Mechanisms of Metabolic Vasodilation

代谢性血管舒张机制

• 批准号: 6865427
• 负责人: INGRID H SARELIUS
• 金额: $ 35.12万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865427
• 关键词: adenosine; arterioles; biological signal transduction; confocal scanning microscopy; exercise; genetically modified animals; hemodynamics; laboratory mouse; metabolism; microcirculation; muscle contraction; nitric oxide; potassium channel; striated muscles; thapsigargin; vascular endothelium; vasodilation; video microscopy

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.

血流和代谢率的调节在横纹肌中紧密耦合，但是专门使血管活性代谢产生综合小动脉反应的途径仍然难以捉摸。 我们已经确定了内皮细胞（EC）和EC Ca 2+的变化，这对于耐药小动脉中的代谢血管舒张至关重要。 这种扩张涉及KATP通道，一氧化氮和腺苷，但是KATP通道活性与NO和NO和腺苷的作用的关系尚不清楚。 重要的是，NO对这种扩张的贡献在缺血性条件下最为突出，即代谢血管舒张的机制是通过流量来改变的。 这些研究将使用麻醉小鼠的Cremaster肌肉来确定在自由流和缺血条件下这种反应的机制。 插入式共聚焦显微镜将用于量化EC Ca 2+和骨骼肌收缩期间动脉直径的变化。 我们将根据我们的初步发现来检验3个假设。 催眠。 I：在代谢式血管舒张中，生产EC Ca 2+变化需要KATP通道。 催眠。 IL：EC Ca 2+变化对于在所有流动条件下代谢血管舒张至关重要。 这些变化由两个组成部分组成 - 早期增加了细胞内存储的动员，以及取决于细胞外钙源的振荡成分。 催眠。 IIL ：（ A部分）没有内皮起源对在缺血性条件下发生的代谢血管舒张作出重大贡献，但在自由流动过程中反应的重要组成部分远不那么重要。 （B部分）NO来自非层状NNO的NNO也通过直接对SMC的影响和刺激从内皮细胞中的NO释放而导致代谢血管舒张（尤其是在缺血期间）。 这些研究将有助于对局部对生理信号的反应如何整合到血管壁中的一般理解，并将为理解代谢反应对运动的代谢反应的广泛目标做出重大贡献。 对锻炼基本机制的充分理解与人类健康的许多领域有关。