Vascular and Neural Mechanisms of Serotonin-induced Reduction in Blood Pressure

描述（由申请方提供）：在几种重要的临床慢性情况下，人体循环游离5-羟色胺（5-羟色胺，5-HT）升高。这些包括过敏性休克，心肺转流，类癌和血液透析，所有这些都表现为血压下降。此外，数百万人使用增加血浆5-HT浓度的药物，血压变化是这些药物的副作用。最后，5-羟色胺合成的底物5-羟色氨酸（5-HTP）被用作睡眠，情绪障碍，更年期和许多其他疾病的助手，并导致血压下降。我们首次证明，在大鼠中，长期给予5-HT（1周）通过降低总外周阻力（TPR）直接降低清醒健康大鼠的血压。5-HT诱导的慢性血压下降依赖于一氧化氮合酶（NOS）的活性，因为NOS抑制剂N-硝基-L-精氨酸（LNNA）在多种情况下消除了5-HT诱导的慢性血压下降。我们对5-HT机制的理解从未如此重要，我们是第一个解决这一临床相关问题的人。本项目的总体目标和我们实验室的长期目标是确定5-HT促进正常血压动物血压下降的机制。我们的中心假设是，5-HT通过1）直接血管和2）通过中枢或外周介导的交感神经张力的去除间接血管效应降低TPR。初步实验支持5-HT增加皮肤和内脏循环流量的能力，因此我们将重点放在这两个床位上。将采用一种综合办法和一个具有重要专门知识的团队来实现三个具体目标。Sprague-Dawley大鼠将是主要模型，但我们也将使用新型5-羟色胺转运体（SERT）敲除大鼠。我们采用了一种强大的技术，使用联合无线电遥测和可编程iPrecio（R）泵在清醒大鼠中进行药物输送，以及在麻醉大鼠中进行神经测量，重复测量血压。目的1直接解决了5-HT是否进入中枢神经系统（CNS）的争议问题。目的2将剖析5-HT是否会引起直接血管舒张和/或减少交感神经活动以降低血压。目的1和2将确定5-HT的作用是否以及在何处是NOS依赖性的。目的3通过测试目的1和2中涉及的5-HT受体的激活是否引起血压的NOS-和5-HT-受体依赖性下降，以及5-HT-输注是否以NOS-和5-HT-受体依赖性方式长期降低血压，有力地结束了这一提议。这项工作的影响和前景在于：1）正面解决争议（5-HT进入CNS？体外5-HT vs体内5-HT？）（2）发现5-HT的作用机制可能对人类调节血压有益，因为慢性5-HT几乎使清醒的盐皮质激素和自发性高血压大鼠的血压升高正常化。

DESCRIPTION (provided by applicant): Humans have elevations in circulating free serotonin (5-hydroxytryptamine, 5-HT) in several important clinical, chronic situations. These include anaphylactic shock, cardiopulmonary bypass, carcinoid cancer and hemodialysis, all of which presents with a fall in blood pressure. Additionally, millions of individuals use medications that increase plasma 5-HT concentration, and changes in blood pressure are a side effect of these medications. Finally, the committed substrate for 5-HT synthesis, 5-hydroxytryptophan (5-HTP), is taken as an aide for sleep, mood disorders, menopause and many other conditions and causes a fall in blood pressure. We were the first to demonstrate that, in the rat, a long-term administration of 5-HT (1 week) directly reduced the blood pressure of the conscious, healthy rat through reduction of total peripheral resistance (TPR). The 5- HT-induced chronic fall in blood pressure is dependent on the activity of nitric oxide synthase (NOS) because the NOS inhibitor N-nitro-L-arginine (LNNA) abolished 5-HT-induced chronic fall in blood pressure in multiple situations. At no time has our understanding of the mechanisms of 5-HT been more important, and ours is the first to address this clinically relevant issue. The overall goal of thi project and long-term goal of our laboratory is to identify the mechanism(s) by which 5-HT elicits a fall in blood pressure in normotensive animals. Our central hypothesis is that 5-HT reduces TPR through 1) direct vascular; and 2) indirect vascular effects through removal of sympathetic tone mediated either centrally or peripherally. Preliminary experiments support the ability of 5-HT to increase flow in cutaneous and splanchnic circulations so we will focus on these two beds. An integrative approach and team with significant expertise will be used to address three specific aims. Sprague-Dawley rats will be the primary model, but we will also use the novel serotonin transporter (SERT) knockout rat. We employ a powerful technique for repeated measures of blood pressure using combined radiotelemetry and the programmable iPrecio(R) pump for drug delivery in conscious rats, as well as neural measures in anesthetized rats. Aim 1 directly addresses the controversial issue of whether 5-HT enters the central nervous system (CNS). Aim 2 will dissect whether 5-HT causes direct vascular relaxation and/or reduces sympathetic nerve activity to decrease blood pressure. Aims 1 and 2 will determine whether and where the effects of 5-HT are NOS-dependent. Aim 3 closes this proposal powerfully by testing whether activation of the 5-HT receptor implicated in Aims 1 and 2 causes a NOS- and 5-HT- receptor dependent fall in blood pressure, and whether 5-HTP-infusion reduces blood pressure chronically in a NOS- and 5-HT-receptor dependent manner. The impact and promise of this work lies in 1) addressing controversies head-on (5-HT enter the CNS? 5-HT in vitro vs 5-HT in vivo?) and 2) in discovering mechanisms of 5-HT action that may be beneficial to human regulation of blood pressure, given that chronic 5-HT nearly normalized elevated blood pressure of the conscious mineralocorticoid and spontaneously hypertensive rat.