MECHANISMS OF ACTION

这一新组件是为了响应人们对聚焦的需求而开发的 关于探索机制的额外实验将改善我们的 了解全身性阿片类激动剂在3个领域的作用： 外周阿片受体、选择性增量非阿片效应 激动剂，以及一种有前景的激动剂的临床相关副作用。这个 这一部分的目标是确定构成 静脉推注给药后的生理反应观察 选择性Mu和Delta阿片肽类似物，已在 第三部分进行的药效学研究。 在这个提案中，任务被提了出来。首先，心血管疾病怎么样？ 静脉注射DALDA(H-Tyr-Arg-Phe-Lys)介导的反应？第二，是 静注DELT的即刻心血管反应(H-Tyr-D-Ala-Phe-Asp-Val. Val-Gly-NH/2)是直接心肌收缩的结果还是它们 起源于迷走神经？第三，是否与怀孕相关的变化 A介导的DALDA和DELT对心血管反应的幅度 雌激素和/或黄体酮水平的变化？具体目标 1)确定静脉注射达尔达的升压效应是否由升压引起 心输出量或外周血管阻力增加；2)确定 如果静脉注射达尔达的心血管效应是通过增强 交感神经活动或副交感神经活动减少或减少 副交感神经活动；3)确定DELT的心动过缓是否 由迷走神经刺激介导；4)测定雌激素和 孕酮对DALDA和DELT心血管效应的影响；5)测定 如果达尔达在心脏有直接的正性变力和变时性作用 和/或Dalda是否改变迷走神经或交感神经传递到 心脏；6)确定DELT是否具有直接负性变时性和变力性 心脏活动和/或DELT是否增加迷走神经传递 对心脏的作用；7)确定雌激素和孕激素在 探讨妊娠对达尔达心脏效应的影响 Delt.体内(慢性仪器化绵羊模型；目标)的组合 1-4)和体外(离体豚鼠心脏；AIMS 5-7) 在这个项目中将使用各种方法。这些具体目标将是 由Clapp博士(体内研究)和司徒华博士(在 体外研究)。我们觉得 对这些领域的了解对于确保安全和确定 未来药物开发的重要结构-功能关系。

This new component was developed in response to a perceived need to focus additional experiments on exploring mechanisms that will improve our understanding of systemic opioid agonist actions in 3 areas: the role of peripheral opioid receptors, the non opioid effects of delta-selective agonists, and clinically relevant side effects of a promising agonist. The goal of this component is to identify the mechanism(s) which underlie the physiological responses observed following iv bolus administration of selective mu and delta opioid peptide analogs that have been identified in the pharmacodynamic studies conducted in Component 3. Three specific quests are asked in this proposal. First, how are the cardiovascular responses to iv DALDA (H-Tyr-Arg-Phe-Lys) mediated? Second, are the immediate cardiovascular responses to iv DELT (H-Tyr-D-Ala-Phe-Asp-Val- Val-Gly-NH/2) the result of direct myocardial contractility or are they vagal in origin? Third, are the pregnancy-associated changes in the magnitude of the cardiovascular responses to DALDA and DELT mediated by a change in either estrogen and/or progesterone levels? The specific aims are: 1) determine if the pressor effect of iv DALDA is due to elevated cardiac output or increased peripheral vascular resistance; 2) determine if the cardiovascular effects of iv DALDA are mediated by enhanced sympathetic activity or decrease parasympathetic activity or decrease parasympathetic activity; 3) determine if the bradycardia to DELT is mediated by vagal stimulation; 4) determine the influence of estrogen and progesterone on the cardiovascular effects of DALDA and DELT; 5) determine if DALDA has direct positive inotropic and chronotropic action in the hear and/or whether DALDA alters vagal or sympathetic nerve transmission to the heart; 6) determine if DELT has direct negative chronotropic and inotropic action in the heart and/or whether DELT increases vagal nerve transmission to the heart; 7) determine the role of estrogen and progesterone in mediating the effects of pregnancy on the cardiac effects of DALDA and DELT. A combination of in vivo (chronically-instrumented sheep model; aims 1-4) and in vitro (isolated perfused guinea pig heart; aims 5-7) approaches will be used in this project. These specific aims will be carried out jointly by Dr. Clapp ( in vivo studies) and Dr. Szeto (in vitro studies) in their respective laboratories. We feel that understanding in these areas is necessary to ensure safety and identify important structure-function relationships for future drug development.