A biochemical and pharmacological approach to the genesis of ulcer disease II. A model study of stress-induced injury to gastric mucosa in rats

Abstract

Biochemical and molecular pharmacological studies were carried out in the gastric fundic mucosa during the development of stress ulcer in rats. The aims of this study were: (1) to evaluate the changes in membrane-bound ATP-dependent energy systems during the development of stress ulcer; (2) to prove (or to exclude) the presence of tissue hypoxia in the rat gastric mucosa during the development of stress ulcer; (3) to obtain further evidence of the existence of a feedback mechanism between ATP-ADP, ATP-cAMP, and cAMP-AMP transformations during the development of stress ulcer; (4) to analyze the different biochemical changes in the gastric mucosa before and after the macroscopic appearance of stress-induced gastric mucosal lesions (ulcers). The observations were carried out on both sexes of CFY-strain rats of 180 to 210 g body weight. The animals were deprived of food for 24 hours before the experiments. The animals were forced to swim in water (at 24 degrees C) for five hours. They were sacrificed at 0, 1, 2, 3, 4, and 5 hours after the introduction of stress. The tissue levels of ATP, ADP, AMP/ADP, and lactate were enzymatically measured; the cAMP was measured by radioimmunoassay. The adenylate pool (ATP + ADP + AMP), ratio of ATP/ADP, and "energy charge" [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] were calculated. The membrane (Mg2(+)-Na(+)-K(+)-dependent) ATPase was prepared from the rat gastric fundic mucosa. Dose-response curves for epinephrine, cAMP, and AMP were determined on Na(+)-K(+)-dependent ATPase; also, the affinity, intrinsic activity curves, pD2, pA2 and alpha were calculated for all components. It was found that: (1) gastric mucosal lesions appeared and increased gradually from three hours after introduction of stress; (2) the extent of ATP-cAMP and cAMP-AMP transformations was increased considerably during the development of stress ulcer; (3) the extent of ATP-ADP transformation was completely inhibited; (4) the activity of Na(+)-K(+)-dependent ATPase from rat gastric fundic mucosa could be inhibited by epinephrine, cAMP, and AMP; (5) the ratio of ATP/ADP was unchanged in the first time period (from 0 to 3 hours), after which its value increased; (6) the value of "energy charge" (e.g., the extent of phosphorylation and/or dephosphorylation) of cells was decreased at two and three hours, after which its value returned to a normal level; (7) there was no increase in the tissue level of lactate; (8) several biochemical changes (decrease of ATP, ADP, "energy charge," increase of cAMP, AMP) preceded the macroscopic appearance of stress ulcer.(ABSTRACT TRUNCATED AT 400 WORDS)