The Dynamics of Nitric Oxide in the Vascular System

一氧化氮在血管系统中的动态

• 批准号: 7070634
• 负责人: Jack R Lancaster
• 金额: $ 29.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7070634
• 关键词: blood vessels; cell wall; electrodes; erythrocytes; fluorescence spectrometry; human tissue; intermolecular interaction; laboratory rat; nitric oxide; oxygen tension; oxygen transport; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasodilation

DESCRIPTION (provided by applicant): Although the endothelium-derived relaxing factor (EDRF) is generally acknowledged to be nitric oxide (including the Nobel committee, 1998), there is much uncertainty regarding the exact molecular identity of EDRF, specifically, whether it is free NO or a related nitrogen oxide species. Much of the reason for this uncertainty is due to the general perception that the dynamics of free NO are not suitable for its role as EDRF, specifically, that it is too short-lived. In this proposal, we will specifically examine this important issue, namely, we will identify and quantify the processes which determine the dynamics of NO in the vascular system. Our three Specific Aims are organized according to the three compartments involved: the vascular lumen, wall, ablumen. In Specific Aim I we will address the dynamics of NO in the lumen. Specifically, we hypothesize that the major process which defines NO dynamics in this compartment is the irreversible consumption of NO by oxyhemoglobin within the erythrocyte. Even though this represents the major sink for NO in vivo, this process is slow enough that free NO can still function as EDRF; we will delineate the origin for this retardation, which is due to encapsulation of oxyhemoglobin within the erythrocyte. We will also examine the kinetic competence of the formation of nitrosothiol-hemoglobin as a possible carrier of NO. In Specific Aim II we will test whether it is free NO which is the direct effector of vascular relaxation in the vessel wall. We will address this by testing the hypothesis that if it is free NO which is the messenger between the endothelial cell and the smooth muscle cell, then relaxation under a variety of conditions should directly correlate with the concentration of free NO (which we will measure directly with NO-specific electrodes). In Specific Aim III we will address the lifetime of NO in the perivascular region surrounding a vessel, and test whether in addition to causing vasodilation a second role for NO is to extend the distance that oxygen diffuses away from the vessel.

描述（由申请人提供）：虽然内皮源性舒张因子（EDRF）通常被认为是一氧化氮（包括诺贝尔委员会，1998），但关于 EDRF 的确切分子身份存在很多不确定性，特别是它是否是一氧化氮。游离 NO 或相关的氮氧化物。 造成这种不确定性的大部分原因是由于人们普遍认为游离 NO 的动力学不适合其作为 EDRF 的作用，特别是它的寿命太短。 在本提案中，我们将专门研究这个重要问题，即我们将识别和量化决定血管系统中 NO 动态的过程。 我们的三个具体目标是根据所涉及的三个隔室来组织的：血管腔、血管壁、血管壁。 在特定目标 I 中，我们将讨论管腔中 NO 的动态。 具体来说，我们假设定义该区室中 NO 动态的主要过程是红细胞内氧合血红蛋白对 NO 的不可逆消耗。 尽管这代表了体内 NO 的主要汇，但这个过程足够慢，游离 NO 仍然可以起到 EDRF 的作用；我们将描述这种迟缓的根源，这是由于红细胞内氧合血红蛋白的封装所致。 我们还将检查亚硝基硫醇血红蛋白作为可能的 NO 载体形成的动力学能力。 在Specific Aim II中，我们将测试它是否是游离NO，它是血管壁中血管舒张的直接效应物。 我们将通过测试以下假设来解决这个问题：如果内皮细胞和平滑肌细胞之间的信使是游离一氧化氮，那么各种条件下的松弛应与游离一氧化氮的浓度直接相关（我们将直接测量游离一氧化氮的浓度）使用 NO 特异性电极）。 在特定目标 III 中，我们将解决血管周围血管周围区域中 NO 的寿命，并测试除了引起血管舒张之外，NO 的第二个作用是否是延长氧气从血管扩散的距离。