GI HISTAMINE H2-RECEPTORS: CHARACTERIZATION/REGULATION

这项拟议中的研究将检验以下假设： 组胺H2受体和H2受体效应系统是 受到上下调节-取决于正常的生理 系统的音调。 H2受体的特征在于其 强和弱激动剂的解离常数。 表观Kd 豚鼠回肠肌间神经丛中H2受体的激动值 和豚鼠右心房将被确定为强激动剂 组胺（仅心房）和二甲双胍;以及弱激动剂，去甲二甲双胍， 咪唑基丙基胍和Impromidine。 表观Kd值为 通过采用不可逆作用的经典技术确定 H2-拮抗剂L-643，441和BMY-25368。 计算机辅助分析 在灭活前和灭活后构建的剂量反应曲线 活性受体的分数将进行估计， 表征受体的剂量反应参数，以及 确定用于UP研究的强弱激动剂对， 下调H2受体。 收缩反应将在 孤立性回肠和孤立性心房的变时性反应。 豚鼠将用竞争性H2拮抗剂长期治疗， 噻替丁，或组胺合成的不可逆抑制剂， 氟甲基组氨酸，以降低H2受体的张力。 同样，动物 将接受H2-激动剂二甲双胍治疗， H2受体。 五肽胃泌素长期治疗的效果将是 研究以确定H2-拮抗剂是否诱导循环中 胃泌素可能是预期结果的部分原因。 组织 将从处理的动物中获得，并进行研究以确定 治疗改变了剂量反应参数， 活性受体浓度的变化以及可能的 效应器系统的变化。 这些实验的结果将 提供了关于GI H2受体的新信息，并可能适用于 H2-拮抗剂的治疗用途。

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.