Role of circulating ATP and smooth muscle cell hyperpolarization in vascular cont

循环 ATP 和平滑肌细胞超极化在血管持续中的作用

• 批准号: 7875778
• 负责人: FRANK A DINENNO
• 金额: $ 21.52万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875778
• 关键词: Acute; Address; Adenosine; Adenosine Triphosphate; Adrenergic Receptor; Arts; Binding; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Respiration; Chronic; Contracts; Coronary; Data; Endothelium; Erythrocytes; Exercise; Exhibits; Forearm; Functional disorder; Goals; Heart failure; Hemoglobin; Homeostasis; Human; Hypertension; Hypoxia; Individual; Ischemia; Laboratories; Measurement; Mediating; Metabolic; Methods; Muscle; Muscle Contraction; Na(+)-K(+)-Exchanging ATPase; Nitric Oxide; Oxygen; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Physiological Processes; Plasma; Populations at Risk; Potassium Channel; Prostaglandins; Purinoceptor; Regional Blood Flow; Regulation; Research; Rest; Risk; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Smooth Muscle Myocytes; Sympatholytics; Testing; Tissues; Vasodilation; Vasodilator Agents; Venous; barium chloride; base; cerebrovascular; design; diabetic; improved; insight; muscle form; novel; patient population; programs; public health relevance; receptor; response; sensor; theories; vasoconstriction

DESCRIPTION (provided by applicant): The matching of blood flow and oxygen delivery to tissue oxygen demand is one of the most fundamental physiological processes. Recent evidence indicates that the red blood cell can act as a "sensor" and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2y) receptors on the endothelium. In addition to the direct vasodilatory effect, we have recently demonstrated that ATP is also capable of inhibiting sympathetic vasoconstriction ("sympatholytic"), which could further aid in blood flow and oxygen distribution. Our preliminary data indicates that the forearm vasodilator responses to ATP are not due to breakdown to adenosine, and importantly, are independent of nitric oxide and vasodilating prostaglandins. Thus, the overall goal of this exploratory research program is to directly test the hypothesis that endothelium-dependent ATP- mediated vasodilation is due to vascular smooth muscle cell hyperpolarization in humans, and to further test whether the proposed pathways are involved in vascular control in contracting muscle. To test our hypotheses we will address the following specific aims: (1) we will determine whether the forearm vasodilator responses to local intra-arterial administration of ATP are reduced by individual and combined inhibition of inward rectifying potassium channels (KIR; via barium chloride) and Na+/K+ ATPase activity (via oubain); and (2) we will determine whether the forearm vasodilator responses to graded rhythmic handgrip exercise and the ability of muscle contractions to blunt sympathetic 1-adrenergic receptor mediated vasoconstriction are impaired after inhibition of KIR channels and Na+/K+ ATPase activity in humans. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest and during exercise, and measurements of forearm arterial and venous plasma ATP concentrations in young healthy humans. The findings from the proposed studies should provide unique insight into the mechanisms by which circulating ATP causes local vasodilation, and whether the hypothesized signaling pathways evoking hyperpolarization are involved in vascular control in contracting skeletal muscle. Given that impaired endothelium-dependent vasodilation is a hallmark of patients at risk or whom already exhibit cardiovascular disease, and that ATP release from red blood cells of certain patients (e.g. diabetics) is impaired, our findings regarding the mechanisms underlying ATP-mediated vasodilation could have significant implications for understanding impaired local vascular control during physiological (e.g., exercise, hypoxia) and pathophysiological (e.g., coronary and cerebrovascular ischemia) conditions in older healthy and diseased humans. PUBLIC HEALTH RELEVANCE: The studies outlined in this application are designed to address fundamental questions regarding how blood flow and oxygen delivery are controlled to peripheral tissues in humans. Understanding these basic regulatory mechanisms will provide important information that may stimulate ideas on how to improve regional blood flow and oxygen delivery in patient populations at risk for both acute and chronic cardiovascular complications.

描述（由申请人提供）：将血流和氧气递送到组织氧的需求的匹配是最基本的生理过程之一。最近的证据表明，红细胞可以充当“传感器”，并在氧气需求和递送不匹配期间释放ATP，并且该ATP可以在这种情况下通过与嘌呤能（P2Y）受体结合在内皮上的嘌呤能（P2Y）受体来唤起血管舒张并改善局部血流。除了直接的血管舒张作用外，我们最近还证明ATP还能够抑制交感神经血管收缩（“交感神经”），这可以进一步帮助血液流动和氧分布。我们的初步数据表明，前臂血管扩张剂对ATP的反应不是由于对腺苷的崩溃而引起的，重要的是，与一氧化氮和血管舒张前列腺素无关。因此，该探索性研究计划的总体目标是直接检验以下假设：内皮依赖性的ATP介导的血管舒张是由于人类血管平滑肌细胞超极化引起的，并进一步测试所提出的途径是否参与了血管控制中的血管控制。为了检验我们的假设，我们将解决以下特定目的：（1）我们将通过个体和对内向整流钾通道（KIR; KIR;通过钡剂）和Na+/K+ Atpase Attiv（通过OUBAIN（通过OUBAIN）（通过OUBAIN）降低了前臂血管舒张剂对ATP局部局部给药的反应； （2）我们将确定前臂血管舒张器对分级节奏的手夹运动的反应以及在抑制KIR通道和Na+/K+ Atpase的抑制后，肌肉收缩对钝性1-肾上腺素能受体介导的血管收缩的能力是否受到损害。解决这些目标的方法是最先进的，涉及在休息和运动过程中对各种研究药物进行局部（动脉内）给药，以及对年轻健康人的前臂动脉和静脉血浆ATP浓度的测量。提出的研究的发现应提供对循环ATP引起局部血管舒张的机制的独特见解，以及假设的信号通路是否引起超极化的诱发性超极化涉及在收缩骨骼肌中的血管控制。鉴于内皮依赖性血管舒张受损是患者有风险或已经表现出心血管疾病的患者的标志，并且ATP从某些患者的红细胞（例如糖尿病患者）中释放出来，我们对在ATP介导的血管降低的机制中的发现受到了影响，并且在局部血管降低的效果上有明显的效果（可能会在局部效应（均可能），并且在局部施加了影响（均可能在体重上施加效果（均可能受到影响）。老年人和患病人类的病理生理（例如，冠状动脉和脑血管缺血）状况。 公共卫生相关性：本应用程序中概述的研究旨在解决有关如何将血流和氧气输送到人类外周组织控制的基本问题。了解这些基本的调节机制将提供重要的信息，这些信息可能会激发有关如何改善急性和慢性心血管并发症风险的患者人群中的区域血流和氧气递送的想法。