Iimuro Y, Ikejima K, Rose M L, Bradford B U, Thurman R G
Department of Pharmacology, University of North Carolina at Chapel Hill 27599-7365, USA.
Hepatology. 1996 Aug;24(2):391-7. doi: 10.1002/hep.510240217.
It has been shown recently that inactivation of Kupffer cells prevents free radical formation and early alcohol-induced liver injury, and that hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells is likely involved in the mechanism. Calcium is essential for the activation of Kupffer cells, which contain L-type voltage-dependent Ca2+ channels. Therefore, the purpose of this study was to determine whether a Ca2+ channel blocker, nimodipine, prevents early alcohol-induced liver injury in vivo and to evaluate its effect on intracellular calcium ([Ca2+]i) in Kupffer cells in vitro. Male Wistar rats were exposed to ethanol (10-12 g/kg/d) continuously for up to 4 weeks via intragastric feeding using an enteral model developed by Tsukamoto and French. In this model, ethanol causes steatosis, necrosis, and inflammation in only a few weeks. In the experimental group, nimodipine (10 mg/kg/d) was added to the diet and was shielded from direct light. Nimodipine had no effect on body weight over a 4-week treatment period, nor were mean ethanol concentrations or their cyclic pattern in urine affected. The mean urine ethanol values were 154 +/- 11 mg/dL in ethanol-fed and 144 +/- 38 mg/dL in ethanol + nimodipine-fed rats. After 4 weeks, serum aspartate transaminase (AST) levels were elevated in ethanol-treated rats to 183 +/- 78 U/L. In contrast, values only reached 101 +/- 9 U/L in rats given nimodipine + ethanol-values which were significantly lower. Steatosis and necrosis assessed histologically were also reduced significantly by nimodipine. Nimodipine (10 micrograms/kg) also blocked the swift increase in alcohol metabolism and elevated oxygen consumption in perfused livers from rats treated with alcohol in vivo. Further, in cultured Kupffer cells, nimodipine (1 mumol/L) largely prevented the elevation in [Ca2+]i caused by lipopolysaccharide (LPS) (LPS, 200 +/- 11 nmol/L; LPS + nimodipine, 94 +/- 31 nmol/L; P < .05). These results indicate that nimodipine prevents alcoholic hepatitis, possibly by inhibition of endotoxin-mediated Kupffer cell activation.
最近的研究表明，枯否细胞失活可防止自由基形成和早期酒精性肝损伤，并且由活化的枯否细胞引起的高代谢状态后的缺氧可能参与了这一机制。钙对于含有L型电压依赖性Ca2+通道的枯否细胞的激活至关重要。因此，本研究的目的是确定Ca2+通道阻滞剂尼莫地平是否能预防体内早期酒精性肝损伤，并评估其对体外枯否细胞内钙（[Ca2+]i）的影响。雄性Wistar大鼠通过使用Tsukamoto和French开发的肠内模型经胃内喂养连续暴露于乙醇（10 - 12 g/kg/d）长达4周。在该模型中，乙醇在短短几周内就会导致脂肪变性、坏死和炎症。在实验组中，将尼莫地平（10 mg/kg/d）添加到饮食中，并避光保存。在为期4周的治疗期间，尼莫地平对体重没有影响，尿液中的平均乙醇浓度或其循环模式也未受影响。乙醇喂养大鼠的平均尿乙醇值为154±11 mg/dL，乙醇 + 尼莫地平喂养大鼠的平均尿乙醇值为144±38 mg/dL。4周后，乙醇处理大鼠的血清天冬氨酸转氨酶（AST）水平升高至183±78 U/L。相比之下，给予尼莫地平 + 乙醇的大鼠的值仅达到101±9 U/L，该值显著更低。组织学评估的脂肪变性和坏死也因尼莫地平而显著减轻。尼莫地平（10微克/千克）还阻断了体内酒精处理大鼠灌注肝脏中酒精代谢的迅速增加和耗氧量的升高。此外，在培养的枯否细胞中（1微摩尔/升）尼莫地平在很大程度上阻止了由脂多糖（LPS）引起的[Ca2+]i升高（LPS，200±11纳摩尔/升；LPS + 尼莫地平，94±31纳摩尔/升；P < 0.05）。这些结果表明尼莫地平可能通过抑制内毒素介导的枯否细胞活化来预防酒精性肝炎。
