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Am J Physiol Gastrointest Liver Physiol (September 2, 2004). doi:10.1152/ajpgi.00060.2004
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Submitted on February 4, 2004
Accepted on August 19, 2004

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

Chikao Shimamoto1, Shoko Fujiwara2, Masumi Kato2, Shigenori Ito3, Ken-ichi Katsu1, Hiroshi Mori4, and Takashi Nakahari2*

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

* To whom correspondence should be addressed. E-mail: takan{at}art.osaka-med.ac.jp.

The effects of indomethacin (IDM) and aspirin (ASA) on acetylcholine (ACh, 10 µM) -stimulated exocytotic events were studied in guinea pig antral mucous cells using video optical microscopy. IDM or ASA, which inhibits cyclo-oxygenase (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 EP receptor) and H-89 (20 µM, an inhibitor of protein kinase A) 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 inhbitor 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.




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