Jouett Noah P, Moralez Gilbert, Raven Peter B, Smith Michael L
Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas; and
Institute for Environmental and Exercise Medicine, Texas Health Presbyterian Hospital, University of Texas Southwestern Medical Center, Dallas, Texas.
J Appl Physiol (1985). 2017 Apr 1;122(4):884-892. doi: 10.1152/japplphysiol.00683.2016. Epub 2017 Jan 12.
Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, which produces elevations in sympathetic nerve activity (SNA) and associated hypertension in experimental models that persist beyond the initial exposure. We tested the hypotheses that angiotensin receptor blockade in humans using losartan attenuates the immediate and immediately persistent increases in ) SNA discharge and ) mean arterial pressure (MAP) after hyperacute intermittent hypoxia training (IHT) using a randomized, placebo-controlled, repeated-measures experimental design. We measured ECG and photoplethysmographic arterial pressure in nine healthy human subjects, while muscle SNA (MSNA) was recorded in seven subjects using microneurography. Subjects were exposed to a series of hypoxic apneas in which they inhaled two to three breaths of nitrogen, followed by a 20-s apnea and 40 s of room air breathing every minute for 20 min. Hyperacute IHT produced substantial and persistent elevations in MSNA burst frequency (baseline: 15.3 ± 1.8, IHT: 24 ± 1.5, post-IHT 20.0 ± 1.3 bursts/min, all < 0.01) and MAP (baseline: 89.2 ± 3.3, IHT: 92.62 ± 3.1, post-IHT: 93.83 ± 3.1 mmHg, all < 0.02). Losartan attenuated the immediate and sustained increases in MSNA (baseline: 17.3 ± 2.5, IHT: 18.6 ± 2.2, post-IHT 20.0 ± 1.3 bursts/min, all < 0.001) and MAP (baseline: 81.9 ± 2.6, IHT: 81.1 ± 2.8, post-IHT: 81.3 ± 3.0 mmHg, all > 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT. This study demonstrates for the first time in humans that losartan, an angiotensin receptor blocker (ARB), abrogates the acute and immediately persistent increases in muscle sympathetic nerve activity and arterial pressure in response to acute intermittent hypoxia. This investigation, along with others, provides important beginning translational evidence for using ARBs in treatment of the intermittent hypoxia observed in obstructive sleep apnea patients.
阻塞性睡眠呼吸暂停（OSA）的特征是间歇性低氧血症，在实验模型中，这会导致交感神经活动（SNA）升高以及相关的高血压，且这种情况在初始暴露后仍会持续。我们采用随机、安慰剂对照、重复测量的实验设计，检验了以下假设：在人类中使用氯沙坦进行血管紧张素受体阻断，可减弱超急性间歇性低氧训练（IHT）后SNA放电和平均动脉压（MAP）的即时及持续升高。我们测量了9名健康人类受试者的心电图和光电容积描记法动脉压，同时使用微神经ography记录了7名受试者的肌肉SNA（MSNA）。受试者暴露于一系列低氧呼吸暂停中，他们每分钟吸入两到三口气氮气，随后是20秒的呼吸暂停和40秒的室内空气呼吸，持续20分钟。超急性IHT导致MSNA爆发频率大幅且持续升高（基线：15.3±1.8，IHT：24±1.5，IHT后20.0±1.3次/分钟，均<0.01）以及MAP升高（基线：89.2±3.3，IHT：92.62±3.1，IHT后：93.83±3.1 mmHg，均<0.02）。氯沙坦减弱了MSNA的即时和持续升高（基线：17.3±2.5，IHT：18.6±2.2，IHT后20.0±1.3次/分钟，均<0.001）以及MAP的升高（基线：81.9±2.6，IHT：81.1±2.8，IHT后：81.3±3.0 mmHg，均>0.70）。这项研究证实了1a型血管紧张素受体在对IHT的即时和持续交感兴奋及升压反应中的作用。本研究首次在人类中表明，血管紧张素受体阻滞剂（ARB）氯沙坦可消除急性间歇性低氧引起的肌肉交感神经活动和动脉压的急性及持续升高。这项研究以及其他研究为使用ARB治疗阻塞性睡眠呼吸暂停患者中观察到的间歇性低氧提供了重要的初步转化证据。
