EFFECT OF A 21-AMINOSTEROID, U74006F, ON LIPID-PEROXIDATION AND GLOMERULOTUBULAR FUNCTION FOLLOWING EXPERIMENTAL RENAL ISCHEMIA

In order to investigate the capacity of the 21-aminosteroid, U74006F, to mitigate ischemic/reperfusion injury (IRI), we studied lipid peroxidation and glomerulotubular function in a rat model of IRI. U74006F, superoxide dismutase (SOD), and their respective vehicles were administered preischemia and prereperfusion to Brown Norway rats subjected to 45 or 60 min of bilateral normothermic ischemia. Lipid peroxidation was assessed by assay of thiobarbituric acid reactive products (TBA-RP) in a forced peroxidation reaction with t-butylhydroperoxide while renal function was assessed by timed determinations of serum creatinine, creatinine clearance, urine volume, and fractional excretion of sodium (FeNa+). Twenty-four hours following a 60-min ischemic insult and uninephrectomy, the glomerular filtration rate (GFR) was markedly reduced in the IRI + vehicle group compared to controls as reflected by a significant elevation in mean serum creatinine (0.138 +/- 0.018 vs 0.045 +/- 0.002 mu mole/liter, P < 0.05) and a significant reduction in mean creatinine clearance (0.200 +/- 0.076 vs 1.130 +/- 0.153 ml/min, P < 0.05). Neither U74006F nor SOD afforded protection against this marked fall in GFR. In contrast, U74006F significantly attenuated both the diuresis (UVol) and the increase in fractional excretion of filtered sodium (FeNa+) seen post-IRI. At 24 hr post-IRI, mean UVol was 22.50 +/- 4.57 ml/day and FeNa+ 1.35 +/- 0.16% in the IRI + vehicle group compared to 11.48 +/- 2.00 ml/day and 0.82 +/- 0.22%, respectively, in the IRI + U74006F group (P < 0.05). While SOD also proved partially protective of tubular function, the effect was not as pronounced as that observed with U74006F. At 15 min postreperfusion following a 45-min ischemic insult, lipid peroxidation was markedly increased as compared to non-IRI controls as assessed by the production of TBA-RP. U74006F, but not SOD, significantly attenuated the elevation in TBA-RP compared to vehicle (P < 0.05). We conclude that U74006F affords partial protection from IRI-induced tubular injury, but not impaired glomerular filtration function, and that this may, in part, be related to a reduction in membrane lipid peroxidation. (C) 1994 Academic Press, Inc.