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

Abstract

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.

Phosphodiesterase Isozymes Involved in Regulation of Secretion in Isolated Mouse Stomach in Vitro

“…Indeed, we observed that the isolated stomach generated NO under basal conditions without any treatment and that the production was significantly reduced by the serosal addition of L-NAME. Consistent with our previous findings (Aihara et al, 2005a), we further observed in this study that NOR-3 stimulated HCO 3 Ϫ secretion in the stomach, partly mediated by endogenous PGs and through the activation of EP1 receptors. Thus, it is assumed that the inhibition of PDE1 and PDE5 first increases intracellular levels of cGMP and then stimulates gastric HCO 3 Ϫ secretion in two ways, directly via cGMP and indirectly mediated by PGE 2 /EP1 receptors.…”

“…Furukawa et al (1999Furukawa et al ( , 2000 showed that the secretion of HCO 3 Ϫ in isolated duodenum in vitro was stimulated by NOR-3, at least partly, via production of PGE 2 through activation of COX-1. We also showed that NOR-3 also increased PGE 2 production in the rat stomach, resulting in stimulation of HCO 3 Ϫ secretion (Aihara et al, 2005a). The levels of cGMP in the isolated mouse stomach were also significantly increased by NOR-3.…”

“…We previously reported that the acid-induced secretion of HCO 3 Ϫ in the stomach was inhibited by the prior administration of L-NAME, an inhibitor of NO production as well as indomethacin (Aihara et al, 2005a, suggesting the involvement of endogenous NO in the response, in addition to PGs. Indeed, HCO 3 Ϫ secretion was stimulated by the NO donor NOR-3 in the rat stomach and duodenum, and these actions were significantly attenuated by indomethacin (Sugamoto et al, 2001;Aihara et al, 2005bAihara et al, , 2006.…”

The Gastrointestinal Circulation: Physiology and Pathophysiology

“…O 2 − , superoxide; H 2 O 2 , hydrogen peroxide; ONOO, peroxynitrite; N2O 3 B2 receptor antagonists also exert a protective effect in the postischemic intestine (465). Bradykinin, PAF and LTB4 are involved in the early immediate recruitment of neutrophils and appear to mediate this effect largely through transcription-independent mechanisms (160,467).…”

“…The submucosal arterioles branch into capillaries at the base of the glands and postcapillary vessels pass to the luminal surface of the mucosa where they form another capillary network surrounding the gastric pits (147). This seriescoupled arrangement allows for the HCO 3 − released from the parietal cell during H + secretion to be delivered to the basal side of the mucosal surface cells (Fig. 1).…”