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Am J Physiol Gastrointest Liver Physiol 288: G39-G47, 2005. First published September 2, 2004; doi:10.1152/ajpgi.00060.2004
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MUCOSAL BIOLOGY

Inhibition of ACh-stimulated exocytosis by NSAIDs in guinea pig antral mucous cells: autocrine regulation of mucin secretion by PGE2

Chikao Shimamoto,2 Shoko Fujiwara,1 Masumi Kato,1 Shigenori Ito,3 Ken-ichi Katsu,2 Hiroshi Mori,4 and Takashi Nakahari1

1Department of Physiology, 2Department of Internal Medicine (Division II), 3Department of Chemistry, and 4Department of Pathology, Osaka Medical College, Takatsuki, Japan

Submitted 4 February 2004 ; accepted in final form 19 August 2004

The effects of indomethacin (IDM) and aspirin (ASA) on ACh (10 µM) -stimulated exocytotic events were studied in guinea pig antral mucous cells by using video optical microscopy. IDM or ASA, which inhibits cyclooxygenase (COX), decreased the frequency of ACh-stimulated exocytotic events by 30% or 60%, respectively. The extent of inhibition induced by ASA (60%) decreased by 30% when IDM or arachidonic acid (AA, the substrate of COX) was added. IDM, unlike ASA, appears to induce the accumulation of AA, which enhances the frequency of ACh-stimulated exocytotic events in ASA-treated cells. ONO-8713 (100 µM; an inhibitor of the EP1–EP4 prostaglandin receptors) and N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, HCl (H-89, 20 µM; an inhibitor of PKA) also decreased the frequency of ACh-stimulated exocytotic events by 60%. However, the supplementation of PGE2 (1 µM) prevented the IDM-induced decrease in the frequency of ACh-stimulated exocytotic events. SC-560 (an inhibitor of COX-1) decreased the frequency of ACh-stimulated exocytotic events by 30%, but NS-398 (an inhibitor of COX-2) did not. Moreover, IDM decreased the frequency of exocytotic events stimulated by ionomycin, suggesting that COX-1 activity is stimulated by an increase in intracellular Ca2+ concentration ([Ca2+]i). ACh and ionomycin increased PGE2 release in antral mucosal cells. In conclusion, in ACh-stimulated antral mucous cells, an increase in [Ca2+]i activates Ca2+-regulated exocytotic events and PGE2 release mediated by COX-1. The released PGE2 induces the accumulation of cAMP, which enhances the Ca2+-regulated exocytosis. The autocrine mechanism mediated by PGE2 maintains the high-level mucin release from antral mucous cells during ACh stimulation.

gastric mucin secretion; cyclic adenosine 5'-monophosphate; cyclooxygenase-1; indomethacin; aspirin


Address for reprint requests and other correspondence: T. Nakahari, Dept. of Physiology, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki 569-8686, Japan (E-mail: takan{at}art.osaka-med.ac.jp)




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