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.

Animal Models of Alcoholic Liver Disease

“…However, it also appears that mechanisms of acute and chronic alcohol-induced liver injury overlap to some extent [10,11,12]. For example, Enomoto et al [13] showed that compounds previously shown to protect against chronic alcohol-induced liver damage [14,15,16] also protected rat liver against acute ethanol-induced steatosis (table 1). Therefore, acute exposure can in principle be used to mimic very early changes caused by ethanol [17,18].…”

Hepatic haemodynamics and reticuloendothelial function in the rat in response to chronic ethanol administration

“…In contrast, Gulati, Srimal & Bhar-acute ethanol-dosing studies which implicate adenosine-mediated increases in portal blood gava (1989) showed that splenic blood¯ow was unaltered after acute ethanol administration, as¯ow in response to ethanol (Orrego et al, 1988). In contrast, Gulati, Srimal & Bhar-acute ethanol-dosing studies which implicate adenosine-mediated increases in portal blood gava (1989) showed that splenic blood¯ow was unaltered after acute ethanol administration, as¯ow in response to ethanol (Orrego et al, 1988).…”

Alcoholic hepatitis---the case for intensive management

“…Calcium channel blockers, which have been shown to be effective in the animal model of alcoholic hepatitis,12have been shown to be ineffective in controlled trials 13…”