SELECTIVE ADENOSINE-2 AGONIST PRODUCES BOTH DIRECT AND REFLEX TACHYCARDIA IN NORMOTENSIVE RATS

Hemodynamic responses to intravenous (i.v.) injection of DPMA [N6-]2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl] adenosine); PD 125,944], a potent adenosine agonist with a 32-fold selectivity for the adenosine-2 (A2) receptor subtype, were characterized in conscious and anesthetized rats. In conscious rats instrumented with miniaturized pulsed-Doppler flow probes, i.v. injection of increasing doses of DPMA (3-30-mu-g/kg) had little effect on mean arterial pressure (MAP, maximal decrease -8 +/- 4 mm Hg) or renal and mesenteric resistance (maximal change 8 +/- 14 and 0 +/- 15%, respectively). In contrast, DPMA markedly reduced MAP (maximal decrease - 61 +/- 8 mm Hg) in a dose-dependent (1-30-mu-g/kg) fashion in pentobarbital-anesthetized rats. The A2 agonist also caused a sustained, dose-dependent increase in heart rate (HR, maximal increase 75 +/- 12 beats/min) in conscious rats. The tachycardia and decrease in arterial pressure were completely reversed by i.v. administration of CGS 15943 (250-mu-g/kg), a selective adenosine receptor antagonist. Pretreatment with propranolol or hexamethonium significantly reduced but did not abolish the tachycardia, suggesting that the increase in HR was mediated only partially through reflex increases in sympathetic tone. These data indicate that (a) anesthesia potentiates the depressor actions of DPMA and (b) stimulation of A2 receptors increases HR through both direct and indirect mechanisms of action.