The pathophysiology of
ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting
prostanoid thromboxane A2 (TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective
thromboxane synthetase inhibitor,
OKY-046, in a unilateral nephrectomized, 60 min
ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right
nephrectomy only (group A), or right
nephrectomy with 60 min of left renal
ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of
OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma
creatinine (CR);
urea nitrogen (BUN);
thromboxane B2 (TXB2) and 6-keto
prostaglandin F(1alpha) (6 kPGF(2alpha)) levels;
creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of
OKY-046 administered after renal
ischemia. (group B 72 hr Cr= 8.01 +/- 1.1 mg% vs. group E=3.99 +/- 1.5 mg%, and group B 72 hr BUN=241.3 +/- 32.8 mg% vs. group E=52.6 +/- 22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance (group B=0.069 ml/min vs. group E=0.194 ml/ min). The 24 hr TXB2 levels were significantly increased in group B (0 hr=754.1 +/- 219.4 pg/ml vs. 24 hr=2055.9 +/- 550.0 pg/ml), and pre- or posttreatment with
OKY-046 abrogated this increase (group C 0 hr=517.1 +/- 80.9 pg/ml vs. 24 hr=384.7 +/- 251.5 pg/ml, and group E 0 hr=781.6 +/- 390.4 pg/ml vs. 24 hr=183.0 +/- 81.4 pg/ml). The 24 hr 6 kPGF(1alpha) levels decreased in all groups, whereas 72 hr 6 kPGF(1alpha) levels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of
thromboxane A2 synthesis inhibition in the setting of
ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory
prostanoid synthesis.