Adaptive Cytoprotection Mediated by Prostaglandin I2 Is Attributable to Sensitization of CGRP-Containing Sensory Nerves

Abstract

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. 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. Preperfusion with mildly hypertonic saline (1 mol/L NaCl) increased generation of gastric PGE(2) and PGI(2) 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 PGI(2), but not of PGE(2), 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. These results indicate that the endogenous PGI(2) generated by 1 mol/L NaCl may have a protective role in gastric mucosal injury through enhancement of CGRP release from gastric mucosa. This mechanism may explain the adaptive cytoprotection observed after treatment with mild irritants.