adenosine-5--(n-ethylcarboxamide) and Bradycardia

The adenosine A

Topics: Adenosine; Adenosine A1 Receptor Agonists; Bradycardia; Humans; Ligands; Purinergic P1 Receptor Agonists; Receptor, Adenosine A1; Receptor, Adenosine A3; Receptors, Purinergic P1

Cardiovascular inhibitory effects induced by the posterior hypothalamic adenosine A(2) receptors were suggested by our previous reports. In this experiment, we examined the influence of the posterior hypothalamic adenosine A(2B) receptors on central cardiovascular regulation of blood pressure (BP) and heart rate (HR). Posterior hypothalamic injection of drugs was performed in anesthetized, artificially ventilated male Sprague-Dawley rats. Injection of 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 2 nmol), an adenosine A(2) receptor agonist, showed the decrease of arterial blood pressure and heart rate, and the alloxazine, an adenosine A(2B) receptor antagonist, partially blocked the depressor and bradycardiac effects of CPCA (2 nmol). To examine the role of adenosine A(2B) receptors among the adenosine A(2) subtypes, we applied the 5'-N-Ethylcarboxamidoadenosine (NECA), an adenosine A(2B) receptor agonist, to the posterior hypothalamus. Injection of NECA (1, 4 and 8 nmol) produced a dose-dependent decrease of arterial blood pressure and HR. Pretreatment with alloxazine (5 nmol) partially blocked the depressor and bradycardiac effects of NECA (4 nmol). Also, pretreatment with LY-83,583 (5 nmol), a soluble guanylate cyclase inhibitor, attenuated the depressor and bradycardiac effects of NECA (4 nmol). However, pretreatment with MDL-12,330 (10 nmol), an adenylate cyclase inhibitor, did not affect these effects of NECA (4 nmol). These results suggest that adenosine A(2B) receptor in the posterior hypothalamus plays an inhibitory role in central cardiovascular regulation, and that guanylate cyclase mediates the depressor and bradycardiac actions of adenosine A(2B) receptors.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine-5'-(N-ethylcarboxamide); Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Aminoquinolines; Anesthesia; Animals; Blood Pressure; Bradycardia; Enzyme Inhibitors; Flavins; Guanylate Cyclase; Heart Rate; Hypothalamus, Posterior; Imines; Male; Microinjections; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2B; Receptors, Adenosine A2; Vasodilator Agents

Previous attempts to discern and quantify the selectivity of agonists for A1 versus A2 adenosine receptors in vivo have been confounded by the activation of baroreceptor reflexes and/or simultaneous expression of responses to both A1 and A2 receptor activation. In anesthetized, vagotomized rats with isolated in situ constant-flow perfused hindquarters (HQ), bradycardic responses to i.v. agonist injections measured A1 receptor activation and HQ vasodilation elicited by i.a. agonist injections measured the stimulation of A2 receptors. Adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) produced A2 receptor-mediated HQ vasodilation at doses 8- and 4-fold lower (-log ED50 values, 7.3 +/- 0.04 mol and 8.7 +/- 0.06 mol, respectively) than those required to evoke A1 receptor-mediated bradycardia (-log ED50 values, 6.4 +/- 0.01 mol and 8.1 +/- 0.07 mol, respectively). N6-cyclopentyladenosine (CPA) was approximately 8-fold selective for A1 receptors (-log ED50 values, A1, 8.5 +/- 0.05 mol; A2, 7.6 +/- 0.16 mol). 2-(Phenylamino)adenosine (CV-1808) and 2[2(4-fluorophenyl)ethoxy]adenosine (FPEA) were at least 125- and 200-fold more potent agonists at A2 receptors (-log ED50 values, 7.7 +/- 0.10 mol and 8.0 +/- 0.24 mol, respectively) than at A1 receptors (-log ED50 values, 5.6 +/- 0.08 mol and 5.7 +/- 0.01 mol, respectively). These studies demonstrated that stimulation of A1 and A2 receptors may be discriminated in vivo and that such responses are selective, reproducible, dose-dependent and quantifiable.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Binding, Competitive; Bradycardia; Male; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Vasodilator Agents

We investigated cardiorespiratory responses to adenosine analogs in the pre- and postnatal periods in an unanesthetized chronic animal preparation. Heart rate, blood pressure, breathing movements and blood gases were measured in 8 fetal lambs (117-130 days gestation) and 9 newborn lambs (4-30 days). Various doses of analogs were given by intravenous infusion. L-N6-5'-Phenylisopropyladenosine (L-PIA), 5-N-ethyl carboxamidoadenosine (NECA) and cyclohexyladenosine (CHA) were studied. All analogs produced dose-dependent bradycardia and hypotension in the fetus. However, in the newborn, NECA produced a dose-dependent tachycardia, whereas PIA and CHA produced a dose-dependent bradycardia. Fetal breathing movements were interrupted by all the analogs, but they did not produce apnea in the newborn. No changes in blood gases were observed. The actions of the adenosine agonists were blocked by caffeine.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Animals, Newborn; Blood Pressure; Bradycardia; Caffeine; Female; Heart; Heart Rate, Fetal; Hydrogen-Ion Concentration; Phenylisopropyladenosine; Pregnancy; Pulmonary Gas Exchange; Respiration; Sheep; Vasodilator Agents