Baby Santhosh M, Tanner Lisa H, Discala Joseph F, Gruber Ryan B, Hsieh Yee-Hsee, Lewis Stephen J
Department of Drug Discovery, Galleon Pharmaceuticals, Inc., Horsham, PA, United States.
Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, United States.
Front Pharmacol. 2022 Feb 9;13:814032. doi: 10.3389/fphar.2022.814032. eCollection 2022.
Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMG) and diaphragmatic (EMG) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1-100 mg/kg) increased EMG without changing EMG in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1-25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.
阻塞性睡眠呼吸暂停（OSA）的特征是睡眠期间咽部反复出现部分/完全塌陷，导致呼吸暂停/低通气，进而引起动脉血氧饱和度下降和觉醒。反复的呼吸暂停/低通气-觉醒发作会导致缺氧/再氧合循环，增加自由基生成和氧化应激，从而导致运动/感觉神经损伤和肌肉损伤。我们假设抗氧化剂可能保护阻塞性睡眠呼吸暂停患者免受氧化应激诱导的损伤和/或使其恢复。为了了解抗氧化剂对呼吸肌的急性保护作用，我们研究了一种可透过细胞膜的超氧化物歧化酶模拟物Tempol对成年异氟烷麻醉的肥胖 Zucker 大鼠（OZR）和年龄匹配的瘦 Zucker 大鼠（LZR）的颏舌肌（肌电图）和膈肌（肌电图）肌电活动、舌下运动神经元（HMN）神经活动以及心肺参数（平均动脉血压、心率）的全身影响。Tempol 剂量依赖性地（1 - 100 mg/kg）增加了 OZR 和 LZR 的肌电图，但未改变其肌电图。Tempol 增加了 OZR 和 LZR 的呼吸频率和潮气量。Tempol（1 - 25 mg/kg）剂量依赖性地增加了健康 Sprague Dawley 大鼠的 HMN 神经活动。Tempol（100 mg/kg）使 OZR 的肌电图输出增加了 189%，使 LZR 的肌电图输出增加了 163%。关于作用机制，在 Sprague Dawley 大鼠双侧 HMN 横断后，Tempol（100 mg/kg）并未增强肌电图。尽管有必要进行进一步研究，但现有数据表明，除了其抗氧化和抗高血压特性外，Tempol 可通过调节 HMN 选择性地增强肌电图，这种作用可能会防止阻塞性睡眠呼吸暂停患者上气道部分和/或完全塌陷发作期间上气道咽部扩张肌的可塌陷性和/或改善其稳定性。
