EFFECT OF N-G-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 (N O) synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) in th e anesthetized rat duodenum and examined whether L-NAME protects again st mepirizole-induced duodenal damage. The proximal duodenal loop was perfused with saline and HCO,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 HCO 3- 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, N-G-monomethy l-L-arginine (L-NMMA; 50 mg/kg, i.v.) but not by N-G-nitro-D-arginine methyl ester (D-NAME), and were all antagonized by co-administration o f L-arginine but not by D-arginine (200 mg/kg, i.v.). The HCO3- stimul atory 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.). Vagoto my and atropine did not affect blood pressure response, but both inhib ited 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 p revented duodenal lesions caused by this agent. These results suggest that L-NAME stimulates duodenal HCO3- secretion in association with th e inhibition of endogenous NO production, mediated by neural reflex th rough vagal efferent nerves, resulting from the presser response to th is agent, and may protect the duodenal mucosa against acid-related dam age.