Regulatory mechanism of duodenal bicarbonate secretion: Roles of endogenous prostaglandins and nitric oxide

Takeuchi, K.; Kita, K.; Hayashi, S.; Aihara, E.

Pharmacology and Therapeutics 130(1): 59-70

2011


ISSN/ISBN: 1879-016X
PMID: 21185865
DOI: 10.1016/j.pharmthera.2010.12.006
Accession: 055456518

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Abstract
The secretion of HCO(3)(-) in the duodenum is increased by exogenous prostaglandin (PG) E(2) and mucosal acidification, the latter being accompanied by a rise in mucosal PGE(2) content and nitric oxide (NO) release. The stimulatory effect of PGE(2) is mediated intracellularly by both Ca(2+) 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 HCO(3)(-) secretion with concomitant increases in mucosal PGE(2) production and NO release. The effects on HCO(3)(-) secretion and PGE(2) production are inhibited by indomethacin [nonselective cyclooxygenase (COX) inhibitor] and SC-560 (selective COX-1 inhibitor) but not rofecoxib (selective COX-2 inhibitor). N(G)-nitro-l-arginine methyl ester [l-NAME: nonselective NO synthase (NOS) inhibitor], but not aminoguanidine [selective inducible NOS inhibitor], attenuates the acid-induced HCO(3)(-) secretion and NO release in an l-arginine-sensitive manner. In addition, the response to PGE(2) 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 HCO(3)(-) secretion; COX-1 and constitutive NOS are key enzymes responsible for the production of PGs and NO, respectively; NO stimulates HCO(3)(-) secretion by increasing PG production; PGE(2) stimulates HCO(3)(-) secretion via activation of EP3/EP4 receptors; and both PDE1 and PDE3 are involved in the regulation of duodenal HCO(3)(-) secretion.