title: Nimodipine, a dihydropyridine-type calcium channel blocker, prevents alcoholic hepatitis caused by chronic intragastric ethanol exposure in the rat.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill 27599-7365, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Iimuro
authors.forename: K
authors.initials: K
authors.lastname: Ikejima
authors.forename: M L
authors.initials: ML
authors.lastname: Rose
authors.forename: B U
authors.initials: BU
authors.lastname: Bradford
authors.forename: R G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D004731:Endotoxins / Q000633:toxicity; D000431:Ethanol / Q000008:administration & dosage; D006519:Hepatitis, Alcoholic / Q000517:prevention & control*; D007728:Kupffer Cells / Q000187:drug effects; D008297:Male; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002121:Calcium Channel Blockers; D004731:Endotoxins; D000431:Ethanol; D009553:Nimodipine; D002118:Calcium