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

描述(由申请人提供)：在几种重要的临床、慢性疾病中，人类循环中的游离5-羟色胺(5-羟色胺，5-羟色胺)水平升高。这些包括过敏性休克、体外循环、类癌和血液透析，所有这些都表现为血压下降。此外，数以百万计的人使用增加血浆5-羟色胺浓度的药物，血压的变化是这些药物的副作用。最后，合成5-羟色胺的底物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，长期服用5-羟色胺(1周)可通过降低总外周阻力(TPR)直接降低清醒健康大鼠的血压。5-羟色胺诱导的慢性血压下降依赖于一氧化氮合酶的活性，因为一氧化氮合酶抑制剂N-硝基-L精氨酸可在多种情况下阻断5-羟色胺诱导的慢性血压下降。我们对5-羟色胺的机制的了解从来没有像现在这样重要，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实验室的长期目标是确定5-羟色胺引起正常血压动物血压下降的机制(S)。我们的中心假设是，5-羟色胺通过1)直接血管效应和2)中枢或外周交感神经张力的去除间接血管效应来减少TPR。初步实验支持5-羟色胺在皮肤和内脏循环中增加血流的能力，所以我们将重点放在这两个床上。将使用综合方法和具有丰富专业知识的团队来实现三个具体目标。SD大鼠将是主要的模型，但我们也将使用新型的5-羟色胺转运体(SERT)基因敲除大鼠。我们使用了一种强大的技术来重复测量血压，使用组合无线电遥测和用于给药的可编程iPrecio(R)泵，以及麻醉大鼠的神经测量。目的1直接解决5-羟色胺是否进入中枢神经系统(CNS)这个有争议的问题。目的2将剖析5-羟色胺是否导致直接血管松弛和/或降低交感神经活动以降低血压。目标1和目标2将决定5-羟色胺的作用是否依赖于一氧化氮合酶，以及在哪里。AIM 3通过测试AIMS 1和2中涉及的5-羟色胺受体的激活是否导致一氧化氮合酶和5-羟色胺受体依赖的血压下降，以及5-羟色胺输注是否以一氧化氮合酶和5-羟色胺受体依赖的方式慢性降低血压，有力地结束了这一提议。这项工作的影响和前景在于：1)迎头解决争议(5-羟色胺进入中枢？体外5-羟色胺与体内5-羟色胺？)2)发现5-羟色胺的作用机制可能有利于人类调节血压，因为慢性5-羟色胺使清醒的糖皮质激素和自发性高血压大鼠的血压升高接近正常。 与公共健康相关：服用大量药物(例如，抗抑郁药)和非处方药补充5-羟色氨酸，目的是增加细胞外激素5-羟色胺(5-HT)的浓度，改善情绪、睡眠和饱腹感。过敏性休克、体外循环、类癌和血液透析中也会出现循环中5-羟色胺的升高，而血压的降低与所有这些事件有关。我们的工作是研究5-羟色胺引起血压下降的机制，以及5-羟色胺类化合物是否可用于控制血压。

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. PUBLIC HEALTH RELEVANCE: A substantial number of medications (antidepressants, for example) and the over the counter supplement 5- hydroxytryptophan are taken with the intent to increase extracellular concentration of the hormone 5- hydroxytryptamine (5-HT) and improve mood, sleep and satiety. Elevations in circulating 5-HT also occur in anaphylactic shock, cardiopulmonary bypass, carcinoid cancer and hemodialysis and a decrease in blood pressure is associated with all these events. Our work investigates the mechanisms of 5-HT-induced fall in blood pressure and whether 5-HT-like compounds might be useful in controlling blood pressure.