Adaptive cytoprotection mediated by generated PGs (PGE_2 and/or PGI_2) through the release of CGRP.

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A mechanism of adaptive cytoprotection believed to be related to production of endogenous prostaglandins (PGs). We tested whether PGs generated by mild irritant prevented gastric mucosal injury through the release of CGRP from the sensory nerves.Assessment of gross lesion in the stomach and Measurement of intragastric levels of CGRP and PGsPreperfusion with mildly hypertonic saline (1M Nacl) increased the generation of gastric PGE_2 and PGI_2, and reduced ethanol-induced mucosal damage. Exposure of ethanol after 1M NaCl increased intragastric CGRP levels and the protective action of 1M NaCl was inhibited by indomethacin and CGRP receptor antagonist, CGRP-(8-37). Intragastric perfusion of 50% ethanol after administration of PGI_2, but not of PGE_2, increased CGRP levels. Application of 1M NaCl to IP receptor-knockout mice (IPKO) did not elicit the protective effects seen in the wild type on ethanol-induced lesions. Protective effect of 1M NaCl was seen in EP3 receptor-knockout mice (EP3 … More KO) and wild-type counterparts. CGRP levels during ethanol perfusion was not increased in IPKO, but was increased in EP3KO and wild type counterparts after preperfusion of 1M NaCl.Gastric mucosal microcirculationThe 50% ethanol-induced constriction of venules (including collecting venules) that is cause of ethanol-induced gastric injury was inhibited by preapplication of 1M Nail. This preventive effect of 1M NaCl was inhibited by CGRP (8-37) or indomethacin. Preapplication of either PGE_2 or PGI_2 analog, which dose did not dilate gastric mucosal vessels directly, completely inhibited constrictions of venules induced by ethanol. This preventive effect of PGI_2 analog was abolished by CGRP (8-37), and the constriction of venules appeared again. That of PGE_2 was not abolished by CGRP (8-37).ConclusionsThese results indicate that the endogenous PGI_2 generated by 1M NaCl may have protective roles in gastric mucosal injury through enhancement of CGRP release from the gastric mucosa and that the endogenous PGE_2 generated may have protective roles through another mechanism. Less