Anti-ulcer activity of cromakalim (BRL 34915), a potassium-channel opener, against experimentally induced gastric and duodenal ulcers in rats and guinea-pigs

Abstract

The effect of cromakalim, a potassium-channel opener, was studied on pylorus ligation-induced, aspirin-induced and water-immersion plus restraint stress-induced gastric ulcers in rats and on histamine-induced duodenal ulcer in guinea-pigs. Pretreatment with cromakalim (50-500 μg kg-1, p.o.) resulted in a significant reduction in the incidence of gastric and duodenal ulceration in each model. The anti-ulcer activity of cromakalim was comparable with that of cimetidine. Cromakalim at 100, 250 and 500 μg kg-1 caused a reduction in the volume of the gastric content in pylorus-ligated rats, and a dose of 250 μg kg-1 resulted in a significant reduction in total acidity (28.81 ± 11.73 mEq L-1, P < 0.02) in the pylorus ligation model. A significant reduction in total acid output was observed at doses of 250 μg kg-1 (84.27 ± 22.33 mEq H+, P < 0.02) and 500 μg kg-1 (120.17 ± 24.49 mEqH+, P < 0.01) in pylorus-ligated rats. A significant reduction in the ulcer index in pylorus-ligated rats was observed at all cromakalim doses: 50 μg kg-1 (0.23 ± 0.09, P < 0.05), 100 μg kg-1 (0.15 ± 0.09, P < 0.02), 250 μg kg-1 (0.12 ± 0.05, P < 0.01) and 500 μg kg-1 (0.14 ± 0.03, P < 0.02). A significant reduction in the ulcer index of aspirin-treated rats was also observed at all cromakalim dose levels: 50 μg kg-1 (0.39 ± 0.03, P < 0.01), 100 μg kg-1 (0.28 ± 0.06, P < 0.01), 250 μg kg-1 (0.22 ± 0.04, P < 0.001) and 500 μg kg-1 (0.28 ± 0.03, P < 0.01). In the water-immersion plus restraint stress-induced gastric ulcer model, cromakalim significantly reduced gastric ulceration at all the dose levels: 50 μg kg-1 (28.2 ± 2.12, P < 0.001), 100 μg kg-1 (20.24 ± 1.71, P < 0.01), 250 μg kg-1 (19.95 ± 1.46, P < 0.001) and 500 μg kg-1 (21.61 ± 3.00, P < 0.001) but there was no consistent reduction of gastric bleeding. In addition to gastric ulcers, duodenal lesions were also reduced by pretreatment with cromakalim at all dose levels: 50 μg kg-1 (97.87 ± 20.03 mm2, P < 0.02), 100 μg kg-1 (70.72 ± 12.82 mm2, P < 0.02), 250 μg kg-1 (48.32 ± 8.42 mm2, P < 0.01) and 500 μg kg-1 (55.50 ± 12.50 mm2, P < 0.01). Cromakalim at a dose of 100 μg kg-1 also reduced total acidity (99.36 ± 9.12 mEq L-1, P < 0.02) and total acid output (172.22 ± 45.33 mEq of H+, P < 0.05) in this model. These findings demonstrate the anti-ulcer activity of cromakalim in different experimental models and suggest its potential use in ulcer therapy.