RENOPROTECTIVE EFFECTS OF THE 21-AMINOSTEROID U74389G IN ISCHEMIA-REPERFUSION INJURY AND COLD-STORAGE PRESERVATION

Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 ami nosteroid U74389G was evaluated in three IRI models. In Model 1 51 uni lateral nephrectomized rats that underwent 60 min of warm Ischemia fol lowed by a 72-hr reperfusion interval were treated with the test vehic le only, or 3, 6, or 12 mg/kg of U743896 intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U7438 96 (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenou sly over 10 min beginning 5 min prior to clamp release. After reperfus ion, LPO was determined by assay of snap frozen tissue for thiobarbitu ric acid (TEA) concentrations (nmol/g tissue weight). In Model 3 domes tic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min o f warm ischemia, Collins C-4 flush, and 24 hr of cold storage preserva tion. Heterotopic autotransplantation and immediate contralateral neph rectomy was then performed in Group A-nonischemic controls (n=4), Grou p B-ischemic controls (n=5), and Group C-U74389G (6 mg/kg) administere d preischemia and at autotransplantation (n=5). In Model 1 maximal ren oprotection was demonstrated with the 6 mg/kg dose of U74389G administ ered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8. 01+/-1.1 mg% vs. 3.32+/-0.96 mg%; ischemic control creatinine clearanc e = 0.069+/-0.03 ml/min vs. 0.206+/-0.04 ml/min; P<0.05). In Model 2 T EA levels were significantly lower in U74389G treated animals (88.5+/- 10.0 vs. ischemic controls = 296.8+/-81.4; P=0.02). In Model 3 graft s urvivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) we re significantly greater in Group C vs. Group A, (Group A Cr = 8.59+/- 0.63 vs. Group C = 12.8+/-1.01; Group A BUN = 64.1+/-2.73 vs. Group C = 104.9+/-12.21)-however, by day 10, thee were no significant differen ces in renal function: (Group A Cr = 2.15+/-0.3 vs. Group C = 2.10+/-0 .06; Group A BUN = 27.0+/-6.0 vs. Group C = 31.1+/-6.4), These results support the beneficial effects of LPO inhibitors in models of ischemi a-reperfusion, as well as preservation/transplantation, and suggest th at this renoprotection correlates with decreased membrane lipid peroxi dation.