ROLE OF L-ARGININE, A SUBSTRATE FOR NITRIC OXIDE-SYNTHASE, IN GASTROPROTECTION AND ULCER HEALING

Nitric oxide (NO) synthesized from L-arginine interacts with prostagla ndins (PG) and sensory neuropeptides in the regulation of mucosal inte grity, but the role of L-arginine, a substrate for NO-synthase, in gas troprotection and healing of chronic gastric ulcers has been little st udied. In this study we compared the effects of intragastric (i.g.) an d systemic (i.v.) administration of L-arginine or D-arginine on gastri c secretion and acute gastric lesions provoked in rats by i.g. applica tion of 100% ethanol. acidified aspirin (ASA). or the exposure to 3.5 h of water immersion and restraint stress (WRS). In addition, the effe cts of L-arginine on ulcer healing and the formation of new vessels (a ngiogenesis) were determined. using monoclonal antibody (MAb E-9). L-a rginine (10-200 mg/kg i.g.) failed to significantly affect gastric sec retion but dose-dependently reduced the gastric lesions induced by 100 % ethanol, ASA, and WRS. the doses inhibiting 50% of these lesions bei ng 65, 94, and 72 mg/kg, respectively. This protection was accompanied by a significant rise in the gastric blood flow (GBF), whereas L-argi nine given i.v. failed to affect the ethanol-lesions and the GBF. D-ar ginine or the NO-related amino acids-L-glutamine. L-citrulline, or L-o rnithine-failed to significantly influence these lesions, Suppression of the generation of mucosal PG by indomethacin or capsaicin-denervati on attenuated the protection and hyperemia induced by L-arginine. The inhibition of constitutive NO synthase by L-NNA had no significant eff ect on the protection afforded by L-arginine, but reduced the gastric hyperemia accompanying this protection. L-arginine (150 mg/kg per day i.g.) accelerated the ulcer healing and increased GBF at the ulcer mar gin, and angiogenesis, whereas treatment with L-NNA had an opposite ef fect. L-arginine added to N-G-nitro-L-arginine (L-NNA) restored the ul cer healing, hyperemia, and angiogenesis. We conclude that: (1) the pr otective activity of L-arginine involves gastric hyperemia mediated by NO and a mild irritant effect due to enhanced generation of endogenou s Pe, and (2) the ulcer healing properties of L-arginine depend upon i ts hyperemic and angiogenic actions, possibly involving NO.