Mechanisms of 5-hydroxytryptamine-induced hypotension

描述（由申请人提供）：高血压是血压持续升高，是常见发病和死亡原因（包括心脏病、卒中和终末期肾病）的重要风险因素。尽管研究工作，原发性高血压的确切机制仍然在很大程度上是未知的，有趣的是，一些证据表明高血压和血清素（5-羟色胺，5-HT）之间的重要关联。研究表明，与正常血压对照组相比，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是导致原发性高血压的原因。然而，我们已经表明，升高的血浆游离5-HT有能力降低雄性醋酸脱氧皮质酮（DOCA）盐高血压和假正常血压大鼠的血压。5-HT诱导的低血压的机制尚不清楚。我们推测血浆游离5-HT水平升高通过降低总外周阻力以一氧化氮依赖的方式降低血压。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。将采用综合方法阐明5-HT诱导性低血压的机制。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DOCA-盐和假手术大鼠中5-HT诱导的低血压由总外周阻力下降介导的假设。具体目标2：将检验慢性5-HT输注减少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舒张的假设。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的空白，并探索5-HT在高血压中的潜在有益作用。此外，该项目可能导致发现用于治疗原发性高血压的新的治疗靶点。

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.