Distinct mechanisms of acid-induced HCO₃⁻secretion in normal and slightly permeable stomachs

Abstract

. 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...

The Gastrointestinal Circulation: Physiology and Pathophysiology

“…Consequently, it is not entirely surprising that sensory nerve activation also contributes to epithelial HCO 3 − secretion that mediates luminal H + neutralization (3,5,244,484). Pharmacologic blockade experiments also implicate prostaglandins (e.g., PGE 2 ) and NO in the HCO 3 − secretion induced by luminal acidification (5,475,485). There is some evidence indicating that acid induced HCO 3 − secretion in the duodenum is a result of an NO/PGE2 pathway (475).…”

“…The resistance of the gastric mucosa to acid has prompted the use of "barrier breakers" to increase acid diffusion into the interstitium. For example, hypertonic NaCl or bile salts are used to disrupt the mucus lining or antisecretory drugs used to inhibit acid secretion; both of which collapse the mucus HCO 3 − gradient (5,481,486). Figure 27 The acid sensing pathway leading to a neurogenic hyperemia and HCO 3…”

The Role of Capsaicin-Sensitive Afferent Nerves in Gastric Mucosal Protection Initiated Centrally or Peripherally under Experimental Conditions

“…In this process primary sensory afferent neurons activated by the back-diffusing acid play a crucial role, since sensory nerve endings can sense acid via acid sensing channel [60][61][62][63][64][65][66][67][68].…”

“…This response is mediated by primary sensory afferent neurons, namely if the mucosal barrier is disturbed or disrupted in the presence of luminal acid, the acid reaching the lamina propria stimulates spinal afferents. This stimulation will initiate the efferent-like function of primary afferents resulting in CGRP and NO formation and release that induces a prompt hyperaemia in the gastro-duodenal mucosa and bicarbonate (HCO 3 − ) secretion [60][61][62][63][64][65][66][67][68].…”

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

“…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. In the present study, we showed that the response to NOR-3 in the mouse stomach was significantly attenuated by the prior addition of methylene blue, an inhibitor of guanylate cyclase as well as indomethacin, suggesting the mediation of this response locally by PGs and intracellularly by cGMP.…”