The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection
Atsufumi Kawabata, … , Yasuo Oda, Kazuaki Kakehi
Atsufumi Kawabata, … , Yasuo Oda, Kazuaki Kakehi
Published June 1, 2001
Citation Information: J Clin Invest. 2001;107(11):1443-1450. https://doi.org/10.1172/JCI10806.
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Article

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Abstract

Protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, modulates smooth muscle tone and exocrine secretion in the salivary glands and pancreas. Given that PAR-2 is expressed throughout the gastrointestinal tract, we investigated effects of PAR-2 agonists on mucus secretion and gastric mucosal injury in the rat. PAR-2–activating peptides triggered secretion of mucus in the stomach, but not in the duodenum. This mucus secretion was abolished by pretreatment with capsaicin, which stimulates and ablates specific sensory neurons, but it was resistant to cyclo-oxygenase inhibition. In contrast, capsaicin treatment failed to block PAR-2–mediated secretion from the salivary glands. Intravenous calcitonin gene–related peptide (CGRP) and neurokinin A markedly elicited gastric mucus secretion, as did substance P to a lesser extent. Specific antagonists of the CGRP1 and NK2, but not the NK1, receptors inhibited PAR-2–mediated mucus secretion. Pretreatment with the PAR-2 agonist strongly prevented gastric injury caused by HCl-ethanol or indomethacin. Thus, PAR-2 activation triggers the cytoprotective secretion of gastric mucus by stimulating the release of CGRP and tachykinins from sensory neurons. In contrast, the PAR-2–mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensory neurons.

Authors

Atsufumi Kawabata, Mitsuhiro Kinoshita, Hiroyuki Nishikawa, Ryotaro Kuroda, Minoru Nishida, Hiromasa Araki, Naoki Arizono, Yasuo Oda, Kazuaki Kakehi

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Figure 2

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Effects of diclofenac (a) and capsaicin (b) on the PAR-2–mediated gastri...
Effects of diclofenac (a) and capsaicin (b) on the PAR-2–mediated gastric mucus secretion in the rat. Diclofenac was administered intravenously 10 minutes before intravenous SLp-NH2 plus amastatin at 2.5 μmol/kg (a). The same dose of SLp-NH2 in combination with amastatin was administered intravenously to the rats that had received repeated doses of capsaicin (b, top panel), as described in Methods. Misoprostol as a positive control was also administered intravenously to capsaicin-treated rats (b, bottom). Data show the mean ± SEM from 4–6 rats. AP < 0.05, BP < 0.01 vs. the respective vehicle-treated (V) group; CP < 0.01 vs. the corresponding control group (treated with SLp-NH2).