MODULATORS OF GASTRIC HISTAMINE RELEASE IN VIVO

这项建议的目的是研究控制释放的因素 胃组织胺在体内的狗。 总的假设是， 胃粘膜组胺受胃促分泌素调节， 通过抗分泌多肽和autocoids调节释放。 狗 是这些研究的正确模型，因为狗胃粘膜 组织学与人胃粘膜组织学中肥大细胞相似 含有大量的粘膜组胺。 拟议的目标将是 通过测量动脉和胃静脉血浆浓度完成 组胺和1-甲基组胺穿过胃体， 大多数含组胺的肥大细胞和内分泌细胞 控制住了 通过从胃静脉抽取血液， 测量流向胃体的胃血流量， 可计算出各种刺激的组胺分泌率。 在 此外，甲基组胺测量将允许评价 在长时间输注促分泌素期间的组胺代谢。 通过 将化合物直接输注到供应胃体的胃动脉中 可以避免这些化合物的胃、全身作用。 组胺 和甲基组胺将通过气相色谱/负离子 化学电离质谱（GC/NICI-MS）。 使用这种技术 在初步的实验中，我们已经证明了五肽胃泌素输注 导致组胺和甲基组胺释放的大量增加， 胃 该提案计划研究组胺释放的作用 五肽胃泌素刺激的酸分泌也将被探索。 和 最后，将检查抗分泌化合物的能力， 调节组胺释放。 这些化合物包括抗分泌的 多肽生长抑素、胰高血糖素和胰泌素;抗分泌类 拟交感神经异丙肾上腺素，和 组胺-2激动剂二甲双胍 这些实验应该 产生关于胃粘膜组胺控制的新信息 在完整的胃中释放。 通过了解生理和 胃粘膜组胺释放的药理学控制，另一个 可以开发药理学方法来控制 治疗消化性溃疡。

The aim of this proposal is to examine the factors controlling the release of gastric histamine in vivo in the dog. The overall hypothesis is that gastric mucosal histamine is regulated by gastric secretagogues, and the release is modulated by antisecretory polypeptides and autocoids. The dog is the correct model for these studies because dog gastric mucosal histology is similar to human gastric mucosal histology in that mast cells contain the bulk of the mucosal histamine. The proposed aim will be accomplished by measuring arterial and gastric venous plasma concentrations of histamine and 1-methyl histamine across the corpus of the stomach where most of the histamine-containing mast cells and endocrine cells are contained. By sampling blood from the gastric veins draining the corpus of the stomach and measuring gastric blood flow to the corpus of the stomach, histamine secretory rates can be calculated to various stimuli. In addition, methylhistamine measurements will allow the evaluation of histamine metabolism during prolonged infusion of secretagogues. By infusing compounds directly into the gastric artery supplying the corpus of the stomach, systemic effects of these compounds can be avoided. Histamine and methylhistamine will be measured by gas chromatography/negative ion chemical ionization mass spectrometry (GC/NICI-MS). Using this technique in preliminary experiments, we have demonstrated that pentagastrin infusion results in a large increase in histamine and methylhistamine release from the stomach. The proposal plans to examine the role of histamine release in pentagastrin-stimulated acid secretion will also be explored. And finally, antisecretory compounds will be examined for their ability to modulate histamine release. These compounds include antisecretory polypeptides somatostatin, glucagon, and secretin; antisecretory autocoids prostaglandins E2 and I2, and adenosine; sympathomimetic isoproterenol,and the histamine-2 agonist, dimaprit. These sets of experiments should generate new information about the control of gastric mucosal histamine release in the intact stomach. By understanding the physiologic and pharmacologic control of gastric mucosal histamine release, another pharmacology approach can be developed to control acid secretion in the treatment of peptic ulcer disease.