BEHAVIORAL STRESS AND OPIOID MECHANISMS IN HYPERTENSION

拟议研究的目标是继续主要的 研究者对改变的阿片样物质抑制的系统性研究 交感神经系统和心血管反应性 行为应激在特发性原发性 高血压阿片类药物对血压的抑制作用也可能很重要 在抗高血压作用的交感神经行为和 药物治疗最近的四项研究结果支持这一论点： 1)阿片拮抗剂纳洛酮的升压作用是 在年轻人的行为压力下， 高血压风险增加，2）血浆β-内啡肽水平 在某些高血压患者组中显著降低，3） 可乐定长期抗高血压治疗使正常化 两 血压和β-内啡肽水平，以及4）抗高血压药 纳洛酮可拮抗可乐定对高血压的降压作用 患者研究建议，以确定内源性的作用， 阿片类药物在原发性高血压病理生理学中的作用机制， 研究一种假设的阿片样物质释放机制在 可乐定降压药物治疗。这将是 通过检查纳洛酮对循环系统的影响来完成 在休息和行为应激时的神经内分泌反应 轻度、无并发症的原发性高血压未用药患者 （与标准对照相比）。纳洛酮的升压作用 在未用药的高血压患者亚组中进行检查， 没有交感神经系统过度活动的迹象的作用 阿片类药物的降压作用机制 交感神经阻滞抗高血压治疗将通过记录 慢性用药后纳洛酮升压作用的变化 可乐定阿片类药物降压机制的研究进展 高血压的失调将促进对高血压的认识， 诊断、病理生理机制和最佳治疗 在这一异质性疾病类别中的策略。

The objectives of the proposed research are to continue the Principal Investigator's systematic study of altered opioidergic inhibition of sympathetic nervous system and cardiovascular reactivity during behavioral stress in the development of idiopathic essential hypertension. Opioid inhibition of blood pressure may also be important in the antihypertensive action of sympatholytic behavioral and pharmacological therapies. Four recent findings support this contention: 1) the pressor effect of the opioid antagonist, naloxone, is significantly diminished during behavioral stress in young adults at enhanced risk for hypertension, 2) plasma levels of beta-endorphin are significantly decreased in some groups of hypertensive patients, 3) chronic antihypertensive treatment with clonidine normalizes both blood pressure and beta-endorphin levels, and 4) the antihypertensive effect of clonidine is antagonized by naloxone in some hypertensive patients. Research is proposed to determine the role of endogenous opioid mechanisms in the pathophysiology of essential hypertension and to investigate the role of an hypothesized opioid-releasing mechanism in antihypertensive pharmacotherapy with clonidine. This will be accomplished by examination of the effects of naloxone on circulatory and neuroendocrine responses during rest and behavioral stress in unmedicated patients with mild, uncomplicated essential hypertension (compared with normative controls). The pressor effect of naloxone will be examined in subgroups of unmedicated hypertensive patients with and without signs of excessive sympathetic nervous system activity. The role of opioid mechanisms in the blood pressure-lowering effect of sympatholytic antihypertensive therapy will be determined by documenting changes in the pressor effect of naloxone after chronic medication with clonidine. Elucidation of opioid mechanisms of blood pressure dysregulation in hypertension will advance understanding of the diagnosis, pathophysiologic mechanisms, and optimum therapeutic strategies in this heterogeneous disease category.