Regulatory mechanism of acid secretion in the damaged stomach: Role of endogenous nitric oxide

The present article overviews the regulatory mechanism of acid secretion in the stomach after damage with taurocholate (TC), one of the bile acids. Mu cosal exposure of a rat stomach to 20 mmol/L TC for 30 min caused a decreas e of acid secretion with a concomitant increase in nitric oxide (NO) and pr ostaglandin (PG) E-2 (PGE(2)) as well as Ca2+ in the luminal contents. Prio r administration of NG-nitro-L-arginine methyl ester (L-NAME), as well as i ndomethacin, significantly attenuated the reduction of acid secretion by TC and acid secretion was even increased in the presence of L-NAME. The acid stimulatory effect of L-NAME in the damaged stomach was not mimicked by ami noguanidine and was antagonized by co-administration of L-arginine but not D-arginine. Increased NO release in the damaged stomach was suppressed by p retreatment with L-NAME or co-application of EGTA and the latter also inhib ited the increase in luminal Ca2+. The enhanced acid secretory response in the presence of L-NAME was also inhibited by cimetidine, FPG-52694 (a mast cell stabilizer) or sensory deafferentation. Mucosal exposure to TC caused an increase in luminal histamine output, together with a decrease in the nu mber of mucosal mast cells in the stomach. These changes were prevented by FPL-52694 and sensory deafferentation and were also partly suppressed by in domethacin. In addition, the acid stimulatory action of L-NAME in the damag ed stomach was significantly mitigated when indomethacin was administered t ogether with L-NAME. We conclude that: (i) damage in the stomach may activa te acid a stimulatory pathway in addition to a PG-, NO- and Ca2+-dependent inhibitory mechanism, but the latter effect overcomes the former, resulting in a decrease in acid secretion; (ii) acid stimulation in the damaged stom ach is mediated by histamine released from the mucosal mast cell, a process interacting with capsaicin-sensitive sensory nerves; (iii) the increase in luminal Ca2+ plays a role in increasing NO production and, hence, in regul ating acid secretion; and (iv) PG may have a dual role in the regulation of acid secretion in the damaged stomach: an inhibitory effect at the parieta l cell and an excitatory effect, probably through enhancing the release of mucosal histamine. (C) 2000 Blackwell Science Asia Pty Ltd.