Mechanisms of 5-hydroxytryptamine-induced hypotension

描述（由申请人提供）：高血压是血压持续升高，是常见疾病和死亡的重要危险因素，包括心脏病、中风和终末期肾病。尽管研究努力，原发性高血压的确切机制在很大程度上仍然未知，有趣的是，一些证据表明高血压与5-羟色胺（5-羟色胺，5-HT）之间存在重要关联。研究表明，与血压正常的对照组相比，人类和动物高血压模型的游离血浆5-羟色胺水平升高。从历史上看，这些水平升高被认为是导致原发性高血压的原因。然而，我们已经表明，升高的游离血浆5-羟色胺具有降低雄性醋酸脱氧皮质酮盐高血压和假正常大鼠血压的能力。5- ht诱导低血压的机制尚不清楚。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(s)受到刺激的结果。一种综合方法将用于阐明5- ht诱导的低血压的机制。我们将使用几种不同的技术，包括全动物测量、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：验证5- ht诱导的低血压是由DOCA-salt和假药大鼠总外周阻力下降介导的。专项目的2：将验证慢性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：将测试假设5-HT刺激血管受体，导致一氧化氮的释放，血管松弛。本研究将填补我们对5-HT在心血管系统中的作用的认识空白，并探索5-HT在高血压中的潜在有益作用。此外，该项目可能会导致发现新的治疗原发性高血压的靶点。

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.