Holt S, Marley R, Fernando B, Harry D, Anand R, Goodier D, Moore K
Department of Surgery and Department of Chemical Pathology, The Royal Free Hospital, London, England, United Kingdom.
Kidney Int. 1999 Jan;55(1):271-7. doi: 10.1046/j.1523-1755.1999.00252.x.
Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function.
The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined.
BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA.
NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.
急性胆管梗阻与肾功能损害及氧化应激的发生有关。在氧化损伤过程中形成的F2-异前列腺素是通过血栓素（TX）样受体起作用的肾血管收缩剂。我们确定了在实验性胆汁淤积中F2-异前列腺素的形成是否增加，以及含硫醇的抗氧化剂或TXA2受体配体是否能改善肾功能。
研究了大鼠急性胆管结扎（BDL）对肾功能的影响，为期两天。然后检查给予N-乙酰半胱氨酸（NAC）、α-硫辛酸（LA）、TX受体拮抗剂（TXRA）BAYu3405或安慰剂的后果。
BDL使肌酐清除率从1.10±0.05降至0.55±0.05 ml/min，钠排泄量从52±3降至17±3 μmol/hr。BDL后尿F2-异前列腺素从14±2增加到197±22 pg/ml。NAC（肌酐清除率0.73±0.05 ml/min）、LA（0.64±0.03 ml/min）和TXRA（0.90±0.15 ml/min）改善了肾功能变化；P<0.05。同样，钠排泄量从17±3 μmol/hr（安慰剂）增加到34±3 μmol/hr（NAC）、29±3 μmol/hr（LA）和38±5 μmol/hr（TXRA）；P<0.005。肝谷胱甘肽浓度从6.5±0.3 μmol/g（正常肝脏）增加到8.8±0.5 μmol/g（NAC）和7.7±0.3 μmol/g（LA），P<0.01。然而，只有LA显著抑制F2-异前列腺素的形成（肌酐清除率从197±22降至36±11 pg/ml；P<0.05）。BDL后尿TXB2排泄增加（2.2±0.5至111.1±20.3 pg/min），但不受NAC和LA的影响。
NAC、LA和TXRA可部分预防实验性胆汁淤积中的肾功能障碍。抗氧化剂的作用与其抑制脂质过氧化或TX合成的能力无关。
