Adenosine A1 receptor antagonist prolongs survival in the hypoxic rat.
The hypothesis that adenosine A1 receptor (A1AdoR) selective antagonism limits cardiac depression and prolongs survival during acute global hypoxia was tested in a postinsult treatment model using KW-3902 ([8-(noradamantan-3-yl)-1,3-dipropylxanthine]), an A1AdoR selective antagonist. Rats were anesthetized, paralyzed, then ventilated with 8% O2 (hypoxia). In protocol I, 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 I, after hypoxia, left ventricular contractility, heart rate, and systemic mean arterial blood pressure decreased rapidly in saline-and vehicle-treated groups. In contrast, KW-3902 significantly attenuated the decline in these variables. Survival time (the time from the commencement of hypoxia until death) was more prolonged with KW-3902 (109.5 +/- 9.1 min) 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 group) and 245.9 +/- 26.1 min (2.5-min group; p < 0.001). KW-3902 prolongs survival in this model, presumably by antagonizing A1AdoR-mediated inhibition of cardiac function. Also, treatment efficacy is highly time dependent.
Gao
E
E
Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.
Kaplan
J L
JL
Shi
Y
Y
Victain
M
M
Dalsey
W C
WC
de Garavilla
L
L
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004232:Diuretics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014970:Xanthines / Q000494:pharmacology*
D004232:Diuretics; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline