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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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 3

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Effect of CGRP, substance P, neurokinin A (NKA), and their antagonists o...
Effect of CGRP, substance P, neurokinin A (NKA), and their antagonists on the basal and PAR-2–mediated gastric mucus secretion in the rat. (a) CGRP, substance P, or NKA, in combination with amastatin at 2.5 μmol/kg, was administered intravenously to the rat. AP < 0.05, BP < 0.01 vs. the vehicle-treated (V) group. Data show the mean ± SEM from 4–7 rats. (b) Effects of the CGRP1 receptor antagonist CGRP8–37 (10 nmol/kg × 2, subcutaneously and intravenously), the NK1 receptor antagonist spantide (100 nmol/kg × 2,subcutaneously and intravenously), or the NK2 receptor antagonist GR83074 (300 nmol/kg × 2, subcutaneously and intravenously) on the gastric mucus secretion due to intravenous administration of CGRP at 0.28 nmol/kg, substance P at 10 nmol/kg, or NKA at 0.01 nmol/kg. AP < 0.05, BP < 0.01 vs. V plus V; CP < 0.05, DP < 0.01 vs. V plus each agonist. n = 5–9. (c) Synergistic effect of CGRP and NKA on mucus secretion. CGRP and/or NKA at subeffective doses were administered intravenously in combination with amastatin. AP < 0.01 vs. V; n = 5–6. (d) Effects of CGRP8–37, spantide, or GR83074, administered as described above, on the gastric mucus secretion due to intravenous administration of the PAR-2 agonist SLp-NH2 at 1 μmol/kg in combination with amastatin at 2.5 μmol/kg. AP < 0.01 vs. V plus V; BP < 0.01 vs. V plus SLp-NH2. n = 4–6 rats.