Takeuchi K, Furukawa O, Okada M, Okabe S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Japan.
Digestion. 1988;39(4):230-40. doi: 10.1159/000199631.
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.
选用体重14.0±0.7千克的杂种犬，雌雄不限，口服吲哚美辛，剂量为70毫克/只，之后禁食。12小时后，每小时给动物肌肉注射4次组胺-2HCl，剂量为40或80微克/千克。先给予吲哚美辛再进行组胺治疗，18小时内在十二指肠近端产生明确的溃疡，胃内有少量病变，尽管单独使用这两种药物中的任何一种都不会对黏膜造成任何损伤。组胺使十二指肠病变的严重程度和发生率呈剂量依赖性增加；组胺剂量为80微克/千克时，病变指数为38.8±8.4平方毫米（n = 7），发生率为100%。十二指肠病变大多由2 - 4个圆形或椭圆形病变组成，有些病例（42.8%）可穿透至黏膜肌层。组胺使具有迷走神经支配的全胃犬的胃酸分泌显著增加，而吲哚美辛显著抑制十二指肠袋（距幽门10厘米处）内由酸（50毫摩尔盐酸，持续10分钟）引起的碱性分泌增加。皮下注射西咪替丁（20毫克/千克）和16,16 - 二甲基前列腺素E2（3微克/千克），通过抑制胃酸分泌和/或增加十二指肠碱性分泌，可预防十二指肠和胃的这些病变。这些结果表明：（a）当组胺诱导胃酸分泌过多时，吲哚美辛在犬十二指肠中持续产生溃疡；（b）十二指肠碱性分泌受损可能是该模型中的一个重要致病因素。
