Vascular Function after Exposure of Humans to Hypoxia

人体缺氧后的血管功能

• 批准号: 7096905
• 负责人: JAMES WOODROW WEISS
• 金额: $ 52.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096905
• 关键词: clinical research; epinephrine; human subject; hypoxia; intraarterial administration; nitric oxide; positive pressure breathing; sleep apnea; sympathetic nervous system; vascular resistance; vasoconstriction; vasoconstrictors; vasodilation; vasodilators; vasomotion

DESCRIPTION (provided by applicant): Nocturnal cyclic intermittent hypoxia, such as experienced by patients with obstructive sleep apnea (OSA) is thought to alter vascular tone and function leading to peripheral vasoconstriction and consequent arterial hypertension. Studies in patients indicate that sleep apnea results in diminished reactivity to endogenous vasodilators, and altered sensitivity to some endogenous vasoconstrictors. Furthermore, OSA patients demonstrate an augmented pressor response when exposed to hypoxia and fail to decrease forearm vascular resistance (FVR) when exposed acutely to progressive isocapnic hypoxia as do non-apneic volunteers. Our own preliminary data, collected in normal volunteers and OSA patients, suggests, however, that intermittent hypoxic exposure may lead to vasodilation rather than vasoconstriction. Normal volunteers exposed to intermittent hypoxia for 14 nights have no change in vascular resistance despite increased sympathetic activity and also fail to vasodilate when acutely exposed to isocapnic hypoxia after the repetitive exposure. Based on these and other observations we propose three hypotheses. First, we hypothesize that hypoxic exposure causes either sustained vasodilator release (e.g., epinephrine, NO) that persists during normoxia or altered sympathetic transduction with diminished vasoconstriction (e.g., altered receptor density or transmitter release), or both. Second, we speculate that an acute re-exposure to hypoxia after a prior intermittent exposure results in an abrupt increase in sympathetic nervous system activity but little further increase in vasodilator release, thus resulting in impaired vasodilation. Finally, we hypothesize that maximum vasodilator release declines over time with continued hypoxic exposure, resulting in a gradual increase in arterial pressure. To test these hypotheses we plan a series of investigations in normal volunteers before and after an exposure to cyclic nocturnal hypoxia for 28 nights, and in OSA patients before and after 30 days of monitored therapy with nasal CPAP. These studies will use selective intra-arterial infusions of specific pharmacological agonists and antagonists to assess the roles of endogenous vasodilators and vasoconstrictors in altering vascular tone following an exposure to hypoxia. We anticipate that these studies will significantly enhance our understanding of how intermittent hypoxia and obstructive sleep apnea influence vascular tone and function.

描述（由申请人提供）：夜间周期性间歇性缺氧，例如阻塞性睡眠呼吸暂停（OSA）患者所经历的情况，被认为会改变血管张力和功能，导致外周血管收缩和随之而来的动脉高血压。对患者的研究表明，睡眠呼吸暂停会导致对内源性血管扩张剂的反应性降低，并改变对某些内源性血管收缩剂的敏感性。此外，OSA 患者在暴露于缺氧时表现出增强的升压反应，并且在急性暴露于进行性等二氧化碳缺氧时无法降低前臂血管阻力（FVR），就像非呼吸暂停志愿者一样。然而，我们在正常志愿者和 OSA 患者中收集的初步数据表明，间歇性缺氧可能会导致血管舒张而不是血管收缩。正常志愿者暴露于间歇性缺氧 14 晚，尽管交感神经活动增加，但血管阻力没有变化，并且在重复暴露后急性暴露于等二氧化碳缺氧时，也无法舒张血管。基于这些和其他观察结果，我们提出三个假设。首先，我们假设缺氧会导致在含氧量正常期间持续的血管舒张剂（例如肾上腺素、NO）持续释放，或交感神经转导改变而血管收缩减弱（例如受体密度或递质释放改变），或两者兼而有之。其次，我们推测，在先前的间歇性暴露后，急性再次暴露于缺氧会导致交感神经系统活动突然增加，但血管舒张剂释放几乎没有进一步增加，从而导致血管舒张受损。最后，我们假设随着持续缺氧暴露，最大血管舒张剂释放量随着时间的推移而下降，导致动脉压逐渐升高。为了检验这些假设，我们计划对正常志愿者进行 28 晚周期性夜间缺氧前后以及 OSA 患者进行鼻 CPAP 监测治疗 30 天前后的一系列调查。这些研究将使用特定药理学激动剂和拮抗剂的选择性动脉内输注来评估内源性血管扩张剂和血管收缩剂在缺氧后改变血管张力中的作用。我们预计这些研究将显着增强我们对间歇性缺氧和阻塞性睡眠呼吸暂停如何影响血管张力和功能的理解。