Mechanisms of 5-hydroxytryptamine-induced hypotension

5-羟色胺诱发低血压的机制

• 批准号: 8437225
• 负责人: Robert Patrick Davis
• 金额: $ 1.98万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-21 至 2013-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437225
• 关键词: Abbreviations; Acetates; Acetylcholine; Afferent Neurons; Animal Model; Animals; Arteries; Blood Platelets; Blood Pressure; Blood Vessels; Calcitonin Gene-Related Peptide; Cardiovascular system; Chronic; Control Animal; Deoxycorticosterone; End stage renal failure; Essential Hypertension; Goals; Heart Diseases; Human; Hypertension; Hypotension; In Vitro; Inbred SHR Rats; Infusion procedures; Lead; Measures; Mediating; Morbidity - disease rate; Nerve; Neuraxis; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Peripheral Resistance; Plasma; Play; Process; Rattus; Relaxation; Research; Research Personnel; Risk Factors; Role; Sensory; Serotonin; Sodium Chloride; Solutions; Stroke; Sympathetic Nervous System; System; Techniques; Testing; Vasodilation; Vasodilator Agents; afferent nerve; falls; hemodynamics; in vivo; inhibitor/antagonist; male; mortality; new therapeutic target; normotensive; pressure; protective effect; receptor; response; reuptake; serotonin receptor; serotonin transporter

DESCRIPTION (provided by applicant): Hypertension is a sustained elevation in blood pressure that represents a significant risk factor for common causes of morbidity and mortality including, heart disease, stroke, and end-stage renal disease. Despite research efforts, the exact mechanism underlying essential hypertension remains largely unknown, interestingly, several lines of evidence suggest an important association between hypertension and serotonin (5-hydroxytryptamine, 5-HT). Studies have demonstrated elevated levels of free plasma 5-HT in Doth human and animal models of hypertension compared to normotensive controls. Historically, these elevated levels were thought to contribute to essential hypertension. However, we have shown that elevated free plasma 5-HT has the ability to lower blood pressure in male deoxycorticosterone acetate (DOCA)-salt hypertensive and sham-normotensive rat. The mechanism underlying 5-HT-induced hypotension is not yet mown. We hypothesize that elevated levels of free plasma 5-HT lower blood pressure in a nitric oxide dependent manner by reducing total peripheral resistance. This may be the result of either a reduction in sympathetic nervous system (SNS) tone and/or stimulation of a vascular 5-HT receptor(s). An integrative approach will be used to elucidate the mechanism underlying 5-HT-induced hypotension. We will use several different techniques, including whole animal measures, SNS activity measures, and measures of vascular reactivity. The aims for this study are as follows: Specific aim 1: will test the hypothesis that 5-HT-induced hypotension is mediated by a fall in total peripheral resistance in the DOCA-salt and sham rat. Specific aim 2: will test the hypothesis that chronic 5-HT infusion reduces sympathetic nerve activity or stimulates sensory afferent nerves. Specific aim 3: will test the hypothesis that 5-HT stimulates vascular receptors, leading to a release of nitric oxide, and vascular relaxation. This research will fill a gap in our understanding of how 5-HT functions in the cardiovascular system and explore the potentially beneficial role of 5-HT in hypertension. Additionally, this project may lead to discovery of novel therapeutic targets for the treatment of essential hypertension.

描述（由申请人提供）：高血压是血压持续升高，是导致心脏病、中风和终末期肾病等常见发病和死亡原因的重要危险因素。尽管进行了研究努力，原发性高血压的确切机制仍然很大程度上未知，有趣的是，一些证据表明高血压和血清素（5-羟色胺，5-HT）之间存在重要关联。研究表明，与正常血压对照相比，Doth 人类和动物高血压模型中游离血浆 5-HT 水平升高。从历史上看，这些升高的水平被认为会导致原发性高血压。然而，我们已经证明，升高的游离血浆 5-HT 能够降低雄性醋酸去氧皮质酮 (DOCA)-盐高血压和假血压正常大鼠的血压。 5-HT 引起的低血压的机制尚未阐明。我们假设游离血浆 5-HT 水平升高，通过降低总外周阻力，以一氧化氮依赖性方式降低血压。这可能是交感神经系统 (SNS) 张力降低和/或血管 5-HT 受体刺激的结果。将采用综合方法来阐明 5-HT 诱发低血压的机制。我们将使用几种不同的技术，包括整体动物测量、SNS 活动测量和血管反应性测量。本研究的目的如下： 具体目的 1：将检验以下假设：5-HT 诱导的低血压是由 DOCA 盐和假大鼠中总外周阻力下降介导的。具体目标 2：将检验长期 5-HT 输注会降低交感神经活动或刺激感觉传入神经的假设。具体目标 3：将检验 5-HT 刺激血管受体，导致一氧化氮释放和血管松弛的假设。这项研究将填补我们对 5-HT 如何在心血管系统中发挥作用的理解空白，并探索 5-HT 在高血压中的潜在有益作用。此外，该项目可能会发现治疗原发性高血压的新治疗靶点。

项目成果

Lack of the serotonin transporter (SERT) reduces the ability of 5-hydroxytryptamine to lower blood pressure.

• DOI: 10.1007/s00210-011-0622-1
• 发表时间: 2011-05
• 期刊: NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
• 影响因子: 3.6
• 作者: Davis, Robert Patrick;Elizabeth Linder, A.;Watts, Stephanie W.
• 通讯作者: Watts, Stephanie W.

Melatonin administration does not affect isoproterenol-induced LVH.

服用褪黑激素不会影响异丙肾上腺素诱导的 LVH。

• DOI: 10.1109/memb.2006.1636358
• 发表时间: 2006
• 期刊: IEEE engineering in medicine and biology magazine : the quarterly magazine of the Engineering in Medicine & Biology Society
• 作者: Flood,ElizabethM;Kumar,RobertS;Shah,Rashmi;Amos,Quinlan;Wren,JonathanD;Shohet,RalphV;Garner,HaroldR
• 通讯作者: Garner,HaroldR