Nitric Oxide and Compensatory Coronary Vasodilation

一氧化氮和代偿性冠状动脉舒张

• 批准号: 6650329
• 负责人: David W Stepp
• 金额: $ 22.99万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650329
• 关键词: adenosine; coronary vasodilator; coronary vessels; dogs; enzyme inhibitors; heart circulation; hemodynamics; myocardial ischemia /hypoxia; nitric oxide; nitric oxide synthase; purinergic receptor; receptor expression; vasodilation

DESCRIPTION: (Verbatim from the application): Ischemic heart disease is the leading cause of death in Western cultures. Ischemia is caused by an imbalance in the heart's consumption of oxygen and the delivery of oxygen by the coronary circulation. Under normal conditions, the heart avoids ischemia by tightly matching myocardial oxygen consumption to coronary blood flow. To date, the mechanistic basis of this matching remains unknown. Many coronary vasodilators have been implicated in this process but conclusions have been confounded by the repeated observation that inhibitors of a single dilator do not impair physiologic adjustments in coronary blood flow. Several recent studies indicate a different paradigm, one in which coronary blood flow is not controlled by a singe vasodilator but by a network of redundant vasodilators. When one vasodilator in this network is inhibited, another increases their contribution such that coronary blood flow is preserved. In this regard, several studies have suggested a link between nitric oxide (NO) and adenosine in moderating coronary blood flow. Specifically, when NO is inhibited, the contribution from adenosine may increase, serving as a mechanism of compensatory vasodilation. The mechanism by which this occurs, however, remains unclear. The application tests the novel idea that NO directly reduces response to adenosine and that, when NO production is inhibited, responses to adenosine are potentiated. We find that, in animals chronically treated with the eNOS inhibitor L-NAME, the contribution of adenosine to metabolic hyperemia is increased. Based on this evidence, we hypothesize that adenosine plays an important role as a compensatory vasodilator when NO production is impaired. This hypothesis will be tested in 3 specific aims. 1) We hypothesize that increased vasodilator sensitivity to adenosine is an important compensatory mechanism that maintains normal coronary blood flow if NO production is chronically impaired. To complete this aim, we will examine coronary blood flow, microvascular diameter, interstitial adenosine concentrations and vascular reactivity to receptor blockade on basal and hyperemic flow I both normal and NO-impaired animals. 2) We hypothesize that adenosine A2a receptor mediated coronary vasodilation is augmented by chronic impairment of NO production. We will test this hypothesis by determining whether the dilation to adenosine A2a receptor stimulation is enhanced in coronary arterioles in vitro. We will assess the specificity of this augmentation by determining if alternative dilator pathways are also augmented by chronic reductions in NO production. (3) We hypothesize that, in the context or chronic impairment of NO production, the increased vasodilatory sensitivity to adenosine is associated with an increased expression of adenosine A2a receptors. We will test this hypothesis by using comparative RT-PCR analysis of individual coronary arterioles and determining if A2a receptors are upregulated without changes in other adenosine signaling molecules. Taken together, these studies will provide a thorough examination of the role and mechanisms of action of adenosine as a compensatory vasodilator during chronic NO impairment. This mechanism may contribute to the ability of the coronary circulation to maintain cardiac perfusion and avoid ischemia during the early stages of coronary artery disease when NO-dependent dilation is compromised.

描述：(来自应用程序的逐字)：缺血性心脏病是 在西方文化中是主要的死因。缺血是由失衡引起的 在心脏的氧气消耗和冠状动脉的氧气输送中 发行量。在正常情况下，心脏通过 将心肌耗氧量与冠脉血流量相匹配。到目前为止， 这种匹配的机制基础尚不清楚。许多冠状动脉血管扩张剂 与这一过程有牵连，但结论被混淆了 反复观察到单一扩张器的抑制剂不会损害 冠脉血流量的生理调节。最近的几项研究表明 一种不同的范式，在这种范式中，冠状动脉血流不受 单一的血管扩张剂，但由多余的血管扩张剂组成的网络。当一个人 这个网络中的血管扩张剂被抑制，另一个网络增加了他们的贡献 这样冠脉血流量就能得到保护。在这方面，几项研究 已经提出了一氧化氮(NO)和腺苷之间的联系 冠脉血流量。具体来说，当NO被禁止时，来自 腺苷可以增加，作为一种代偿性血管扩张机制。 然而，这种情况发生的机制尚不清楚。应用程序 测试了NO直接降低对腺苷的反应这一新想法， 当NO的产生被抑制时，对腺苷的反应就会增强。我们 研究发现，在长期使用eNOS抑制剂L治疗的动物中， 腺苷对代谢性充血的贡献增加。在此基础上 证据，我们假设腺苷作为一种 无分泌受损时的代偿性血管扩张剂。这一假说将 在三个具体目标上进行测试。1)我们假设血管扩张剂增加 对腺苷的敏感性是维持 如果NO产生慢性受损，则冠脉血流量正常。至 完成这个目标，我们将检测冠脉血流量，微血管直径， 间质腺苷浓度与血管对受体的反应性 对基础血流和充血血流的阻断作用，无论是正常动物还是非受损动物。2) 我们假设腺苷A2a受体介导的冠脉血管扩张 伴随着一氧化氮产生的慢性损害。我们将检验这一假设 通过确定对腺苷A2a受体刺激的扩张是否 在体外冠状小动脉中增强。我们将评估该病毒的特异性 通过确定替代的扩张器通路是否也 通过长期减少NO产量来加强这一点。(3)我们假设，在 NO产生的背景或慢性损害，血管舒张性增加 对腺苷的敏感性与其基因表达的增加有关 腺苷A2a受体。我们将使用比较工具来检验这一假设 单个冠脉小动脉的RT-PCR分析及A2a 受体上调，其他腺苷信号不变 分子。综上所述，这些研究将提供对 腺苷作为代偿性血管扩张剂的作用及其机制 慢性期间无损伤。这一机制可能有助于 冠脉循环以维持心脏灌注量和避免缺血 在冠状动脉疾病的早期阶段，当NO依赖的扩张 已经妥协了。