Adenosine and Nitric Oxide Deficiency

描述(逐字摘自申请)：一氧化氮(NO)和腺苷 在调节血管张力和保护器官方面发挥重要作用 与缺血相关的损伤。越来越多的证据表明，没有任何机制是 在许多情况下受损，例如高脂血症患者甚至 在动脉粥样硬化变得明显之前。人们相信，这一“无缺憾” 会导致更大的心血管风险 病人。动物实验显示腺苷显著增加。 在实验上抑制NO合成时的产物。我们将使用 前臂血管系统测试腺苷起代偿作用的假说 在没有任何机制受损的情况下发挥作用。我们将利用血管反应来 臂内注射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。前臂血管系统良好 以无机制为特征，以及我们的初步研究 提示在该模型中，腺苷也参与了血管调节。 在特定的目标I和2中，我们将确定腺苷是否释放并用于 当实验上抑制前臂NO的合成时，或 当其他正常受试者的机制没有受损时， 高胆固醇血症。为此，我们将测量血管内和 微透析法测定组织间质腺苷浓度。在……里面 具体目标3我们将探索腺苷对反应性和 正常人群和非药物高脂血症患者的代谢性充血 病人。 以没有缺乏为特征的情况将从治疗中受益 增强一氧化氮和腺苷的作用的方法。这 可以通过联合抑制磷酸二酯酶而获得，因此 增强NO介导的cGMP增加，并抑制腺苷摄取。 双嘧达莫在体外具有这些特征，但其确切的机制 这种药物在人体内的作用还没有得到很好的描述。具体而言 目的4我们将确定双嘧达莫是否增强血管作用。 腺苷，NO介导的血管扩张剂(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 腺苷是NO缺乏症的有效代偿机制 状态，或者如果存在NO和腺苷机制的联合损害 在这些病人身上。无论是哪种情况，我们的最终目标都是开发小说 一氧化氮缺乏症的治疗方法。 本申请提出以下建议：(1)确定腺苷是否释放 和/或当实验中前臂合成NO时，动作增强 抑制或当没有机制受损时，其他正常受试者有 高胆固醇血症(2)探讨腺苷对反应性的贡献 和代谢性充血，包括正常和无药物治疗的高脂血症 患者和(3)确定双嘧达莫是否增强血管作用 NO介导的血管扩张剂和c-GMP介导的血管扩张剂的腺苷。

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.