Regulatory mechanism of duodenal bicarbonate secretion Roles of endogenous prostaglandins and nitric oxide
2011
Takeuchi, Koji | Kita, Kazutomo | Hayashi, Shusaku | Aihara, Eitaro
The secretion of HCO₃ ⁻ in the duodenum is increased by exogenous prostaglandin (PG) E₂ and mucosal acidification, the latter being accompanied by a rise in mucosal PGE₂ content and nitric oxide (NO) release. The stimulatory effect of PGE₂ is mediated intracellularly by both Ca²⁺ and 3′,5′-adenosine cyclic adenosine monophosphate (cAMP), and this action is inhibited by EP3 and EP4 antagonists. The secretion is also increased by NOR3 (NO donor), and this response is mimicked by dibutyryl 3′,5′-cyclic guanosine monophosphate (dbcGMP) and attenuated by indomethacin. Mucosal acidification stimulates HCO₃ ⁻ secretion with concomitant increases in mucosal PGE₂ production and NO release. The effects on HCO₃ ⁻ secretion and PGE₂ production are inhibited by indomethacin [nonselective cyclooxygenase (COX) inhibitor] and SC-560 (selective COX-1 inhibitor) but not rofecoxib (selective COX-2 inhibitor). Nᴳ-nitro-l-arginine methyl ester [l-NAME: nonselective NO synthase (NOS) inhibitor], but not aminoguanidine [selective inducible NOS inhibitor], attenuates the acid-induced HCO₃ ⁻ secretion and NO release in an l-arginine-sensitive manner. In addition, the response to PGE₂ is potentiated by vinpocetine [phosphodiesterase (PDE) 1 inhibitor] and cilostamide (PDE3 inhibitor), while the response to NOR3 is increased by vinpocetine. We conclude that endogenous PGs and NO are both involved in the local regulation of acid-induced duodenal HCO₃ ⁻ secretion; COX-1 and constitutive NOS are key enzymes responsible for the production of PGs and NO, respectively; NO stimulates HCO₃ ⁻ secretion by increasing PG production; PGE₂ stimulates HCO₃ ⁻ secretion via activation of EP3/EP4 receptors; and both PDE1 and PDE3 are involved in the regulation of duodenal HCO₃ ⁻ secretion.
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