title: Adenosine A1 receptor antagonist prolongs survival in the hypoxic rat.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: E
authors.initials: E
authors.lastname: Gao
authors.forename: J L
authors.initials: JL
authors.lastname: Kaplan
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: M
authors.initials: M
authors.lastname: Victain
authors.forename: W C
authors.initials: WC
authors.lastname: Dalsey
authors.forename: L
authors.initials: L
authors.lastname: de Garavilla
mesh_terms: 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*
chemical_list: D004232:Diuretics; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline