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

描述（由申请人提供）：在一些重要的临床慢性情况下，人类循环游离血清素（5-羟色胺，5-HT）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，5-羟色胺合成的底物5-羟色氨酸（5-HTP）被认为是睡眠、情绪障碍、更年期和许多其他疾病的助手，并导致血压下降。我们首先证明，在大鼠中，长期给药5-HT（1周）通过降低总外周阻力（TPR）直接降低了有意识的健康大鼠的血压。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）在多种情况下可消除5- ht诱导的慢性血压下降。我们对5-羟色胺机制的理解从未像现在这样重要，我们是第一个解决这个临床相关问题的人。这个项目的总体目标和我们实验室的长期目标是确定5-羟色胺引起正常动物血压下降的机制。我们的中心假设是5-HT通过1)直接血管降低TPR；2)通过消除交感神经张力介导的中枢或外周间接血管效应。初步实验支持5-羟色胺增加皮肤和内脏循环的能力，因此我们将重点关注这两个床。将采用综合方法和具有重要专业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血清素转运体（SERT）敲除大鼠。我们采用了一种强大的技术，通过联合无线遥测和可编程iPrecio(R)泵来重复测量血压，用于清醒大鼠的药物输送，以及麻醉大鼠的神经测量。Aim 1直接解决了5-HT是否进入中枢神经系统（CNS）这一有争议的问题。目的2将剖析5-HT是否直接引起血管松弛和/或减少交感神经活动以降低血压。目的1和2将确定5-羟色胺的作用是否以及在何处依赖于nos。目的3通过测试目的1和目的2中涉及的5-HT受体的激活是否导致NOS和5-HT受体依赖性的血压下降，以及5- htp输注是否以NOS和5-HT受体依赖性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)正面解决争议(5-HT进入中枢神经系统？5-羟色胺在体外与体内的对比？)和2)发现5-羟色胺的作用机制，这可能有利于人类调节血压，因为慢性5-羟色胺几乎使有意识的矿化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.