Vascular Function after Exposure of Humans to Hypoxia

人体缺氧后的血管功能

• 批准号: 7231011
• 负责人: JAMES WOODROW WEISS
• 金额: $ 49.21万
• 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/7231011
• 关键词: Vascular; Function; after; Exposure; Humans

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）：夜间循环间歇性缺氧，例如，阻塞性睡眠呼吸暂停（OSA）经历会改变血管张力和功能，从而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，并改变了对某些内源性血管收缩剂的敏感性。此外，当暴露于缺氧时，OSA患者表现出增强的压力反应，并且当急性地暴露于进行性等异型性缺氧的情况下，并且与非族裔志愿者一样，前臂血管耐药性（FVR）无法降低。但是，我们自己的初步数据（在正常志愿者和OSA患者中收集）表明，间歇性低氧暴露可能导致血管舒张而不是血管收缩。暴露于间歇性缺氧14晚的正常志愿者尽管交感神经活动增加，但在重复暴露后急性暴露于同含等性缺氧时，血管抵抗力没有变化。基于这些和其他观察结果，我们提出了三个假设。首先，我们假设低氧暴露会导致持续的血管扩张剂释放（例如，肾上腺素，NO），在正态氧气中持续存在，或者在交感神经转导变化时会随着血管收缩减少（例如，受体密度变化或变性剂释放）或两者或两者或两者或两者。其次，我们推测先前间歇性暴露后急性重新暴露于缺氧导致交感神经系统活动的突然增加，但血管舒张释放的释放几乎没有进一步增加，从而导致血管舒张受损。最后，我们假设随着时间的推移，最大血管舒张释放会随着时间的推移而下降，导致动脉压的逐渐增加。为了检验这些假设，我们计划在暴露于环状夜间低氧28晚之前和之后对正常志愿者进行一系列调查，并在使用鼻CPAP进行监测的30天治疗之前和之后的OSA患者中进行了一系列研究。这些研究将使用特定药理激动剂和拮抗剂的动脉内输注来评估内源性血管扩张剂和血管收缩剂在暴露于缺氧后改变血管张力方面的作用。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。