Duodenal ulcers induced by indomethacin plus histamine in the dog. Involvement of the impaired duodenal alkaline secretion in their pathogenesis.

Mongrel dogs of either sex, weighing 14.0 +/- 0.7 kg, were given indomethacin orally in a dose of 70 mg/dog, and they were deprived of food thereafter. Twelve hours later, the animals were given histamine-2HCl intramuscularly 4 times every hour in a dose of 40 or 80 micrograms/kg. Indomethacin followed by histamine treatment produced well-defined ulcers in the proximal duodenum within 18 h with a few lesions in the stomach, although either of these agents alone did not induce any damage in the mucosa. Both the severity and incidence of the duodenal lesions were increased dose-dependently by histamine; the lesion index was 38.8 +/- 8.4 mm2 (n = 7) with an incidence of 100% at the dose of 80 micrograms/kg of histamine. The duodenal lesions mostly consisted of 2-4 round or elongated lesions which penetrated to the muscularis mucosae in some cases (42.8%). Histamine caused a marked increase in acid secretion in dogs with a vagally innervated total pouch, while indomethacin significantly inhibited the increased alkaline secretion caused by acid (50 mM HCl for 10 min) in the duodenal pouch (10 cm distal to the pylorus). Both cimetidine (20 mg/kg) and 16,16-dimethyl prostaglandin E2 (3 micrograms/kg), given subcutaneously, prevented these lesions in the duodenum as well as in the stomach by inhibiting acid secretion and/or increasing duodenal alkaline secretion. These results suggest that (a) indomethacin consistently produced ulcers in the duodenum of the dog when acid hypersecretion was induced by histamine, and (b) an impaired duodenal alkaline secretion may be an important pathogenetic element in this model.