The effects of capsaicin and mucosal acidification on gastric HCO 3 Ϫ secretion were compared in wild-type and prostacyclin (PGI 2 ) IP receptor or prostaglandin E receptor EP1 or EP3 knockout C57BL/6 mice as well as rats. Under urethane anesthesia, the stomach was mounted on an ex vivo chamber, perfused with saline, and the secretion of HCO 3 Ϫ was measured at pH 7.0 using the pH-stat method. Capsaicin or 200 mM HCl was applied to the chamber for 10 min. Capsaicin increased the secretion of HCO 3 Ϫ in rats and wild-type mice, the response at 0.3 mg/ml being equivalent to that induced by acidification. This effect of capsaicin in rats was abolished by ablation of capsaicin-sensitive afferent neurons and attenuated by indo- Ϫ , and the effect of bradykinin was blocked by indomethacin and L-NAME as well as FR172357. The stimulatory effect of capsaicin disappeared in IP (Ϫ/Ϫ) mice, whereas that of acidification disappeared in EP1 (Ϫ/Ϫ) mice. Intragastric application of capsaicin increased mucosal PGI 2 but not PGE 2 levels in the rat stomach. These results suggested that both capsaicin and acid increase gastric HCO 3 Ϫ secretion via a common pathway, involving PG and NO as well as capsaicin-sensitive afferent neurons, yet their responses differ concerning TRPV1 or prostanoid receptor dependence.

We compared the HCO3- secretory responses induced by mucosal acidification at different HCl concentrations (100 and 200 mM HCl) in the rat stomach. Under urethane anesthesia, the stomach was mounted on an ex vivo chamber and perfused with saline under inhibition of acid secretion by omeprazole (60 mg/kg, i.p.). TheHCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. The acidification was performed by exposure of the mucosa to 100 mMor 200 mM HCl for 10 min. The secretion of HCO3- was increased by acidification of the mucosa at both 100 and 200 mM of HCl, and the maximal HCO3- response was 1.5-times greater at the latter concentration. The HCO3- responses induced by 100 and 200 mM HCl were both totally inhibited by prior administration of indomethacin, an inhibitor of prostaglandin (PG) production. The HCO3- stimulatory effect of 200 mM HCl was also significantly attenuated by pre-treatment with N(G)-nitro L-arginine methyl ester (L-NAME), the inhibitor of nitric oxide (NO) synthase, as well as chemical ablation of capsaicin-sensitive afferent neurons, whereas that of 100 mM HCl was affected by neither of these treatments. We conclude that the mucosal acidification stimulates gastric HCO3- secretion in different mechanisms, depending on the concentration of acid; the response caused by 100 mM HCl is mediated only by PGs, while that caused by 200 mM HCl is mediated by both capsaicin-sensitive afferent neurons and NO, in addition to PGs.

Gastroduodenal HCO3- secretion is a key process that aids in preventing acid-peptic injury. Endogenous prostaglandins (PGs) play a particularly important role in the local control of this secretion. The secretion of HCO3- in both the stomach and duodenum was increased in response to PGE2 as well as mucosal acidification, the latter occurring with concomitant enhancement of mucosal PG generation. These HCO3- responses in the duodenum were markedly reduced by prior administration of the EP4 antagonist in rats, and profoundly decreased in the animals lacking EP3 receptors but not EP1 receptors. In contrast, gastric HCO3- responses induced by PGE2 and mucosal acidification were prevented by the EP1 antagonist and disappeared in EP1, but not EP3-knockout mice. Consistent with these findings, duodenal HCO3- secretion was stimulated by both EP3 and EP4 agonists but not EP1 or EP2 agonists, while gastric HCO3- secretion was increased by the EP1 agonist but not EP2, EP3 or EP4 agonists. In addition, the HCO3- stimulatory action of sulprostone (EP1/EP3 agonist) in the stomach was inhibited by the Ca2+ antagonist verapamil but not affected by IBMX, the inhibitor of phosphodiesterase, while that in the duodenum was inhibited by verapamil and enhanced by IBMX. Forskolin, the stimulator of adenylate cyclase, increased HCO3- secretion in the duodenum but not the stomach. Thus, the HCO3- stimulatory action of PGE2 in the duodenum is mediated by both EP3 and EP4 receptors being coupled intracellularly with both Ca2+ and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca2+.

No abstract