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 \u3c 0.001). Survival, heart rate, and contractility were preserved with BG-9719 compared with atropine and vehicle (p \u3c 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 \u3c 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