Adenosine and Nitric Oxide Deficiency

腺苷和一氧化氮缺乏

• 批准号: 6638762
• 负责人: Italo Biaggioni
• 金额: $ 26.43万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638762
• 关键词: adenosine; arm; blood circulation; cyclic GMP; dipyridamole; enzyme inhibitors; human subject; hypercholesterolemia; hyperlipidemia; nitric oxide; patient oriented research; phosphodiesterase inhibitors; vasodilators; vasomotion

DESCRIPTION (Verbatim from the application): Nitric oxide (NO) and adenosine play an important role in modulating vascular tone and protecting organs from ischemia-related injury. There is increasing evidence that NO mechanisms are impaired in a number of conditions, such as in patients with hyperlypemia even before atherosclerosis is apparent. This 'NO deficiency' is believed to contribute to the greater cardiovascular risk that characterizes these patients. Animal experiments show a substantial increase in adenosine production when NO synthesis is experimentally inhibited. We will use the forearm vasculature to test the hypothesis that adenosine plays a compensatory role when NO mechanisms are impaired. We will use the vascular response to intrabrachial infusions of NO-mediated vasodilators and NO synthesis inhibitors to carefully define our patients and controls. The forearm vasculature is well characterized with regards to NO mechanisms, and our preliminary studies indicate that adenosine also contributes to vascular regulation in this model. In Specific Aims I and 2 we will determine if adenosine release and for actions are enhanced when the forearm synthesis of NO is experimentally inhibited, or when NO mechanisms are impaired in otherwise normal subjects with hypercholesterolemia. For this purpose we will measure intravascular and interstitial adenosine concentrations using the microdialysis technique. In Specific Aim 3 we will explore the contribution of adenosine to reactive and metabolic hyperemia, both in normals and in medication-free hyperlipemic patients. Conditions characterized by NO deficiency would benefit from therapeutic approaches that would potentiate the actions of both NO and adenosine. This could be obtained by combined inhibition of phosphodiesterases, thus potentiating NO-mediated cGMP increases, and inhibition of adenosine uptake. Dipyridamole shares these characteristics in vitro, but the precise mechanism of action of this drug has not been well characterized in humans. In Specific Aim 4 we will determine if dipyridamole potentiates the vascular actions of adenosine, of NO-mediated vasodilators (e.g., acetylcholine) and of c-GMP-mediated vasodilators (e.g. nitroprusside). Our focus is to determine if adenosine constitutes an effective compensatory mechanism in NO-deficient states, or if a combined impairment of NO and adenosine mechanisms is present in these patients. In either case, our ultimate target is to develop novel approaches for the treatment of NO-deficiency. This application proposes the following: (1) to determine if adenosine release and/or actions are enhanced when the forearm synthesis of NO is experimentally inhibited or when No mechanisms are impaired in otherwise normal subjects with hypercholesteroiemia (2) to explore the contribution of adenosine to reactive and metabolic hyperemia, both in normal and medication free hyperlipemic patients and (3) to determine if dipyridamole potentiates the vascular actions of adenosine of NO-mediated vasodilators and of c-GMP-mediated vasodilators.

描述（来自应用程序的逐字描述）：一氧化氮（NO）和腺苷 在调节血管张力和保护器官免受 缺血相关损伤。越来越多的证据表明，NO机制 在许多情况下受损，例如在患有高血脂症的患者中， 在动脉粥样硬化明显之前。据信，这种“NO缺乏症" 导致更大的心血管风险， 患者动物实验显示腺苷的大量增加 当NO合成被实验性抑制时产生。我们将使用 前臂脉管系统来测试腺苷在血管中起代偿作用的假设。 当NO机制受损时，我们将利用血管反应 肱动脉内输注NO介导的血管扩张剂和NO合成抑制剂 仔细定义我们的病人和对照组。前臂的血管系统 关于NO机制的特点，我们的初步研究 表明腺苷在该模型中也有助于血管调节。 在具体目标I和2中，我们将确定腺苷释放和行动 在实验上抑制前臂的NO合成时增强，或 当NO机制在其他正常受试者中受损时， 高胆固醇血症。为此，我们将测量血管内和 间质腺苷浓度使用微透析技术。在 具体目标3，我们将探讨腺苷对反应性和 代谢性充血，无论是在正常人和无药物治疗的贫血 患者 以NO缺乏为特征的病症将受益于治疗性的 这些方法将增强NO和腺苷的作用。这 可以通过磷酸二酯酶的联合抑制来获得，因此 增强NO介导的cGMP增加，并抑制腺苷摄取。 双嘧达莫在体外也具有这些特征，但其确切机制 这种药物在人体中的作用还没有得到很好的表征。在特定 目的4：我们将确定潘生丁是否能增强 腺苷，NO介导的血管扩张剂（例如，乙酰胆碱）和 c-GMP介导的血管扩张剂（如硝普钠）。我们的重点是确定 腺苷构成了NO缺乏的有效补偿机制， 状态，或者如果存在NO和腺苷机制的联合损伤， 在这些患者中。无论哪种情况，我们的最终目标都是开发新的 治疗NO缺乏症的方法。 本申请提出以下建议：（1）确定腺苷释放是否 和/或当实验性地合成NO时， 在其他正常受试者中， 高胆固醇血症（2），探讨腺苷对反应性 和代谢性充血，无论是在正常的和无药物治疗的贫血 患者和（3）以确定是否潘生丁增强血管活动 腺苷的NO介导的血管扩张剂和c-GMP介导的血管扩张剂。