OPIATE RECEPTOR INHIBITION IN CONGESTIVE HEART FAILURE

内源性阿片肽具有多种心血管作用， 已经被证明是升高的，并发挥重要作用， 急性循环衰竭的病理生理学 的血浆水平升高 阿片肽也在体育锻炼中出现。 我们建议研究 内源性阿片类物质是否在慢性充血性心力衰竭中发挥类似的作用 心力衰竭（CHF）伴或不伴运动应激。 我们推测 内源性阿片类物质在静息时增加， 更多的是在锻炼的时候。 阿片拮抗剂的施用将是 预期改善心脏性能并增加器官血流量， 了以下条件 我们的初步研究表明， 静息血浆β-内啡肽、ACTH和皮质醇水平升高， CHF犬和阿片拮抗剂（纳洛酮和纳美芬）增加 左心室dP/dt、心输出量、动脉血压和血液 流向骨骼肌心肌和肾脏。 拟议 研究表明，CHF将由三尖瓣撕脱和进行性 清醒狗的肺动脉收缩。 的血浆水平 β-内啡肽、促肾上腺皮质激素、皮质醇（均通过放射免疫测定）和儿茶酚胺 （使用高效液相色谱法）将进行测量 在CHF和假手术的狗在休息和运动期间。 在 此外，心率、主动脉血压、心输出量（使用 碘花青绿色稀释技术），左心室dP/dt和dP/dt/P， 并测量局部血流量（使用放射性微球） 静脉注射纳洛酮前后。 进而 确定纳洛酮的作用是否通过 β-肾上腺素能受体，纳洛酮将给予预处理的犬 心得安 纳洛酮的作用也将与那些 纳洛酮甲基溴，不穿透脑血屏障 以确定神经系统是否 最后，特异性阿片受体 将静脉内施用阻断剂以确定是否 纳洛酮通过mu或delta发挥其心血管作用 受体。 研究结果将进一步加深我们对 CHF循环的神经体液控制，并产生有用的信息 关于阿片拮抗剂在临床中的潜在用途， 管理CHF。

Endogenous opioid peptides, which have a variety of cardiovascular effects, have been shown to be elevated and play an important role in the pathophysiology of acute circulatory failure. Increased plasma levels of opioid peptides also occur during physical exercise. We propose to study whether the endogenous opiods play a similar role during chronic congestive heart failure (CHF) with and without added exercise stress. We speculate that the endogenous opioids are increased in CHF at rest and significantly more during exercise. Administration of opiate antagonists would be expected to improve cardiac performance and increase organ blood flow under these conditions. This is supported by our preliminary studies that show resting plasma levels of beta-endorphin, ACTH and cortisol were elvated in the CHF dogs and that opiate antagonists (naloxone and nalmefene) increased left ventricular dP/dt, cardiac output, arterial blood pressure and blood flow to the skeletal muscle, myocardium and kidneys. In the proposed study, CHF will be produced by tricuspid valve avulsion and progressive pulmonary artery constriction in conscious dogs. Plasma levels of beta-endorphin, ACTH, cortisol (all by radioimmunoassay) and catecholamines (using a high performance liquid chromatographic method) will be measured in the CHF and sham-operated dogs both at rest and during exercise. In addition, heart rate, aortic blood pressure, cardiac output (using an idocyanine green dilution technique), left ventricular dP/dt and dP/dt/P, and regional blood flow (using radioactive microspheres) will be measured before and after intravenous naloxone administration. Furthermore, to determine whether the effects of naloxone are mediated via the beta-adrenergic receptors, naloxone will be administered to dogs pretreated with propranolol. The effects of naloxone also will be compared to those of naloxone methylbromide which does not penetrate the brain blood barrier to determine if the nervous system. Finally, specific opiate receptor blocking agents will be administered intravenously to determine whether naloxone exerts its cardiovascular effects via either mu or delta receptors. Results of the study will further our understanding of neurohumoral control of the circulation in CHF and yield useful information regarding the potential use of opiate antagonists in the clinical management of CHF.