title: Regulatory mechanism of acid secretion in the damaged stomach: role of endogenous nitric oxide.
abstract: The present article overviews the regulatory mechanism of acid secretion in the stomach after damage with taurocholate (TC), one of the bile acids. Mucosal exposure of a rat stomach to 20 mmol/L TC for 30 min caused a decrease of acid secretion with a concomitant increase in nitric oxide (NO) and prostaglandin (PG) E2 (PGE2) as well as Ca2+ in the luminal contents. Prior administration of N(G)-nitro-L-arginine methyl ester (L-NAME), as well as indomethacin, 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 aminoguanidine and was antagonized by co-administration of L-arginine but not D-arginine. Increased NO release in the damaged stomach was suppressed by pretreatment with L-NAME or co-application of EGTA and the latter also inhibited the increase in luminal Ca2+. The enhanced acid secretory response in the presence of L-NAME was also inhibited by cimetidine, FPL-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 number of mucosal mast cells in the stomach. These changes were prevented by FPL-52694 and sensory deafferentation and were also partly suppressed by indomethacin. In addition, the acid stimulatory action of L-NAME in the damaged stomach was significantly mitigated when indomethacin was administered together with L-NAME. We conclude that: (i) damage in the stomach may activate 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 stomach 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 regulating 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 parietal cell and an excitatory effect, probably through enhancing the release of mucosal histamine.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan. takeuchi@mb.kyoto-phu.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: H
authors.initials: H
authors.lastname: Araki
authors.forename: S
authors.initials: S
authors.lastname: Kawauchi
authors.forename: T
authors.initials: T
authors.lastname: Kunikata
authors.forename: H
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: K
authors.initials: K
authors.lastname: Tashima
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors; D005744:Gastric Acid / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D013272:Stomach Diseases / Q000139:chemically induced / Q000503:physiopathology*; D013656:Taurocholic Acid
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D013656:Taurocholic Acid; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin