Abstract
The gastric mucosa responds to mucosal damaging agents by significantly decreasing acid secretion. However, the inhibition of nitric oxide (NO) biosynthesis by NG-nitro-l -arginine methyl ester (l -NAME) turned the acid-secretory response in the damaged stomach from the ‘inhibition’ into ‘stimulation’ state. The present study was performed to investigate the mechanism underlying stimulation of acid secretion in the stomach after damage in the presence of l -NAME. Exposure of the chambered rat stomach to 20 mmol/L taurocholate (TC) for 30 min decreased acid secretion with concomitant reduction of transmucosal potential difference (PD). Pretreatment with l -NAME, although it had no effect on basal acid secretion, apparently increased the acid secretion in the stomach after exposure to TC without any change in the PD response. The acid-stimulatory effect of l -NAME in the damaged stomach was reversed by the co-administration of l -arginine but not d -arginine. Such acid-secretory responses in the presence of l -NAME were also inhibited by prior administration of cimetidine, FPL-52694 (a mast cell stabilizer), spantide (a substance P antagonist) or sensory defunctionalization with capsaicin pretreatment. In contrast, mucosal exposure to TC significantly decreased the number of mucosal mast cells and increased histamine output in the lumen, and these responses were significantly inhibited by FPL-52794, spantide or sensory deafferentation. These findings suggest that: 1 Damage in the stomach may activate the acid-stimulatory pathway in addition to the NO-dependent inhibitory pathway, although the latter effect overcomes the former, resulting in a decrease in acid secretion 2 The stimulatory pathway is dependent on histamine which may be released from mucosal mast cells in association with capsaicin-sensitive sensory nerves; and 3 l -NAME unmasks the acid-stimulatory response by suppressing the inhibitory pathway
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