The effects of the nitric oxide synthase inhibitor 7-nitroindazole on ethanol pharmacokinetics in rats after acute and chronic ethanol administration.
The aim of this work was to study the effects of the nitric oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI) and NG-nitro-L-arginine (L-NOARG) on the effects and pharmacokinetics of ethanol in rats. Ethanol at a dose of 4 g/kg, i.p. induced sleep in rats (sleep time: 117.2+/-30.7 min). Administration of the NOS inhibitors 7-NI (20 mg/kg, i.p.) and L-NOARG (20 mg/kg, i.p.) 30 min before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG also significantly increased the toxicity of ethanol as evidenced by increased post-experimental lethality. Ethanol at a dose of 2 g/kg (i.p.) did not induce sleep in vehicle-treated rats; however, the combined administration of ethanol (2 g/kg) and 7-NI at doses of 40, 80, and 120 mg/kg caused sleep, for 49.4+/-3.7, 204.0+/-13.3, and 447.5+/-62.8 min, respectively. L-NOARG (20 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (4 g/kg). 7-NI in lower doses (20 and 40 mg/kg) had no effect and in higher doses (80 and 120 mg/kg) significantly slowed ethanol clearance during the 12 h after ethanol administration. The effect of 7-NI (20 mg/kg) on ethanol pharmacokinetics after chronic ethanol administration (inhalation for 18 days) was also studied. The administration of 7-NI immediately after the end of ethanol exposure had a pronounced effect on ethanol pharmacokinetics; in 7-NI-treated rats the fall in ethanol concentrations was significantly slower as compared with vehicle-treated rats. In 7-NI-treated rats, blood-ethanol levels were higher at 3, 6, 9, and 12 h after the end of ethanol exposure.
Vassiljev
V
V
Department of Pathologic Anatomy and Forensic Medicine, Faculty of Medicine, University of Tartu, Estonia.
Kalda
A
A
Pokk
P
P
Väli
M
M
Zharkovsky
A
A
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D007191:Indazoles; D019335:Nitroarginine; D000431:Ethanol; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole