Effects of tetrodotoxin and OKY-046 in renal ischemia reperfusion

Ischemia reperfusion injury (IRI) contributes significantly to posttranspla nt graft dysfunction. An emphasis, therefore, has been directed toward the identification of novel renoprotective agents. In this study, the renoprote ctive effect of tetrodotoxin (TTX) alone, or in combination with a thrombox ane synthetase inhibitor (OKY-046), was investigated in a 60-min warm ische mia, 72-h reperfusion, IRI rodent model. Unilateral nephrectomized rats were treated with the test vehicle alone, 1, 2, or 4 mu g/kg of TTX or 2 mg/kg of OKY-046 intravenously, either 15 min pre- or postischemia, or 2 mu g/kg TTX administered simultaneously with OKY -046 (2 mg/kg), following the ischemic interval. Baseline, 24, and 72 h mea n plasma creatinine (Cr) and urea nitrogen (BUN) were compared. Maximal renoprotection was demonstrated by significantly improved 72-h Cr a nd BUN levels with the 2 mu g/kg of TTX or with 2 mg/kg of OKY-046, each ad ministered 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; isc hemic 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 utilizin g TTX with OKY-046 resulted in reduced animal survival, demonstrating no re noprotection 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 pote ntial of TTX in preservation/transplantation, warrants further study. (C) 1 999 Academic Press.