5-HT7 receptor and blood pressure regulation

项目摘要 尽管进行了深入的调查，但血压调节障碍--高血压和 低血压--仍然是严重的、普遍的和难以解决的医学问题。相对较少的有效 在过去的几十年里，血压失调的管理方法出现了，非常新颖 战略是必要的。5-羟色胺(5-羟色胺，5-羟色胺)最早发现于心血管。 但内源性5-羟色胺在心血管生理学和病理生理学中的作用尚不清楚。 已定义。这是因为5-羟色胺在CV系统中有复杂的影响，这些影响是由几个不同的 受体亚型。当考虑到血压的终点时，这一点得到了很好的说明。取决于 注射部位、给药剂量和受体靶向，5-羟色胺能药物可升高或升高 血压。在CV系统中表达的5-羟色胺受体(5-HT1B/1D、5-HT2A、5-HT3、5-HT4和5-HT4) HT7受体)，5-羟色胺与5-HT7受体的亲和力最高。由于内源性血浆和组织 5-羟色胺的水平估计在低NM范围内，内源性的5-羟色胺可能主要作用于5-羟色胺7 影响血压变化的受体。以前的研究支持这一猜想，即急性 (秒至分钟)外源性5-羟色胺的影响。在过去的十年里，我们已经证明了这一点也适用于 外源性5-羟色胺对慢性(数天至数周)血压的影响 方法和我们建立的新的遗传模型(5-HT7受体基因敲除大鼠)。因此，我们现在是 能够很好地测试内源性5-羟色胺改变正常和 病理生理状态主要是通过激活外周血管中的5-HT7受体， 利用5-HT7受体药理作用治疗血压调节障碍的最终目标。 我们建议通过三个具体目标来检验这一假说：目标1：检验5-HT7受体 激活扩张微循环；目标2：检验血管5-HT7受体是 (结构性)激活以降低正常大鼠的血压；目标3：测试 在5-羟色胺释放或形成增加的大鼠模型中产生的低血压是5-HT7受体依赖的。 提出了一系列集成的技术，这些技术是我们联合实验室的优势。 这些包括等长收缩的隔离组织浴测量，受体激活的测量 包括结构性活动的概念，以及用于测量心血管参数的无线电遥测 清醒的老鼠。我们已有的专业知识与新获得的内脏静脉成像能力相结合。 以及整个大鼠的动脉直径。本项目旨在发现5-羟色胺的独特能力 通过5-HT7受体选择性地激活静脉(可能还有微循环)，减少血液 压力，一种有希望的治疗多种心血管疾病的药物。

Project Summary Despite intensive investigation, disorders of blood pressure regulation -- both hypertension and hypotension -- continue to be serious, widespread and intractable medical problems. Relatively few effective approaches to management of blood pressure dysregulation have emerged over the last few decades so novel strategies are needed. Serotonin (5-hydroxytryptamine, 5-HT) was first discovered in the cardiovascular system, but the roles of endogenous 5-HT in cardiovascular physiology and pathophysiology are not well defined. This is because 5-HT has complex effects within the CV system that are mediated by several distinct receptor subtypes. This is well-illustrated when considering the endpoint of blood pressure. Depending on the site of injection, the dose administered, and the receptor targeted, serotonergic drugs can raise or elevate blood pressure. Of the 5-HT receptors expressed in the CV system (the 5-HT 1B/1D, 5-HT2A, 5-HT3, 5-HT4 and 5- HT7 receptor), 5-HT has the highest affinity for the 5-HT7 receptor. Since endogenous plasma and tissue levels of 5-HT are estimated to be in the low nM range, endogenous 5-HT likely acts primarily at 5-HT7 receptors to effect changes in blood pressure. Previous studies support this conjecture regarding the acute (seconds to minutes) effects of exogenous 5-HT. Over the last decade, we have proven this is also true for the chronic (days to weeks) blood pressure effects of exogenous 5-HT, using both traditional pharmacological approaches and a new genetic model (5-HT7 receptor knockout rat) that we developed. Therefore, we now are well-positioned to test the overall hypothesis that endogenous 5-HT modifies blood pressure in normal and pathophysiological conditions primarily by activation of 5-HT7 receptors in the peripheral vasculature, with the ultimate goal of capitalizing on 5-HT7 receptor pharmacology to treat disorders of blood pressure regulation. We propose to test this hypothesis via three Specific Aims: Aim 1: To test the hypothesis that 5-HT7 receptor activation dilates the microcirculation; Aim 2: To test the hypothesis that the vascular 5-HT7 receptor is (constitutively) activated endogenously to lower blood pressure in normal rats; and Aim 3: To test that the hypotension created in rat models with increased release or formation of 5-HT is 5-HT7 receptor-dependent. An integrated series of techniques that are the strengths of our combined laboratories are proposed. These include isolated tissue bath measurement of isometric contraction, measures of receptor activation that include the concept of constitutive activity, and radiotelemetry to measure cardiovascular parameters in conscious rats. Our established expertise is combined with newly gained abilities to image splanchnic venous and arterial diameters in the whole rat. This project is aimed to discover the unique ability of 5-HT to selectively activate the venous (and possibly micro) circulation through the 5-HT7 receptor and reduce blood pressure, a promising therapeutic lead for numerous cardiovascular disorders.