Ischemia reperfusion injury (IRI) contributes significantly to posttransplant graft dysfunction. An emphasis, therefore, has been directed toward the identification of novel renoprotective agents. In this study, the renoprotective effect of tetrodotoxin (TTX) alone, or in combination with a thromboxane synthetase inhibitor (OKY-046), was investigated in a 60-min warm ischemia, 72-h reperfusion, IRI rodent model. Unilateral nephrectomized rats were treated with the test vehicle alone, 1, 2, or 4 microgram/kg of TTX or 2 mg/kg of OKY-046 intravenously, either 15 min pre- or postischemia, or 2 microgram/kg TTX administered simultaneously with OKY-046 (2 mg/kg), following the ischemic interval. Baseline, 24, and 72 h mean plasma creatinine (Cr) and urea nitrogen (BUN) were compared. Maximal renoprotection was demonstrated by significantly improved 72-h Cr and BUN levels with the 2 microgram/kg of TTX or with 2 mg/kg of OKY-046, each administered after ischemia (ischemic control Cr = 8. 01 +/- 1.07 mg/dl vs TTX = 3.84 +/- 0.80 mg/dl, P = 0.008; vs OKY-046 = 4.0 +/- 1.5, P + 0.008; ischemic control BUN = 241.3 mg/dl +/- 32.8 vs TTX = 85.7 mg/dl +/- 18.7, P < 0.008; vs OKY-046 = 52.6 +/- 22.5, P = 0.008). The combination therapy utilizing TTX with OKY-046 resulted in reduced animal survival, demonstrating no renoprotection as measured with the biochemical parameters. These results support the renoprotective effects of TTX in a severe, rodent IRI model. The exact mechanism of action, as well as the therapeutic potential of TTX in preservation/transplantation, warrants further study.