l-365260 and Stomach-Ulcer

Bombesin has been shown to have trophic effects on the gastrointestinal tissue. Bombesin has direct mitogenic effects besides stimulating release of gastric hormones. The aim of this study was to investigate the effect of bombesin in hemorrhagic shock-induced stress ulcers in rats, and the role of cholecystokinin (CCK) receptors in this activity. Hemorrhagic shock was created by withdrawing 3 ml blood/200 g b.w. of rats. At the end of the 1-hour hypovolemic shock period, histological analysis, gastric ulcer index, gastric myeloperoxidase activity and gastric protein oxidation levels were determined. When given before the hemorrhage, subcutaneous bombesin (10 microg/kg) reduced macroscopically gastric ulcer index (p < 0.05). Blockade of CCK-A receptors with intraperitoneal MK-329 (1 mg/kg) did not reverse bombesin-induced gastroprotection. Blockade of CCK-B receptors with intraperitoneal L-365,260 (25 mg/kg) reversed bombesin-induced gastroprotection. Blockade of the two receptors resulted in no gastroprotection at all. It is concluded that bombesin treatment attenuated hemorrhagic shock-induced stress ulcers in rats via CCK receptors.

Topics: Animals; Benzodiazepinones; Bombesin; Devazepide; Gastric Mucosa; Hormone Antagonists; Male; Phenylurea Compounds; Rats; Rats, Wistar; Receptors, Cholecystokinin; Shock, Hemorrhagic; Stomach Ulcer

The antigastrinic, antisecretory and antiulcer activities of CR 2945, (R)-1-naphthalenepropanoic acid,beta-[2-[[2-(8-azaspiro[4.5]dec-8-yl-carbonyl)-4,6-dimethylph enyl] amino]-2-oxoethyl], were investigated in vitro and in vivo in rats and cats. Its activities were compared with those of two gastrin/CCK(B) receptor antagonists, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-N'-(3-methylphenyl)urea and CAM-1028 (4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[1,7,7-trimethylbicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino -4-oxo-[1S-1alpha,2beta[S'(S')4alpha]]-butanoate -N-methyl-D-glucamine), of the histamine H2 receptor antagonist, ranitidine, and the proton pump inhibitor, omeprazole. Cytosolic Ca2+ elevation in rabbit parietal cells induced by gastrin (50 nM) was blocked by CR 2945 with an IC50 value of 5.9 nM. CAM-1028 and L-365,260 showed similar activity. CR 2945 antagonized pentagastrin-stimulated gastric acid secretion in rats (ED50 = 1.3 mg kg(-1) i.v. and 2.7 mg kg(-1) i.d.) and cats (1.6 mg kg(-1) i.v.). CR 2945 was slightly less potent than the reference compounds after i.v. administration, whereas after intraduodenal (i.d.) administration, it was more potent than both ranitidine and omeprazole. In the rat, the gastrin antagonism exhibited by CR 2945 was reversible and competitive, with a pA2 value of 7.33. CR 2945 had specific antigastrin activity, as it was unable to antagonize the gastric acid secretion stimulated by histamine or carbachol in rats up to the dose of 30 mg kg(-1). CR 2945 was about as efficacious as ranitidine against the indomethacin- and ethanol-induced gastric ulcers and the cysteamine-induced duodenal ulcer in rats. On the contrary, L-365,260 was only slightly effective. These results suggest that CR 2945 might be a promising compound for the therapy of acid-related disorders, and that its clinical use could help clarify the therapeutic potential of gastrin/CCK(B) receptor antagonists in the gut.

Topics: Animals; Anti-Anxiety Agents; Anti-Ulcer Agents; Benzodiazepines; Benzodiazepinones; Calcium; Cats; Chronic Disease; Cysteamine; Dose-Response Relationship, Drug; Ethanol; Gastric Acid; Gastric Fistula; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Indomethacin; Male; Omeprazole; Parietal Cells, Gastric; Pentagastrin; Perfusion; Phenylurea Compounds; Rabbits; Ranitidine; Rats; Receptors, Cholecystokinin; Stomach; Stomach Ulcer

We have investigated the effect of intravenous injection of cholecystokinin-8 (CCK-8) and other peptides on gastric lesion formation in response to an intragastric perfusion with 25% ethanol in rats anaesthetized with urethane. 2. Intravenous injection of CCK-8 (50-100 nmol kg-1), but not bombesin (1-100 nmol kg-1), calcitonin gene-related peptide (1-50 nmol kg-1), neurokinin A (1 mumol kg-1) or substance P (100 nmol kg-1), induced protection against gastric haemorrhagic lesions produced by ethanol. 3. The CCKA-antagonist L-364,718 (2.45 mumol kg-1, i.v.) increased the lesion index induced by ethanol and reversed the protective effect of CCK-8 (50 nmol kg-1, i.v.). The CCKB-antagonist L-365,260 (5 mumol kg-1, i.v.) and a lower dose of L-364,718 (0.25 mumol kg-1, i.v.) were ineffective. 4. The gastric protective effects afforded by CCK-8 (50 nmol kg-1, i.v.) were not observed in vagotomized-rats and were reduced by capsaicin pretreatment. In capsaicin-pretreated rats there was a worsening of gastric lesions induced by ethanol-perfusion as compared to those observed in vehicle-pretreated rats. 5. These results demonstrate that the mucosal protective effect of CCK-8 involves, at least in part, the activation of CCKA-receptors and is mediated by vagal capsaicin-sensitive fibres.

Topics: Animals; Benzodiazepinones; Capsaicin; Devazepide; Ethanol; In Vitro Techniques; Male; Neurons; Phenylurea Compounds; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Sensory Deprivation; Sincalide; Stomach Ulcer; Vagotomy; Vagus Nerve