Intramucosal activation of pepsinogens in the pathogenesis of acute gastric erosions and their prevention by the potent semisynthetic amphipathic inhibitor pepstatinyl-glycyl-lysyl-lysine.

This study was designed to test the proposal that a critical event in the formation of acute gastric erosions is the intramucosal activation of pepsinogens. Gastric erosions were induced in rats by controlled haemorrhagic shock. Free acid proteinase activity in homogenates of gastric mucosa taken to include erosions increased progressively throughout the period of hypotension. Free enzyme activity in homogenates of apparently normal mucosa between erosions remained substantially unchanged. Luminal pepstatin, the potent but hydrophobic specific acid proteinase inhibitor which does not penetrate gastric mucosa, did not prevent the development of erosions. The equally potent but amphipathic water-soluble analogue pepstatinyl-gly-lys-lys, which does penetrate gastric mucosa, substantially reduced mucosal ulceration in this system. These findings suggest that focal intramucosal pepsinogen activation at the site of acute experimental erosions is causally related to their development, and suggest the inclusion of potent water soluble acid proteinase inhibitors of appropriate molecular structure in their clinical prevention and treatment.