Attenuation of renal reperfusion injury in rats by the 21-aminosteroid U74006F.
OBJECTIVE
The 21-aminosteroids represent a new class of compounds that serve as potent inhibitors of iron-dependent lipid peroxidation, the latter being an important component of ischemia-reperfusion tissue injury. It is hypothesized that reperfusion injury accompanies renal ischemia, and postischemic administration of one of these steroids, U74006F, will reduce renal damage in a rodent model, as assessed by renal function (plasma creatinine), histologic evidence of renal injury, and animal survival during a 72-hour interval.


METHODS
Fifty-one rats subjected to 45 minutes of renal ischemia were treated on clamp release with 3 or 10 mg/kg U74006F intravenously (n = 5 and 19, respectively), an inactive vehicle (n = 23), or sham operation (n = 4).


RESULTS
Both doses of U74006F improved morphologic outcome compared with vehicle-treated animals. Statistically significant improvement in renal function was observed with the 10 mg/kg dose of U74006F (p = 0.029, 0.014, and 0.065 at 24, 48, and 72 hours, respectively) but not with the 3 mg/kg dose. Only one (5.2%) of 19 rats receiving high-dose U74006F (10 mg/kg) died within 72 hours after ischemia, compared with five deaths (29.4%) in 17 rats receiving citrate vehicle alone (p = 0.060). All sham-operated animals survived 72 hours with normal morphology and plasma creatinine levels.


CONCLUSIONS
These data suggest that iron-dependent lipid peroxidation is a component of reperfusion injury and indicate that U74006F may be useful in reducing this form of renal ischemic damage.
Stanley
J J
JJ
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622.
Goldblum
J R
JR
Frank
T S
TS
Zelenock
G B
GB
D'Alecy
L G
LG
D000818:Animals; D004353:Drug Evaluation, Preclinical; D007511:Ischemia / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008297:Male; D009392:Nephrectomy; D011281:Pregnatrienes / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad