Effects of CL-1700 on duodenal ulcer formation in the rat.

Abstract

We have reported that CL-1700 (N acetyl-L-carnosine aluminum) has a potent antiulcer effect on both acute and chronic types of gastric ulcers in rats (1). In addition, we found that the effects of CL-1700 are much more potent than its constituents, L carnosine, N-acetyl-L-carnosine or AI(OH)3, to inhibit the development of different forms of induced acute gastric ulcers (2). The present experiment was done to determine whether CL-1700 also has an antiduodenal ulcer activity in two types of duodenal ulcer models in rats. AI(OH)3, pirenzepine 2HCI, cimetidine, and aluminum sucrose sulfate were used as reference drugs.Male Sprague-Dawley rats (210-230 g) were divided into two groups. In one group, mepirizole (Daiichi) at 200 mg/kg, suspended in 1 % carboxymethylcellulose (CMC) solu tion, was given to normally fed rats by gastric intubation in a volume of 0.5 ml/100 g of body weight (3, 4). The animals were killed under ether anesthesia 24 hr after the adminis tration of mepirizole. The duodenum and stomach of each rat were taken together, inflated with 12 ml of 2% formalin solution, and immersed in 2% formalin solution for 10 min. After fixing, only the duodenum was incised along the antimesenteric border and the area (mm2) of the ulcers was measured under a dissecting microscope (10X) with a square grid. The sum of the area of each ulcer in the duodenum was taken as the ulcer index. The person measuring the area of ulceration was unaware of which treatment the animals had been given. Test compounds, either dissolved or suspended in distilled water, were given p.o. twice (once, 10 min before the administration of mepirizole and again, 9 hr after the administration of mepirizole) or thrice (once, 10 min before the adminis tration of mepirizole and again, 5 and 10 hr after the administration). Control animals received distilled water only. In another group, histamine 2HCI (40 mg/kg)+ carbachol (0.08 mg/kg), dissolved in saline solution containing 16% gelatin, was given s.c. to 24 hr-fasted rats hourly, 10 times, in a volume of 0.05 ml/100 g of body weight. This method is a modification of the original method described by Robert et al. (5), who developed duodenal ulcers by a continuous s.c. infusion of histamine 2HCI+carbachol solution for 48 hr. Animals were killed under ether anesthesia 15 hr after the final adminis tration of histamine 2HCI+carbachol solution. The duodenum and stomach were taken together and then treated with 2% formalin solution, as previously described. The areas (mm2) of all ulcers developed in the duodenum were measured. Since the ulcers varied in size from small to large in each rat, the sum of the ulcerated area was divided into 6 degrees as the ulcer index.