GI HISTAMINE H2-RECEPTORS: CHARACTERIZATION/REGULATION

拟议中的研究将检验以下假设，即存在亚型 组胺H2受体和H2受体效应系统是 受上下调节-取决于正常的生理 系统的音调。氢受体的特征将是它们的 强激动剂和弱激动剂的离解常数。表观KD 豚鼠回肠肌间神经丛H2受体激动性的价值 并将豚鼠右心房确定为强激动剂 组胺(仅限心房)和去甲普利特；以及弱激动剂去甲硝普特， 咪唑基丙基胍和异丙咪啶。表观Kd值将为 由使用不可逆作用的经典技术决定的 H2拮抗剂L-643,441和B-25368。计算机辅助全过程分析 A灭活前后剂量反应曲线的构建 活性受体的一部分将被用来估计 剂量-反应参数将表征受体以及 确定用于UP和UP研究的强弱激动剂对 H2受体的下调。收缩反应将在 孤立性肠梗阻和孤立性心房变时性反应。 豚鼠将接受一种竞争性的H2拮抗剂的长期治疗， 硫代替丁，或一种不可逆转的组胺合成抑制剂， 氟甲基组氨酸，以降低H2受体的音调。同样，动物也是如此 将接受H2激动剂dimapritt的治疗，以增加音调 H2受体。五肽胃泌素慢性治疗的效果将是 研究确定H2拮抗剂是否导致循环增加 胃泌素可能在一定程度上对预期结果负责。组织 将从经过处理的动物身上获得，并进行研究以确定是否 治疗改变剂量-反应参数的方式与 活性受体浓度的变化以及可能的 效应器系统中的更改。这些实验的结果将 提供有关GIH2受体的新信息，并可能适用于 H2受体拮抗剂的治疗应用。

The proposed research will test the hypotheses that there are subtypes of histamine H2-receptors and that the H2-receptor-effector systems are subject to up and down regulation - depending upon the normal physiological tone of the system. H2-receptors will be characterized by their dissociation constants for strong and weak agonists. The apparent Kd values for agonism at H2-receptors in the guinea pig ileal myenteric plexus and guinea pig right atrium will be determined for the strong agonists histamine (atrium only) and dimaprit; and the weak agonists, nordimaprit, imidazoylpropylguanidine, and impromidine. Apparent Kd values will be determined by classical techniques employing the irreversibly acting H2-antagonists L-643,441 and BMY-25368. Computer assisted analysis of full dose response curves constructed before and after inactivation of a fraction of the active receptors will be carried out to estimate the dose-response parameters that will characterize the receptors as well as determine the strong-weak agonist pairs to be used in studies on up and down regulation of H2-receptors. Contractile responses will be measured in isolated ilei and chronotropic responses in isolated atria. Guinea pigs will be treated chronically with a competitive H2-antagonist, tiotidine, or an irreversible inhibitor of histamine synthesis, fluoromethylhistidine, to reduce tone at H2-receptors. Similarly, animals will be treated with an H2-agonist, dimaprit, to increase tone at H2-receptors. The effects of chronic treatment with pentagastrin will be studied to determine if H2-antagonist induced increases in circulating gastrin might in part be responsible for the anticipated results. Tissues will be obtained from treated animals and studied to determine if the treatments altered dose-response parameters in a manner consistent with changes in the concentration of active receptors as well as possible changes in the effector system. The results of these experiments will provide new information on GI H2-receptors and may be applicable to the therapeutic use of H2-antagonists.