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. Distinct mechanisms of acidinduced HCO 3 Ϫ secretion in normal and slightly permeable stomachs. Am J Physiol Gastrointest Liver Physiol 291: G464 -G471, 2006. First published May 18, 2006 doi:10.1152/ajpgi.00048.2006.-We investigated the regulatory mechanism of acid-induced HCO 3 Ϫ secretion in the slightly permeable rat stomach after an exposure to hyperosmolar NaCl. Under urethane anesthesia, a rat stomach was mounted on a chamber and perfused with saline, and the secretion of HCO 3 Ϫ was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. Acidification of the normal stomach with 100 mM HCl increased HCO 3 Ϫ secretion, and this response was totally inhibited by pretreatment with indomethacin but not N G -nitro-L-arginine methyl ester (L-NAME) or chemical ablation of capsaicin-sensitive afferent neurons. Exposure of the stomach to 0.5 M NaCl deranged the unstirred mucus gel layer without damaging the surface epithelial cells. The stomach responded to 0.5 M NaCl by secreting slightly more HCO 3 Ϫ , in an indomethacin-inhibitable manner, and responded to even 10 mM HCl with a marked rise in HCO 3 Ϫ secretion, although 10 mM HCl did not have an effect in the normal stomach. The acid-induced HCO 3 Ϫ response in the NaCl-treated stomach was significantly but partially attenuated by indomethacin, L-NAME, or sensory deafferentation and was totally abolished when these treatments were combined. These results suggest that gastric HCO 3 Ϫ secretion in response to acid is regulated by two independent mechanisms, one mediated by prostaglandins (PGs) and the other by sensory neurons and nitric oxide (NO). The acid-induced HCO 3 Ϫ secretion in the normal stomach is totally mediated by endogenous PGs, but, when the stomach is made slightly permeable to acid, the response is markedly facilitated by sensory neurons and NO.gastric HCO 3 Ϫ secretion; mucosal acidification; capsaicin-sensitive afferent neurons; prostaglandin; nitric oxide; rat THE SECRETION of HCO 3 Ϫ plays a crucial role in the protection of the gastroduodenal mucosa from acid (5, 10). The secretion increases in response to mucosal acidification, and the process is mediated by multiple factors, including endogenous prostaglandins (PGs) and nitric oxide (NO) as well as neuronal pathways (12,22,29,30). Recently, we found that the mechanism underlying acid-induced HCO 3 Ϫ secretion in the stomach differed depending on the concentration of acid; the response caused by 100 mM HCl was mediated only by PGs, whereas that caused by 200 mM HCl was mediated by both capsaicinsensitive afferent neurons and NO in addition to PGs (1). It is assumed that 100 mM HCl applied topically to the stomach increases PG biosynthesis by itself but does not acidify the mucosa enough to activate afferent neurons, resulting in an increase of HCO 3 Ϫ secretion that is totally dependent on endogenous PGs but not afferent neurons or NO.Mucus adherent to the luminal surface of the mucosa provides a zone of low turbulence (unstirred layer), allowing the development of a gradient f...

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(Ϯ)-(E)-4-Ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide](NOR-3), a nitric-oxide (NO) donor, is known to increase HCO 3 Ϫ secretion in rat stomachs, intracellularly mediated by cGMP; yet, there is no information about the phosphodiesterase (PDE) isozyme involved in this process. We examined the effects of various isozyme-selective PDE inhibitors on the secretion of HCO 3 Ϫ in the mouse stomach in vitro and the type(s) of PDE isozymes involved in the response to NO. The gastric mucosa of DDY mice was stripped of the muscle layer and mounted on an Ussing chamber. HCO 3 Ϫ secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. NOR-3, 8-bromoguanosine 3Ј,5Ј-cyclic monophosphate (8-Br-cGMP), and various PDE inhibitors were added to the serosal side. Vinpocetine (PDE1 inhibitor) or zaprinast (PDE5 inhibitor) was also added serosally 30 min before NOR-3 or 8-Br-cGMP. Both NOR-3 and 8-Br-cGMP stimulated HCO 3 Ϫ secretion in a dosedependent manner, and the response to NOR-3 was significantly inhibited by methylene blue. Likewise, the secretion induced by NOR-3 or 8-Br-cGMP was significantly attenuated by 6-((2S,3S)-3-(4-chloro-2-methylphenylsulfonylaminomethyl)-bicyclo(2.2.2)octan-2-yl)-5Z-hexenoic acid (ONO-8711), the PGE receptor (EP)1 antagonist, as well as indomethacin and potentiated by both vinpocetine and zaprinast at doses that had no effect by themselves on the basal secretion, whereas other subtype-selective PDE inhibitors had no effect. NOR-3 increased the mucosal PGE 2 content in a methylene blueinhibitable manner. These results suggest that NO stimulates gastric HCO 3 Ϫ secretion mediated intracellularly by cGMP and modified by both PDE1 and PDE5, and this response is finally mediated by endogenous PGE 2 via the activation of EP1 receptors.

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We examined the effect of various carbonated beverages, especially Coca-Cola, on the HCO3- secretion in the rat stomach and duodenum. Under urethane anaesthesia, a chambered stomach or a proximal duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. The amount of CO2 contained in these beverages was about 4-7 g/mL. Coca-Cola topically applied to the mucosa for 10 min significantly increased the HCO3- secretion in both the stomach and the duodenum. The HCO3- response in the duodenum was totally abolished by indomethacin and also partially inhibited by acetazolamide, an inhibitor of carbonic anhydrase. Likewise, the response in the stomach was also markedly inhibited by either acetazolamide or indomethacin. The mucosal application of Coca-Cola increased the PGE2 contents in both the stomach and the duodenum. Other carbonated beverages, such as sparkling water, Fanta Grape or cider, also increased the HCO3- secretion in these tissues. These results suggest that Coca-Cola induces HCO3- secretion in both the stomach and the duodenum, and these responses may be attributable to both the intracellular supply of HCO3- generated via carbonic anhydrase, and endogenous PGs, probably related to the acidic pH of the solution.