Antagonism of the cardiodepressant effects of adenosine during acute hypoxia

Objective: To determine whether pharmacologic antagonism of adenosine A(I)- receptor-mediated cardiovascular changes can improve cardiac function and p rolong survival during systemic hypoxia. Methods: Rats were anesthetized wi th ketamine, instrumented [including left ventricular (LV) pressure transdu cing 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, 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 pos t-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 rat e [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, selective antagonist prolonged surviv al in this model. This prolongation was attributed to inhibition of adenosi ne A(1) receptor-mediated decline in cardiac inotropy and chronotropy. Aden osine A, receptor-selective antagonists show promise as adjunctive therapy for hypoxia-induced cardiac insufficiency by prolonging the treatment windo w until more definitive resuscitation measures are taken.