These results suggest that H₂S increases HCO₃⁻ secretion in the rat duodenum, and that this action is partly mediated by PG and NO as well as by capsaicin-sensitive afferent neurones. It is assumed that endogenous H₂S is involved in the regulatory mechanism of acid-induced HCO₃⁻ secretion and mucosal protection in the duodenum.

We examined the effect of the tricarbonyl-dichlororuthenium (II) dimer (CORM-2), a carbon monoxide (CO) donor, on duodenal HCO 3 Ϫ secretion in rats and investigated whether endogenous CO produced by heme oxygenase (HO) is involved in the regulation of this secretion. Under urethane anesthesia, a duodenal loop was perfused with saline, and HCO 3 Ϫ secretion was measured at pH 7.0 using a pH stat method. CORM-2, biliverdin, FeCl 2 , or ruthenium (III) chloride hydrate (RuCl 3 ) was applied to the loop for 5 min. The mucosal application of CORM-2 dose-dependently increased HCO 3 Ϫ secretion, whereas neither RuCl 3 , FeCl 2 , nor biliverdin had an effect. The stimulatory effect was significantly attenuated by indomethacin but not N G -nitro-L-arginine methyl ester. The application of CORM-2 increased the mucosal prostaglandin (PG) E 2 content of the duodenum. The acid-induced HCO 3 Ϫ response was markedly inhibited by indomethacin and Sn(IV) protoporphyrin IX dichloride (SnPP; an inhibitor of HO) but not Cu(II) protoporphyrin dichloride, and the inhibitory effect of SnPP was significantly reversed by pretreatment with hemin, a substrate of HO. Perfusion of the duodenal loop with 100 mM HCl for 2 h caused a few hemorrhagic lesions in the mucosa, and this response was significantly worsened by the prior administration of SnPP and indomethacin. The expression of HO-1 but not HO-2 protein was up-regulated in the duodenum after the acid treatment. These results suggest that CO, generated endogenously or exogenously, stimulates HCO 3 Ϫ secretion in the duodenum, and this effect is mediated by endogenous PGs. It is assumed that HO/CO plays a role in maintaining the integrity of the duodenal mucosa.

(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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