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 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G 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 U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A-nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C-U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01+/-1.1 mg% vs. 3.32+/-0.96 mg%; ischemic control creatinine clearance = 0.069+/-0.03 ml/min vs. 0.206+/-0.04 ml/min; P<0.05). In Model 2 TBA 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 survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were 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 differences 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 ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.
Garvin
P J
PJ
Department of Surgery, Saint Louis University Health Sciences Center, Missouri 63110-0250, USA.
Niehoff
M L
ML
Robinson
S M
SM
Mistry
B
B
Esterl
R
R
Heisler
T
T
Combs
C
C
Berson
A
A
Solomon
H
H
Salinas-Madrigal
L
L
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D003080:Cold Temperature; D003404:Creatinine / Q000097:blood; D005260:Female; D006085:Graft Survival; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009336:Necrosis; D009392:Nephrectomy; D009926:Organ Preservation / Q000379:methods*; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D013997:Time Factors; D014182:Transplantation, Autologous; D016042:Transplantation, Heterotopic
D000975:Antioxidants; D011281:Pregnatrienes; D017392:Thiobarbituric Acid Reactive Substances; C074965:U 74389F; D003404:Creatinine