The Influence of the Nitric Oxide Synthase InhibitorL‐NOARG on the Effects of Ethanol in Rats after Acute Ethanol Administration

Abstract

The aim of this work was to study the effects of the nitric oxide synthase inhibitor N G -nitro-L-arginine (L-NOARG) on the sedative and toxic effects of ethanol in rats. Ethanol at a dose of 3 g/kg, intraperitoneally induced sleep in rats (sleep time: 111.2∫10.3 min.). Administration of the nitric oxide synthase inhibitor L-NOARG (20 and 40 mg/ kg, intraperitoneally) 30 min. before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG at doses of 20 and 40 mg/kg reduced the exploratory activity of rats in the open-field test and significantly enhanced the sedative effect of ethanol in this test. It is possible that this effect is not caused by the interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L-NOARG. L-NOARG (20 and 40 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (2 and 3 g/kg). Moreover, the combined administration of ethanol (2 g/kg) and L-NOARG (20 and 40 mg/kg) caused a decrease in the body weight of animals, observed for 14 days. Also, livers of these rats were studied for necrosis and connective tissue reaction. In histological studies L-NOARG at a dose of 40 mg/kg had no effect on hepatic necrosis caused by the acute administration of ethanol but strenghtened connective tissue reaction. L-NOARG is widely used in pharmacological studies, including those concerning the effects of ethanol. However, on the basis of our data the possibility of toxic interactions with ethanol should be considered.Nitric oxide, an unusual neurotransmitter molecule, is synthesized on demand by the enzyme nitric oxide synthase from its precursor L-arginine (Dawson & Dawson 1994). It has been proposed that some of the effects of ethanol are mediated through nitric oxide pathways (Adams et al. 1994). Nitric oxide-related agents, i.e. nitric oxide donors and nitric oxide synthase inhibitors, influence ethanol narcosis (Adams et al. 1994(Adams et al. & 1995, consumption (Calapai et al. 1996), tolerance (Khanna et al. 1995) and withdrawal (Adams et al. 1995;Uzbay et al. 1997) and ethanol-induced organ damage (Lancaster 1995;Zou et al. 1996).In our previous works nitric oxide synthase inhibitors, 7-nitroindazole and N G -nitro-L-arginine (L-NOARG) significantly increased the duration of ethanol (4 g/kg, intraperitoneally)-induced sleep. 7-Nitroindazole also slowed ethanol clearance after acute (at doses of 80 and 120 mg/ kg) and chronic administration (at a dose of 20 mg/kg) (Vassiljev et al. 1998a). 7-Nitroindazole attenuated the behavioural signs of ethanol withdrawal in mice due to pharmacokinetic interaction when administered immediately after the end of ethanol exposure (Vassiljev et al. 1998b). L-NOARG also significantly increased the toxicity of ethanol as evidenced by increased post-experimental lethality (Vassiljev et al. 1998a)