Vascular Role of Carbon Monoxide during Chronic Hypoxia

一氧化碳在慢性缺氧期间的血管作用

基本信息

批准号：
6396615
负责人：
BENJIMEN R WALKER
金额：
$ 30万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6396615
关键词：
arterioles carbon monoxide environmental adaptation enzyme activity heme oxygenase hypoxia laboratory rat vasoconstriction

项目摘要

DESCRIPTION (provided by the applicant): Recent studies suggest that chronic exposure to hypoxia causes a persistent attenuation of systemic vasoconstrictor reactivity that is not reversed upon re-exposure to normoxia. This alteration in vascular control may be responsible for the impaired ability of patients with lung disease associated with chronic hypoxia (CH) to respond adequately to cardiovascular stress. Recent work from our laboratory demonstrates that the vascular expression of heme oxygenase (HO) may be elevated following CR, with resultant enhanced production of the vasodilator carbon monoxide (CO). Several additional pilot studies strongly suggest that endogenous CO may be responsible for attenuated vasoconstrictor reactivity and may be an important component of vascular regulation under these clinically relevant conditions. Experiments planned for this proposal will validate the physiological significance of the HO/CO system as a regulator of vascular tone during CH. Thus, this proposal has the following specific aims: Specific Aim #1-Establish the time course and oxygen threshold for chronic hypoxia-induced attenuation of systemic vasoconstrictor reactivity. Specific Aim #2-Determine the functional differences that account for diminished constrictor reactivity in arterioles from chronically hypoxic rats compared to controls. Specific Aim #3-Demonstrate that in vivo attenuation of systemic vasoconstrictor reactivity following chronic hypoxia involves enhanced release of a heme oxygenase product. Specific Aim #4-Assess the vascular expression and activity of heme oxygenase in tissue from control and chronically hypoxic rats. Specific Aim #5-Establish the mechanisms by which endogenous CO diminishes constrictor responsiveness in arterioles from chronically hypoxic rats. The proposed experiments utilize a variety of in vivo and in vitro approaches to examine questions central to the regulation of the systemic circulation by a novel vasodilatory pathway under clinically relevant conditions.

描述（由申请人提供）：最近的研究表明，慢性暴露于缺氧会导致全身血管收缩持续减弱重新暴露于含氧量正常时，反应性不会逆转。此次改动血管控制可能是导致患者能力受损的原因患有与慢性缺氧（CH）相关的肺部疾病，以充分应对心血管压力。我们实验室最近的工作表明 CR 后血红素加氧酶 (HO) 的血管表达可能升高，从而增加血管舒张剂一氧化碳（CO）的产生。一些其他试点研究强烈表明内源性二氧化碳可能是造成这种情况的原因用于减弱血管收缩反应性，可能是这些临床相关条件下的血管调节。实验该提案计划将验证的生理意义 H2O/CO 系统作为 CH 期间血管张力的调节器。因此，该提案具有具体目标如下：具体目标#1——确定慢性病的时程和氧阈缺氧引起的全身血管收缩反应性减弱。具体目标#2——确定造成的功能差异慢性缺氧大鼠小动脉收缩反应性减弱与对照相比。具体目标#3-证明全身性的体内衰减慢性缺氧后的血管收缩反应涉及增强的释放血红素加氧酶产物。具体目标#4-评估血红素加氧酶的血管表达和活性对照大鼠和长期缺氧大鼠的组织中。具体目标#5——建立减少内源二氧化碳的机制慢性缺氧大鼠小动脉的收缩反应。所提出的实验利用了多种体内和体外方法研究与系统循环调节有关的核心问题临床相关条件下的新型血管舒张途径。