Acute cholestasis-induced renal failure:: Effects of antioxidants and ligands for the thromboxane A2 receptor

Background. Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F(2)-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F(2)-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA(2) receptor could improve renal function. Methods. 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. Results. 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 mu mol/hr. Urinary F(2)-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 mu mol/hr (placebo) to 34 +/- 3 mu mol/hr (NAC), 29 +/- 3 mu mol/hr (LA), and 38 +/- 5 mu mol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 mu mol/g (normal liver) to 8.8 +/- 0.5 mu mol/g (NAC) and 7.7 +/- 0.3 mu mol/g (LA), P < 0.01. However, only LA markedly inhibited F(2)-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB(2) excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA. Conclusion. NAG, 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.