Mechanisms Underlying Capsaicin-Stimulated Secretion in the Stomach: Comparison with Mucosal Acidification

The effects of capsaicin and mucosal acidification on gastric \(\mathrm{HCO}_{3}^{-}\) 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 \(\mathrm{HCO}_{3}^{-}\) 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 \(\mathrm{HCO}_{3}^{-}\) 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 indomethacin, N G -nitro-l-arginine methylester (l-NAME), and capsazepine [transient receptor potential vanilloid type 1 (TRPV1) antagonist] but not FR172357 [3-bromo-8-[2,6-dichloro-3-[ N [( E )-4-( N , N -dimethylcarbamoyl) cinnamidoacetyl]- N -methylamino]benzyloxy]-2-metylimidazo[1,2- a ]pyridine; bradykinin B2 antagonist] or the EP1 antagonist. The acid-induced \(\mathrm{HCO}_{3}^{-}\) secretion was attenuated by indomethacin, l-NAME, the EP1 antagonist, and sensory deafferentation, but not affected by capsazepine or FR172357. Prostaglandin E 2 (PGE 2 ), NOR-3 [(±)-( E )-ethyl-2-[( E )-hydroxyimino]-5-nitro-3-hexeneamine] (NO donor), and bradykinin stimulated the secretion of \(\mathrm{HCO}_{3}^{-}\) , and the effect of bradykinin was blocked by indomethacin and l-NAME as well as FR172357. The stimulatory effect of capsaicin disappeared in IP (-/-) mice, whereas that of acidification disappeared in EP1 (-/-) 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 \(\mathrm{HCO}_{3}^{-}\) 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.