MECHANISMS OF ACTION

这一新的组成部分是为了响应一种认识到的需要， 探索机制的额外实验，将改善我们的 了解系统性阿片激动剂在3个方面的作用： 外周阿片受体，δ选择性的非阿片效应 激动剂和有前景的激动剂的临床相关副作用。的 这一部分的目标是确定 静脉推注给药后观察到的生理反应 选择性μ和δ阿片肽类似物已经在 在组分3中进行的药效学研究。三个具体 在这个提议中提出了一些问题。首先，心血管系统如何 iv DALDA（H-Tyr-Arg-Phe-Lys）介导的反应？第二， 静脉注射DELT（H-Tyr-D-Ala-Phe-Asp-瓦尔-）即刻心血管反应 Val-Gly-NH/2）直接心肌收缩的结果，或者它们是 起源于迷走神经第三，妊娠相关的变化是否 DALDA和DELT介导的心血管反应的幅度 雌激素和/或孕激素水平的变化？具体目标 是：1）确定静脉注射DALDA的升压作用是否是由于升高的 心输出量或外周血管阻力增加; 2）确定 如果静脉注射DALDA的心血管效应是由增强的 交感神经活动或减少副交感神经活动或减少 副交感神经活动; 3）确定DELT的心动过缓是否 通过迷走神经刺激介导; 4）确定雌激素的影响， 孕酮对DALDA和DELT的心血管作用; 5）确定 如果DALDA在听觉中具有直接的正性变力和变时作用 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 在心脏中的作用和/或DELT是否增加迷走神经传递 7）确定雌激素和孕激素在心脏中的作用， 调节妊娠对DALDA心脏效应的影响， DELT.结合体内（慢性器械绵羊模型;目的 1-4)和体外（离体灌注豚鼠心脏;目标5-7） 将在该项目中使用的方法。这些具体目标将是 由Dr. Clapp（体内研究）和Dr. Szeto（体内研究）联合进行 体外研究）。我们觉得 了解这些领域是必要的，以确保安全和识别 为未来药物开发提供重要的结构-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.