1.83 micrograms/mL, respectively. In contrast, N0861 did not inhibit but had a tendency to potentiate the vasodilatory action of adenosine (thought to be mediated by the A2 adenosine receptor subtype (A2-AdoR)) on the left anterior descending and circumflex coronary arteries. These data indicate that two different receptors, similar to the typical A1-AdoR and A2-AdoR, mediate the electrophysiologic and vasodilatory actions of adenosine in the canine heart, respectively, and that N0861 is a selective antagonist of adenosine at A1-AdoR in the canine heart in vivo.