Oshita M, Takei Y, Kawano S, Fusamoto H, Kamada T
First Department of Medicine, Osaka University Medical School, Japan.
J Pharmacol Exp Ther. 1994 Oct;271(1):20-4.
The effect of an organoselenium compound, ebselen [2-phenyl-1,2-benzisoselenazol-3-(2H)-one], on ethanol-induced liver damage through perturbation of microcirculation was investigated in perfused livers from fed rats. Infusion of ethanol at concentrations > or = 25 mM into the portal vein increased portal pressure in a concentration-dependent manner. Release of lactate dehydrogenase (LDH) into the effluent perfusate was minimal at 30 min; thereafter LDH release began to increase gradually until the end of the experiment (60 min after the onset of ethanol infusion) and was dependent on ethanol concentration. Simultaneous infusion of ebselen at a concentration of 10 or 30 microM with ethanol reduced significantly this ethanol-induced increase in portal pressure by 50 to 75% (P < .05) and LDH release by 70% (P < .05). When endothelin-1 or phenylephrine was infused into the liver, portal pressure was increased, reaching maximal levels (50 +/- 17 and 46 +/- 7 mm of H2O, respectively) and then decreasing gradually. Ebselen reduced the maximal increase in portal pressure induced by endothelin-1 (18 +/- 2 mm of H2O) by 64% (P < .05). In addition, ebselen decreased the maximal levels of portal pressure induced by phenylephrine (8 +/- 1 mm of H2O) by 83% (P < .05). These data indicate that ebselen has a vasodilative effect on constriction of hepatic vasculature and diminishes ethanol-induced hepatic damage by offsetting ethanol-induced increase in portal pressure. Thus, ebselen may prove useful for treatment of alcoholic liver injury via improvement of microcirculatory disturbances.
在喂食大鼠的灌注肝脏中，研究了有机硒化合物依布硒啉[2-苯基-1,2-苯并异硒唑-3-(2H)-酮]通过干扰微循环对乙醇诱导的肝损伤的影响。向门静脉输注浓度≥25 mM的乙醇会以浓度依赖的方式增加门静脉压力。乳酸脱氢酶（LDH）在灌注30分钟时释放到流出液中的量最少；此后，LDH释放开始逐渐增加，直至实验结束（乙醇输注开始后60分钟），且依赖于乙醇浓度。同时以10或30 μM的浓度与乙醇一起输注依布硒啉，可使乙醇诱导的门静脉压力升高显著降低50%至75%（P<.05），LDH释放降低70%（P<.05）。当向内皮素-1或去氧肾上腺素注入肝脏时，门静脉压力升高，达到最高水平（分别为50±17和46±7 mmH₂O），然后逐渐降低。依布硒啉使内皮素-1诱导的门静脉压力最大升高值（18±2 mmH₂O）降低了64%（P<.05）。此外，依布硒啉使去氧肾上腺素诱导的门静脉压力最高水平（8±1 mmH₂O）降低了83%（P<.05）。这些数据表明，依布硒啉对肝血管收缩具有血管舒张作用，并通过抵消乙醇诱导的门静脉压力升高来减轻乙醇诱导的肝损伤。因此，依布硒啉可能通过改善微循环紊乱对酒精性肝损伤的治疗有用。
