The hypothesis that adenosine A1 receptor (A1AdoR) selective antagonism limits cardiac depression and prolongs survival during acute global hypoxia was tested in a postinsult treatment model using KW-3902 ([8-(noradamantan-3-yl)-1,3-dipropylxanthine]), an A1AdoR selective antagonist. Rats were anesthetized, paralyzed, then ventilated with 8% O2 (hypoxia). In protocol I, 5 min after hypoxia, rats were treated with saline, drug vehicle, or KW-3902 (0.1 mg/kg i.v.). In protocol II, KW-3902 treatment occurred 2.5, 5, or 7.5 min after hypoxia. In protocol I, after hypoxia, left ventricular contractility, heart rate, and systemic mean arterial blood pressure decreased rapidly in saline-and vehicle-treated groups. In contrast, KW-3902 significantly attenuated the decline in these variables. Survival time (the time from the commencement of hypoxia until death) was more prolonged with KW-3902 (109.5 +/- 9.1 min) than with saline (37.6 +/- 5.0 min) or vehicle (35.0 +/- 4.2 min) (p < 0.001). In protocol II, survival time increased from 29.2 +/- 5.5 min in the 7.5-min treatment group to 109.5 +/- 9.5 min (5-min group) and 245.9 +/- 26.1 min (2.5-min group; p < 0.001). KW-3902 prolongs survival in this model, presumably by antagonizing A1AdoR-mediated inhibition of cardiac function. Also, treatment efficacy is highly time dependent.

Survival, heart rate, and contractility were better preserved with BG-9719 than atropine. A1AdoR selective antagonism, possibly because of its multiple mechanisms for attenuating hypoxic cardiac insufficiency, resulted in better hemodynamic and clinical outcomes. That attenuation seems to have a component of vagal mediation.

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Objectives: In states such as hypoxia, shock, and cardiac arrest, compromised systemic oxygenation or perfusion appears to induce cardiac insufficiency that can be resistant to b-adrenergic drugs. Elevated levels of adenosine may mediate such b-adrenergic-resistant cardiac insufficiency via the adenosine A 1 receptor (A 1 AdoR). The objective of this study was to test the hypothesis that selective A 1 AdoR antagonism attenuates hypoxic cardiac insufficiency more efficaciously than b 1 -adrenergic agonism or nonselective adenosine antagonism. Methods: Rats were paralyzed and ventilated to a pCO 2 level of 35-40 mm Hg. Ten minutes before hypoxia (inspired O 2 concentration = 5%), rats were treated intravenously with one of the following: 0.1 mg/kg BG-9719 (n = 9), 10 mg/kg NPC-205 (n = 10; BG-9719 and NPC-205 are selective A 1 AdoR antagonists, with durations of action of 30-60 minutes and 60-90 minutes, respectively), 10 mg/kg aminophylline (n = 12), 5 mg/kg/min dobutamine (n = 11), or control solutions. These drug doses maximized survival duration in dose-response studies.Results: Before hypoxia, cardiac work was increased more by aminophylline and dobutamine than by BG-9719. Mean (6SEM) duration of survival (in minutes) after hypoxia increased from ,13 (control solutions) to 13.8 (61.4) (dobutamine), 20.0 (61.6) (aminophylline), 31.7 (64.6) (BG-9719), and 40.5 (67.5) (NPC-205) (p , 0.0001). Heart rate and dP/dt decreased rapidly after hypoxia, but decreases were attenuated with BG-9719 and NPC-205 compared with dobutamine (p , 0.05) and tended toward attenuation with aminophylline. Conclusions: BG-9719 and NPC-205 improved survival duration, heart rate, and left ventricular contractility during hypoxia more efficaciously than dobutamine and possibly aminophylline. Selective A 1 AdoR antagonists warrant further study as alternatives to b-adrenergic agonists in hypoxia, shock, and cardiac arrest, in which compromised systemic perfusion or oxygenation impairs cardiac output.