The development of the endothelin-1-induced gastric ulcer: time sequence analysis of morphologic changes.

We have recently reported that the submucosal injection of endothelin-1 induces gastric ulcers in rats. In the present study, we have examined the time sequence of the macroscopic, histologic and ultramicroscopic features of the formation and development of the gastric ulcer induced by endothelin-1 (100 pmol submucosally). In rats, we examined the effect of endothelin-1 on the gastric mucosa macroscopically, on the gastric mucosal cells and vessels by light microscopy and on the ultra-structure of the gastric mucosal surface and of the gastric glands by electron microscopy. Gastric mucosal changes were evaluated 1, 4, 30 minutes, 1, 4, 8, 16, 20, 24 hours and 2, 4, 7, 14, 21 days after teh submucosal injection of endothelin-1. Application of endothelin-1 was immediately followed by arterial vasoconstriction and venous dilatation, 5 minutes later by interstitial haemorrhage and 30 minutes later by demise of epithelial cells. Electron microscopy showed almost complete exfoliation of the inter-pit cells 30 minutes after the injection. By 1 hour, superficial redness, apoptosis of superficial cells and loss of the intra-pit cells was detected. By 8 hours, there was mucosal haemorrhage and complete loss of intra-pit cells from the basal part of the gastric glands. Forty-eight hours later, there was a deep gastric ulcer with penetration of the muscularis mucosae. By 4 days, the ulcers had entered the chronic phase and by 1 week abnormal glands were covering the area of damage with no mucous production. By 3 weeks the damaged area was still structurally abnormal. The results of this study suggest that injury to the microvasculature may initiate the degenerative and structural changes of the gastric mucosa that lead to the production of this novel type of experimental gastric ulcer in rats.