5-HT7 receptor and blood pressure regulation

5-HT7受体与血压调节

• 批准号: 10361571
• 负责人: Gregory D Fink
• 金额: $ 42.52万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361571
• 关键词: 5-Hydroxytryptophan; Acute; Affinity; Agonist; Arteries; Basic Science; Bathing; Blood Circulation; Blood Pressure; Blood Vessels; Blood pressure determination; Caliber; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Chronic; Complex; Conscious; Development; Disease; Dose; Experimental Models; Foundations; Functional disorder; Genetic Models; Goals; HTR2A gene; Heart failure; Hematological Disease; Hypertension; Hypotension; Image; Infusion procedures; Injections; Investigation; Isometric Contraction; Knock-out; Knowledge; Laboratories; Lead; Measurement; Measures; Mediating; Mediation; Medical; Microcirculation; Modeling; Names; Outcome; Peripheral; Peripheral Resistance; Pharmacology; Physiologic arteriovenous anastomosis; Physiological; Plasma; Play; Population; Positioning Attribute; Publishing; Rattus; Receptor Activation; Regulation; Relaxation; Research; Resistance; Rodent Model; Role; Science; Series; Serotonin; Serotonin Agents; Serum; Site; System; Techniques; Testing; Therapeutic; Tissues; Venous; Weight; Work; antagonist; arteriole; blood pressure control; blood pressure reduction; blood pressure regulation; cardiovascular effects; falls; in vivo; novel; novel strategies; receptor; recruit; response; serotonin 7 receptor; serotonin receptor; therapeutic development; venule; 5-Hydroxytryptophan; Acute; Affinity; Agonist; Arteries; Basic Science; Bathing; Blood Circulation; Blood Pressure; Blood Vessels; Blood pressure determination; Caliber; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Chronic; Complex; Conscious; Development; Disease; Dose; Experimental Models; Foundations; Functional disorder; Genetic Models; Goals; HTR2A gene; Heart failure; Hematological Disease; Hypertension; Hypotension; Image; Infusion procedures; Injections; Investigation; Isometric Contraction; Knock-out; Knowledge; Laboratories; Lead; Measurement; Measures; Mediating; Mediation; Medical; Microcirculation; Modeling; Names; Outcome; Peripheral; Peripheral Resistance; Pharmacology; Physiologic arteriovenous anastomosis; Physiological; Plasma; Play; Population; Positioning Attribute; Publishing; Rattus; Receptor Activation; Regulation; Relaxation; Research; Resistance; Rodent Model; Role; Science; Series; Serotonin; Serotonin Agents; Serum; Site; System; Techniques; Testing; Therapeutic; Tissues; Venous; Weight; Work; antagonist; arteriole; blood pressure control; blood pressure reduction; blood pressure regulation; cardiovascular effects; falls; in vivo; novel; novel strategies; receptor; recruit; response; serotonin 7 receptor; serotonin receptor; therapeutic development; venule

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.

项目摘要 尽管进行了深入的调查，但血压调节疾病 - 高血压和 低血压 - 继续严重，广泛且棘手的医学问题。相对较少的有效性 在过去的几十年中，出现了血压失调的管理方法 需要策略。 5-羟色胺（5-羟色胺，5-HT）首次在心血管中发现 系统，但是内源性5-HT在心血管生理和病理生理学中的作用不好 定义。这是因为5-HT在CV系统中具有复杂的效果，这些效果由几种不同 受体亚型。考虑血压的终点时，这是很好的插图。取决于 注射部位，给药的剂量和受体靶向的血清素能药物可以升高或升高 血压。在CV系统中表达的5-HT受体（5-HT 1B/1D，5-HT2A，5-HT3、5-HT4和5-- HT7受体），5-HT对5-HT7受体的亲和力最高。由于内源血浆和组织 估计5-HT的水平在低NM范围内，内源性5-HT可能主要作用于5-HT7 受体影响血压的变化。先前的研究支持有关急性的猜想 （秒至分钟）外源5-HT的影响。在过去的十年中，我们证明了这也是如此 使用两种传统药理 我们开发的方法和一种新的遗传模型（5-HT7受体敲除大鼠）。因此，我们现在是 定位良好以检验总体假设，内源性5-HT修饰了正常和 病理生理条件主要是通过在外周脉管系统中激活5-HT7受体，并具有 利用5-HT7受体药理学来治疗血压调节疾病的最终目标。 我们建议通过三个特定目的检验这一假设：目标1：检验5-HT7受体的假设 激活扩张了微循环；目的2：测试血管5-HT7受体的假设 （组成型）内源性激活以降低正常大鼠的血压；和目标3：测试 在释放或形成5-HT的大鼠模型中产生的低血压是5-HT7受体依赖性。 提出了一系列集成的技术，这些技术是我们合并实验室的优势。 这些包括等距收缩的孤立组织浴测量，受体激活的测量 包括构成活动的概念以及用于测量心血管参数的radiotelemetry 有意识的老鼠。我们已建立的专业知识与新获得的能力相结合，可以图像闪烁的静脉 和整个大鼠的动脉直径。该项目的目的是发现5-HT的独特能力 选择性地激活通过5-HT7受体的静脉（可能是微型）循环，并减少血液 压力是多种心血管疾病的有前途的治疗铅。