CARDIOVASCULAR EFFECTS OF A NON-XANTHINE-SELECTIVE ANTAGONIST OF THE A(1) ADENOSINE RECEPTOR IN THE ANESTHETIZED PIG - PHARMACOLOGICAL AND THERAPEUTIC IMPLICATIONS

Objective: To study antagonism of A(1) adenosine receptors in an anaesthetised open chest swine model, the selective A(1) receptor antagonist, N-6-endonorbornan-2-yl-9-methyladenine (N-0861), was examined to see if it attenuates bradycardia, augments reflex tachycardia associated with adenosine infusion, or both. Its effects were compared with those of the non-selective antagonist of adenosine A(1) and A(2) receptors, 8-(p-sulphophenyl)-theophylline (8-pST). Methods: Twenty nine pigs were studied. The prolongation of P-R interval mediated by A(1) receptors, the increase in left anterior descending coronary artery blood flow mediated by A(2) receptors, and decreases in systemic and left ventricular pressures and first derivative of left ventricular pressure (dP/dt) were monitored in each animal assigned to one of three protocols. (1) Adenosine, 40 to 180 mu g.kg(-1).min(-1), was infused for more than 6 min before and immediately after rapid infusion of 8-pST, 5 mg.kg(-1) intravenously, or a solvent that did or did not contain N-0861, 0.2 mg.kg(-1) intravenously (n=14). (2) In the same animal, we compared N-0861 and 8-pST in reversing responses mediated by A(1) and A(2) receptors during two 10 min infusions of adenosine separated by a 1 h washout period (n=7). (3) N-0861 with adenosine (mean dose, 0.4 mg.kg(-1)) was infused with or without complete autonomic blockade with atropine (2.5 mg.kg(-1)) and propranolol (2 mg.kg(-1)) (n=8). Results: Adenosine prolonged P-R interval (and cycle length in non-paced hearts), increased coronary flow, and decreased calculated coronary resistance. N-0861 alone did not affect any variable, but N-0861 with adenosine prevented or reversed A(1) receptor mediated prolongation of P-R interval in paced hearts and cycle length in non-paced hearts and enhanced A(2) receptor mediated coronary vasodilatation. Left ventricular dP/dt and rate-pressure product were maintained with N-0861 and adenosine, and N-0861 unmasked a postadenosine reflex tachycardia. Prolonged PR interval, decreased heart rate, and increased coronary flow were prevented or reversed by the non-selective antagonist 8-pST. Conclusions: Selectivity of N-0861 for the adenosine A(1) receptor may, without reducing coronary blood flow, ameliorate bradyarrhythmia and maintain the positive inotropic response when exogenous adenosine is given or when interstitial myocardial adenosine is increased.