Gastroenterology

Gastroenterology

Volume 120, Issue 1, January 2001, Pages 134-143
Gastroenterology

Alimentary Tract
Adaptive cytoprotection mediated by prostaglandin I2 is attributable to sensitization of CGRP-containing sensory nerves,☆☆

https://doi.org/10.1053/gast.2001.20916Get rights and content

Abstract

Background & Aims: The phenomenon by which the gastric mucosa is protected in response to mild irritants has been called adaptive cytoprotection, a mechanism believed to be related to production of endogenous prostaglandins (PGs). We tested whether PGs generated by mild irritant prevent injury through the release of calcitonin gene-related peptide (CGRP) from the sensory nerves using prostanoid receptor–knockout mice. Methods: The stomach was doubly cannulated and perfused with 1 mol/L NaCl or 50% ethanol. CGRP levels in the perfusate were determined by enzyme immunoassay, and the injured area was estimated at the end of perfusion. Results: Preperfusion with mildly hypertonic saline (1 mol/L NaCl) increased generation of gastric PGE2 and PGI2 and reduced ethanol-induced mucosal damage. Exposure of ethanol after 1 mol/L NaCl increased intragastric CGRP levels from 166 ± 27 to 713 ± 55 pg/2 min (n = 4, P < 0.05), and the protective action of 1 mol/L NaCl was inhibited by indomethacin treatment. CGRP antagonist blocked 1 mol/L NaCl–induced protective effect. Intragastric perfusion of 50% ethanol after administration of PGI2, but not of PGE2, increased CGRP levels. Application of 1 mol/L NaCl to IP receptor–knockout mice (IP−/−) did not elicit the protective effects seen in the wild-type on ethanol-induced gastric mucosal lesions. Protective effect of 1 mol/L NaCl was observed in EP3 receptor–knockout mice (EP3−/−). CGRP level during ethanol perfusion was not increased in IP−/− but was increased in EP3−/− and wild-type counterparts after preperfusion of 1 mol/L NaCl. Conclusions: These results indicate that the endogenous PGI2 generated by 1 mol/L NaCl may have a release from gastric mucosa. This mechanism may explain the adaptive cytoprotection observed after treatment with mild irritants.

GASTROENTEROLOGY 2001;120:134-143

Section snippets

Rats and prostanoid receptor–knockout mice

Male Sprague–Dawley strain rats (specific pathogen free; Japan SLC, Inc., Hamamatsu, Japan), weighing 300–400 g, were starved for 18 hours before experiments began, but had free access to water. The experiments were performed on animals anesthetized with urethane (0.875 g/kg, by intraperitoneal injection; Aldrich Chemical Co., Milwaukee, WI).22 In some experiments, we also used IP receptor–knockout mice (IP−/−, male, 8 weeks old) recently developed by us.26 The IP receptor is specific for PGI2.

Effect of preperfusion of 1 mol/L NaCl on ethanol-induced gastric mucosal lesion in anesthetized rats

Perfusion with 50% ethanol after the preperfusion of physiologic saline resulted in gastric mucosal lesions that affected 20% of the area of the glandular stomach (Figure 1A, open column).

. (A) Effect of preperfusion of 1 mol/L NaCl on mucosal injury and (B) changes in intragastric CGRP levels during 50% ethanol perfusion in rats. Perfusion was performed according to the protocol described in Materials and Methods. (A) Immediately after the perfusion experiment, the stomach was excised, and the

Discussion

The major arachidonate metabolites in the stomach were reported to be PGI2 and PGE2.30, 36 It has also been reported that the mild irritants that induce cytoprotection, such as NaCl solution, NaOH solution, and sodium taurocholate, increased the endogenous PG formation in the stomach.5 There are suggestions that the cytoprotection by endogenous PGs is attributable to the increased mucosal blood flow.7 The simple idea was that PGI2 and PGE2 generated by mild irritant–dilated arterioles

Acknowledgements

The authors thank C. W. P. Reynolds for correction of the English of this manuscript.

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    Address requests for reprints to: Masataka Majima, M.D., Ph.D., Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 228-8555, Japan. e-mail: [email protected]; fax: (81) 427-78-4467/8441.

    ☆☆

    Supported by a grant from Academic Frontier Project of The Ministry of Education, Science, Sports, and Culture; a Parents' Association grant from Kitasato University School of Medicine; and a Kitasato University research grant.

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