Mechanisms of Metabolic Vasodilation

代谢性血管舒张机制

• 批准号: 7191656
• 负责人: INGRID H SARELIUS
• 金额: $ 29.87万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191656
• 关键词: Address; Adenosine; Agonist; Animals; Area; Arginine; Blood Vessels; Blood flow; Calcium; Caliber; Cells; Characteristics; Communication; Condition; Confocal Microscopy; Contracts; Coupled; Coupling; Electrodes; Endothelial Cells; Exercise; Goals; Health; Human; Ischemia; Knockout Mice; Literature; Metabolic; Minor; Modeling; Mus; Muscle Contraction; Nitric Oxide; Pathway interactions; Perfusion; Physiological; Preparation; Production; Prostaglandins; Protocols documentation; Rate; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Smooth Muscle Myocytes; Source; Striated Muscles; Testing; Thapsigargin; Tissues; Vasodilation; Vasodilator Agents; Work; arteriole; base; cremaster muscle; extracellular; latent nuclear antigen; paracrine; response

Regulation of blood flow and metabolic rate are closely coupled in striated muscle, but the pathways that specifically enable vasoactive metabolites to produce integrated arteriolar responses remain elusive. We have identified endothelial cells (EC), and EC Ca 2+ changes, as essential for metabolic vasodilation in resistance arterioles. This dilation involves, KATP channels, nitric oxide and adenosine, but how KATP channel activity relates to the actions of NO and adenosine is not clear. Importantly, the contribution of NO to this dilation is most prominent in ischemic conditions, i.e. mechanisms of metabolic vasodilation are modified by flow. The studies will use cremaster muscle of anesthetised mice to determine the mechanisms of this response in free flow and ischemic conditions. Intravital confocal microscopy will be used to quantify EC Ca 2+ and arteriolar diameter changes during skeletal muscle contraction. We will test 3 hypotheses that are based on our preliminary findings. Hyp. I: In metabofic vasodilation, KATP channels are required for the production of EC Ca 2+ changes. Hyp. Il: EC Ca 2+ changes are essential for metabolic vasodilation in all flow conditions. These changes consist of two components - an early increase mobilised from intracellular stores, and an oscillatory component dependent on extracellular calcium sources. Hyp. IIl: (Part A) NO of endothelial origin contributes significantly to the metabolic vasodilation that occurs during ischemic conditions, but is a much less important component of the response during free flow. (Part B) NO from non-endothelially located nNOS also contributes to metabofic vasodilation (particularly during ischemia) both by a direct effect on SMCs and by stimulating release of NO from endothelial cells. The studies will contribute to the general understanding of how local responses to physiological signals are integrated in blood vessel walls, and will contribute significantly to the broad goal of understanding the metabolic response to exercise. A full understanding of the mechanisms underlying exercise is relevant to many areas of human health.

在横纹肌中，血流量和代谢率的调节是密切相关的，但具体使血管活性代谢物产生综合小动脉反应的途径仍然难以捉摸。我们已经确定内皮细胞（EC）和EC ca2 +的变化，是抵抗性小动脉代谢血管舒张的必要条件。这种扩张涉及到KATP通道、一氧化氮和腺苷，但KATP通道活性如何与NO和腺苷的作用相关尚不清楚。重要的是，一氧化氮对这种扩张的贡献在缺血条件下最为突出，即代谢血管舒张的机制被血流改变。该研究将使用麻醉小鼠的肌肌来确定这种反应在自由流动和缺血条件下的机制。活体共聚焦显微镜将用于量化EC ca2 +和骨骼肌收缩期间小动脉直径的变化。我们将测试基于我们初步发现的3个假设。hypp . I：在代谢性血管扩张中，KATP通道是产生EC ca2 +变化所必需的。Hyp. Il: EC ca2 +的变化对所有血流条件下的代谢性血管舒张是必不可少的。这些变化包括两个组成部分-细胞内储存的早期增加和依赖于细胞外钙源的振荡成分。Hyp. il:（A部分）内皮细胞来源的NO对缺血性条件下发生的代谢性血管舒张有重要贡献，但在自由血流反应中则不太重要。（B部分）来自非内皮细胞nNOS的NO也有助于代谢性血管舒张（特别是在缺血期间），这是通过直接作用于SMCs和刺激内皮细胞释放NO来实现的。这些研究将有助于了解局部对生理信号的反应如何整合到血管壁中，并将对理解运动代谢反应的广泛目标做出重大贡献。充分了解运动背后的机制与人类健康的许多领域有关。