Adenosine A1 antagonism attenuates beta-adrenergic-resistant sudden hypoxic cardiac insufficiency.

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 beta-adrenergic drugs. Elevated levels of adenosine may mediate such beta-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 beta(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 microg/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 (+/-SEM) duration of survival (in minutes) after hypoxia increased from <13 (control solutions) to 13.8 (+/-1.4) (dobutamine), 20.0 (+/-1.6) (aminophylline), 31.7 (+/-4.6) (BG-9719), and 40.5 (+/-7.5) (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 beta-adrenergic agonists in hypoxia, shock, and cardiac arrest, in which compromised systemic perfusion or oxygenation impairs cardiac output.

Adenosine A1 antagonism attenuates atropine-resistant hypoxic bradycardia in rats.

OBJECTIVES: To test the following hypotheses: Hypoxia induces bradycardia and hemodynamic compromise that are resistant to atropine but responsive to selective antagonism of the adenosine A1 receptor (A1AdoR). The mechanism for such attenuation is independent of the vagus nerve. METHODS: Ten minutes after sham or actual bilateral cervical vagotomy, paralyzed ventilated rats were made hypoxic (5% fractional inspired oxygen, continued until death). Five minutes after beginning hypoxia, intravenous treatment with BG-9719, a selective A1AdoR antagonist (0.1 mg/kg); atropine (0.1 mg/kg); BG-9719 vehicle; or saline was initiated. These drug doses were based on pilot studies. Of the eight treatment groups (eight possible combinations of vagotomy status and drug/vehicle treatment), n = 8 in all except nonvagotomized, vehicle-treated rats (where n = 7). RESULTS: Heart rate and left ventricular contractility decreased rapidly with hypoxia. Atropine had minimal effects in prolonging survival (from mean +/- SEM of 15.5 +/- 2.1 minutes to 20.2 +/- 2.5 minutes, p = 0.94) and attenuating posthypoxic decreases in heart rate (p = 0.89) and contractility (p = 0.83) compared with saline. BG-9719 prolonged survival, however, from 14.4 +/- 1.9 minutes (with vehicle treatment) to 37.2 +/- 6.8 minutes (p < 0.001). Survival, heart rate, and contractility were preserved with BG-9719 compared with atropine and vehicle (p < 0.05, all comparisons). Vagotomy prevented the effects of BG-9719 on survival prolongation (p = 0.003), heart rate (p = 0.01), and contractility (p < 0.001) but did not affect those outcomes in saline-treated rats. CONCLUSIONS: 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.