An unusual receptor mediates adenosine-induced SA nodal bradycardia in dogs

Abstract

To characterize the receptor mediating the negative chronotropic effect of adenosine in dogs, experiments were performed on conscious dogs with chronically implanted cardiovascular instrumentation. Autonomic blockade was used to eliminate any reflex influences on heart rate. Intravenous bolus injections of various adenosine analogues caused dose-dependent, aminophylline-blockable reductions in heart rate with a potency order of 5'-(N-ethylcarboxyamido)-adenosine (NECA)-78:2-chloroadenosine-17:adenosine-1. Dipyridamole enhanced the potency of adenosine to equal that of 2-chloroadenosine. Moderately selective A1-receptor agonists N6-(L-2-phenylisopropyl)-adenosine (R-PIA) and N6-cyclohexyladenosine and an A2-selective agonist 2-phenylaminoadenosine (200 nmol/kg) had no negative chronotropic effect in the conscious dog. Adenosine and its analogues, including R-PIA, caused coronary vasodilatation at smaller doses than were required to slow the heart rate. The selective A1-adenosine receptor blocker xanthine amine congener (XAC) antagonized the negative chronotropic action of adenosine but did so nonselectively, as the coronary vasodilative and negative chronotropic actions of adenosine were antagonized equally well. The spontaneous contraction rate of isolated perfused dog right atrial preparations, which included the sinoatrial node, was reduced by intrasinoatrial node artery infusions of adenosine analogues with a potency ratio of NECA-100:adenosine-15:N6-cyclopentyladenosine-2.3:R-PIA-1. We conclude that the adenosine receptor mediating the negative chronotropic action of adenosine in the dog does not display the pharmacological characteristics of either typical A1- or A2-adenosine receptors. Instead, either a novel adenosine receptor or an A1-receptor with unusual agonist and antagonist binding properties appears to exist in the dog's sinoatrial node.