EFFECTS OF H-2-RECEPTOR ANTAGONISTS ON MATRIX METALLOPROTEINASES IN RAT GASTRIC TISSUES WITH ACETIC ACID-INDUCED ULCER

To investigate the destructive process of connective tissues in gastric ulcer, both collagenolytic and gelatinolytic activities were examined in the homogenates of rat acetic acid-induced gastric ulcer, a typical model of chronic ulcer. Gelatinolytic activity in the ulcerous lesion was significantly higher than that in the normal tissue. However, collagenase was not detected in both normal and ulcerated tissues either by the enzyme assay or by the immunoblotting. By gelatin-gel-zymographic analyses, the gelatinlytic activity was found to be composed of a number of species, mainly 60-, 72- and 92-kDa, all of which were inhibited by ethylenediaminetetraacetic acid. Among the induced matrix metalloproteinases, one crossreacted with a sheep anti-(rabbit prostromelysin)antibody. Thus, in chronic gastric ulcer, it is likely that several metalloproteinases participate in degradation of connective tissue matrices including components of basement membranes. The elevated levels of gelatinolytic activities in the ulcerous tissues and ulcer index were significantly suppressed by treating the animals with famotidine or a new H-2-receptor antagonist, 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-1,2-dione hydrochloride (IT-066).