Silverstein Aaron L, Alilain Warren J
Department of Neuroscience, Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, 741 S. Limestone St., Lexington, KY 40508, USA..
Respir Physiol Neurobiol. 2025 Feb-Mar;332:104373. doi: 10.1016/j.resp.2024.104373. Epub 2024 Nov 25.
Obstructive sleep apnea (OSA) is a breathing disorder in which airway obstruction during sleep leads to periodic bouts of inadequate (hypopneic) or absent (apneic) ventilation despite neurorespiratory effort. Repetitive apneic and hypopneic exposures can induce intermittent hypoxemia and lead to a host of maladaptive behavioral and physiological outcomes. Intermittent hypoxia treatment (IH), which consists of alternating exposure to hypoxic and normal air, can induce a long-lasting increase in breathing motor outputs called long term facilitation (LTF). IH models key aspects of the hypoxemia experienced during OSA and LTF might serve to prevent OSA or ameliorate its severity by stimulating ventilatory output during or after apnea/hypopnea. Ethanol consumption prior to sleep exacerbates existing OSA, but it is unknown how ethanol affects LTF expression. Thus, we hypothesized that ethanol treatment would attenuate LTF expression and the magnitude of the ventilatory response during acute hypoxic exposure. We administered either low-dose (0.8 g/kg) or high-dose (3 g/kg) ethanol or saline to adult female Sprague-Dawley rats through intraperitoneal injection and then measured subjects' ventilatory output by whole-body plethysmography during baseline, a 5 by 3-minute moderate IH protocol (hypoxia: FO = 0.11, Normoxia: room air), and for one hour following the end of IH. Results indicate that low-dose ethanol abolishes LTF of respiratory rate and minute ventilation and trends suggest that low-dose ethanol might attenuate respiratory rate and minute ventilation during acute hypoxic exposure. While high-dose ethanol significantly diminished subjects' respiratory rate and minute ventilation during hypoxia, LTF expression was not significantly different between high-dose ethanol and saline-treated subjects. Overall, data indicate that ethanol exposure dramatically attenuates LTF expression following IH treatment and impairs ventilatory responses to hypoxia in a dose-dependent manner. Such findings inspire further consideration of ethanol's negative effects upon endogenous compensatory mechanisms for repeated hypoxic exposure, both in the context of OSA and beyond.
阻塞性睡眠呼吸暂停（OSA）是一种呼吸障碍，睡眠期间气道阻塞会导致尽管有神经呼吸努力，但仍会出现周期性的通气不足（呼吸浅慢）或通气缺失（呼吸暂停）发作。反复的呼吸暂停和呼吸浅慢发作可诱发间歇性低氧血症，并导致一系列适应不良的行为和生理后果。间歇性低氧治疗（IH），即交替暴露于低氧和正常空气中，可诱导呼吸运动输出的持久增加，称为长期易化（LTF）。IH模拟了OSA期间经历的低氧血症的关键方面，LTF可能通过在呼吸暂停/呼吸浅慢期间或之后刺激通气输出，起到预防OSA或减轻其严重程度的作用。睡前饮酒会加重现有的OSA，但乙醇如何影响LTF表达尚不清楚。因此，我们假设乙醇治疗会减弱LTF表达以及急性低氧暴露期间的通气反应幅度。我们通过腹腔注射给成年雌性Sprague-Dawley大鼠给予低剂量（0.8 g/kg）或高剂量（3 g/kg）乙醇或生理盐水，然后在基线、5次3分钟的中度IH方案（低氧：FO = 0.11，常氧：室内空气）期间以及IH结束后1小时，通过全身体积描记法测量受试者的通气输出。结果表明，低剂量乙醇消除了呼吸频率和分钟通气量的LTF，趋势表明低剂量乙醇可能会在急性低氧暴露期间减弱呼吸频率和分钟通气量。虽然高剂量乙醇在低氧期间显著降低了受试者的呼吸频率和分钟通气量，但高剂量乙醇组和生理盐水处理组之间的LTF表达没有显著差异。总体而言，数据表明乙醇暴露在IH治疗后会显著减弱LTF表达，并以剂量依赖的方式损害对低氧的通气反应。这些发现促使人们进一步考虑乙醇对反复低氧暴露的内源性代偿机制的负面影响，无论是在OSA背景下还是其他情况。
