Garvin P J, Niehoff M L, Robinson S M
Abdominal Organ Transplant Division, St. Louis University Health Sciences Center, St. Louis, Missouri, 63110-0250, USA.
J Surg Res. 1999 Aug;85(2):273-8. doi: 10.1006/jsre.1999.5685.
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.
缺血再灌注损伤（IRI）是导致移植后移植物功能障碍的重要因素。因此，人们一直致力于寻找新型肾脏保护剂。在本研究中，我们在一个60分钟热缺血、72小时再灌注的IRI啮齿动物模型中，研究了河豚毒素（TTX）单独使用或与血栓素合成酶抑制剂（OKY-046）联合使用的肾脏保护作用。对单侧肾切除的大鼠，在缺血前15分钟或缺血后、或缺血期后，静脉注射单独的试验载体、1、2或4微克/千克的TTX或2毫克/千克的OKY-046，或者同时给予2微克/千克TTX与2毫克/千克OKY-046。比较基础值、24小时和72小时的平均血浆肌酐（Cr）和尿素氮（BUN）。在缺血后给予2微克/千克的TTX或2毫克/千克的OKY-046，72小时的Cr和BUN水平显著改善，显示出最大程度的肾脏保护作用（缺血对照组Cr = 8.01±1.07毫克/分升，TTX组 = 3.84±0.80毫克/分升，P = 0.008；与OKY-046组 = 4.0±1.5，P = 0.008；缺血对照组BUN = 241.3毫克/分升±32.8，TTX组 = 85.7毫克/分升±18.7，P < 0.008；与OKY-046组 = 52.6±22.5，P = 0.008）。TTX与OKY-046联合治疗导致动物存活率降低，从生化参数衡量未显示出肾脏保护作用。这些结果支持了TTX在严重的啮齿动物IRI模型中的肾脏保护作用。TTX的确切作用机制以及其在保存/移植中的治疗潜力，值得进一步研究。
