Adenosine A(1) receptor antagonist prolongs survival in the hypoxic rat

The hypothesis that adenosine A(1) receptor (A(1)AdoR) selective antagonism limits cardiac depression and prolongs survival during acute global hypoxi a was tested in a postinsult treatment model using KW-3902 ([8-(noradamanta n-3-yl)-1,3-dipropylxanthine]), an A(1)AdoR selective antagonist. Rats were anesthetized. paralyzed, then ventilated with 8% O-2 (hypoxia). In protoco l 1.5 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 1, after hypoxia, left ventricular co ntractility. heart rate. and systemic mean arterial blood pressure decrease d rapidly in saline- and vehicle-treated groups. In contrast, KW-3902 signi ficantly attenuated the decline in these variables. Survival time (the time from the commencement of hypoxia until death) was more prolonged with KW-3 902 (109.5 +/- 9.1 nim) 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 g roup) and 245.9 +/- 26.1 min (2.5-min group; p < 0.001). KW-3902 prolongs s urvival in this model, presumably by antagonizing A(1)AdoR-mediated inhibit ion of cardiac function. Also, treatment efficacy is highly time dependent.