Effect of NG-nitro-L-arginine methyl ester, the nitric oxide synthase inhibitor, on duodenal alkaline secretion and mepirizole-induced duodenal lesions in rats.
We investigated the HCO3- stimulatory mechanism of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the anesthetized rat duodenum and examined whether L-NAME protects against mepirizole-induced duodenal damage. The proximal duodenal loop was perfused with saline and HCO3- secretion was measured at pH 7.0 using a pH-stat with added HCl (10 mM). L-NAME (1-5 mg/kg, i.v.) increased HCO3- secretion in a dose-dependent manner, with concomitant elevation in arterial blood pressure and an apparent decrease in heart rate. These changes were mimicked by another NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg, i.v.) but not by NG-nitro-D-arginine methyl ester (D-NAME), and were all antagonized by co-administration of L-arginine but not by D-arginine (200 mg/kg, i.v.). The HCO3- stimulatory effect of L-NAME was also inhibited by vagotomy and pretreatment with atropine (1 mg/kg, s.c.) or indomethacin (5 mg/kg, s.c.). Vagotomy and atropine did not affect blood pressure response, but both inhibited the decrease of heart rate caused by L-NAME, whereas indomethacin did not affect either of these changes. In addition, L-NAME increased HCO3- secretion in the presence of mepirizole (200 mg/kg, s.c.) and prevented duodenal lesions caused by this agent. These results suggest that L-NAME stimulates duodenal HCO3- secretion in association with the inhibition of endogenous NO production, mediated by neural reflex through vagal efferent nerves, resulting from the pressor response to this agent, and may protect the duodenal mucosa against acid-related damage.
Takeuchi
K
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Japan.
Takehara
K
K
Kato
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D050260:Carbohydrate Metabolism; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004840:Epirizole / Q000633:toxicity*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D004840:Epirizole; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester