Antagonism of the Cardiodepressant Effects of Adenosine during Acute Hypoxia

. Objective: To determine whether pharmacologic antagonism of adenosine A 1 ‐receptor‐mediated cardiovascular changes can improve cardiac function and prolong survival during systemic hypoxia. Methods: Rats were anesthetized with ketamine, instrumented [including left ventricular (LV) pressure transducing catheters], paralyzed with vecuronium, then ventilated to pCO 2 = 35‐40 torr. After 10 minutes of equilibration (baseline), treatment commenced with saline (n = 7), NPC‐205, an adenosine A 1 receptor selective antagonist, at doses of 1 mg/kg ( n = 10) or 10 mg/kg ( n = 10), or drug vehicle ( n = 9). Ten minutes later, inspired oxygen was reduced to 5%. Results: Survival duration (min) post‐hypoxia increased in a dose‐dependent fashion from 10.4 ± 1.4 (mean ± SEM) with vehicle control to 23.0 ± 4.7 and 41.1 ± 5.7 with 1 and 10 mg/kg NPC‐205, respectively (p < 0.000). Five minutes post‐hypoxia, dose‐dependent increases were also seen in the percentage of pre‐hypoxic values of LV contractility [25.9 ± 8.1 (vehicle), 39.5 ± 9.6 (1 mg/kg NPC‐205), and 56.5 ± 8.7 (10 mg/kg NPC‐205), p = 0.01], heart rate [60.6 ± 8.3 (vehicle), 74.7 ± 8.2 (1 mg/kg NPC‐205), and 90.4 ± 24.1 (10 mg/kg NPC‐205), p = 0.02], and blood pressure [16.1 ± 4.8 (vehicle), 28.8 ± 8.6 (1 mg/kg NPC‐205), and 51.7 ± 8.2 (10 mg/kg NPC‐205), p = 0.004]. Conclusions: The adenosine A 1 selective antagonist prolonged survival in this model. This prolongation was attributed to inhibition of adenosine A 1 receptor‐mediated decline in cardiac inotropy and chronotropy. Adenosine A 1 receptor‐selective antagonists show promise as adjunctive therapy for hypoxia‐induced cardiac insufficiency by prolonging the treatment window until more definitive resuscitation measures are taken.