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

血清素诱导血压降低的血管和神经机制

• 批准号: 8369691
• 负责人: Stephanie W Watts
• 金额: $ 33.96万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369691
• 关键词: 5-Hydroxytryptophan; Acute; Address; Adverse effects; Agonist; Anaphylaxis; Animals; Antidepressive Agents; Arginine; Arteries; Beds; Biochemical; Blood Circulation; Blood Pressure; Blood Vessels; Brown Fat; Carcinoid Tumor; Cardiopulmonary Bypass; Cell Nucleus; Cerebrospinal Fluid; Chronic; Clinical; Commit; Conscious; Cutaneous; Data; Dependence; Drug Delivery Systems; Event; Excision; Ganglia; Goals; Head; Hemodialysis; Hormones; Human; Hydroxyindoleacetic Acid; Hypotension; In Vitro; Inbred SHR Rats; Individual; Infusion procedures; Knock-out; Knowledge; Laboratories; Malignant Neoplasms; Measures; Mediating; Menopause; Metabolism; Mineralocorticoids; Modeling; Monoamine Oxidase Inhibitors; Mood Disorders; Moods; Nerve; Neuraxis; Neuroeffector Junction; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Parnate; Peripheral; Peripheral Resistance; Pharmaceutical Preparations; Physiological; Plasma; Prozac; Pump; Rattus; Relaxation; Role; Satiation; Serotonin; Serotonin Agonists; Shapes; Sleep; Splanchnic Circulation; Sprague-Dawley Rats; Sympathetic Nervous System; Techniques; Testing; Time; United States National Center for Health Statistics; Vasoconstrictor Agents; Work; animal tissue; blood pressure regulation; clinically relevant; clinically significant; extracellular; falls; improved; in vivo; inhibitor/antagonist; male; nerve supply; neuromechanism; neurophysiology; neurotransmitter release; normotensive; novel; receptor; relating to nervous system; research study; response; reuptake; serotonin receptor; serotonin transporter

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.

描述（由申请人提供）：人类在几种重要的临床慢性情况下循环自由羟色胺（5-羟色胺，5-HT）的升高。这些包括过敏性休克，心肺旁路，类癌癌和血液透析，所有这些都呈现出血压下降。此外，数以百万计的人使用增加血浆5-HT浓度和血压变化的药物是这些药物的副作用。最后，用于5-HT合成的授权底物，5-羟色质（5-HTP），被视为睡眠，情绪障碍，更年期和许多其他疾病的助手，并导致血压下降。我们是第一个证明，在大鼠中，长期给药5-HT（1周）直接通过降低总周围耐药性（TPR）直接降低了有意识，健康大鼠的血压。 5-HT诱导的血压慢性下降取决于一氧化氮合酶（NOS）的活性，因为在多种情况下，NOS抑制剂N-抑制剂N-硝基-L-精氨酸（LNNA）废除了5-HT诱导的血压下降。我们对5-HT机制的理解从来没有更重要的是，我们的机制是第一个解决这一临床相关问题的问题。该项目的总体目标和我们实验室的长期目标是确定5-HT引起正常动物血压下降的机制。我们的中心假设是5-HT将TPR降低至1）直接血管； 2）通过去除中央或外围介导的交感神经来介导的间接血管作用。初步实验支持5-HT增加皮肤和斜视循环中流量的能力，因此我们将重点放在这两张床上。具有重要专业知识的综合方法和团队将用于解决三个特定目标。 Sprague-Dawley大鼠将是主要模型，但我们还将使用新型的5-羟色胺转运蛋白（SERT）敲除大鼠。我们采用一种强大的技术，使用合并的放射性骨骼组和可编程的Iprecio（R）泵重复进行血压测量，以在有意识的大鼠中输送药物，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）的有争议的问题。 AIM 2会剖析5-HT是否引起直接血管松弛和/或降低交感神经活动以降低血压。目标1和2将确定5-HT的效果是否依赖于NOS的效果。 AIM 3通过测试与目标1和2有关的5-HT受体的激活是否会导致血压中的NOS和5-HT受体依赖性下降，以及5-HTP输注是否会慢性地降低NOS和5-HT-HT受体受体受体依赖性的方式。 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. 公共卫生相关性：大量药物（例如，抗抑郁药）和柜台补充剂5-羟色化剂的目的是提高细胞外浓度5-羟色胺（5-HT）的细胞外浓度，并改善情绪，睡眠和睡眠和睡眠。循环5-HT的升高也发生在过敏性休克，心肺旁路，类癌和血液透析中，血压降低与所有这些事件有关。我们的工作调查了5-HT诱导的血压下降的机制，以及5-HT样化合物是否可能对控制血压有用。