N‐Acetyl Cysteine Reduces Sympathetic Activation during Acute Intermittent Hypoxia in Healthy Human Subjects: Implications for Obstructive Sleep Apnea

Abstract

The intermittent apneas and hypopneas that occur in Obstructive Sleep Apnea (OSA) patients result in dysregulated chemoreflex control of sympathetic nerve activity (SNA) and contribute to the enhanced cardiovascular disease risk in these patients. Developing novel pharmacological therapies to manage the cardiovascular disease burden of OSA patients would provide significant public health benefit. Prior studies in animal models of OSA have demonstrated that reactive oxygen species (ROS) generated at the peripheral chemoreceptors and in the brainstem results in an exaggerated SNA in response to intermittent hypoxia. This investigation tested the hypotheses that: (a) N‐Acetyl Cysteine (N‐AC) attenuates acute intermittent hypoxia induced sympathoexcitation; by (b) suppressing ROS measured in peripheral venous blood. 28 healthy human subjects were recruited. One hour prior to experimentation, each subject randomly ingested either 70 mg·kg−1 of N‐Acetyl Cysteine (N‐AC, n=16) or vehicle placebo (PL, n=12). Subjects underwent a 20 minute intermittent hypoxia training (IHT) protocol consisting of cyclical end‐expiratory apneas with 100% N2. Three lead electrocardiogram (ECG) and arterial blood pressure (ABP), muscle sympathetic nerve activity (MSNA, n=19) and ROS derived from antecubital venous whole blood using electron paramagnetic resonance (EPR, n=18) spectroscopy were measured. N‐AC decreased MSNA burst frequency during IHT compared to PL (PL 24 ± 2 bursts/min vs. N‐AC: 18 ± 2 bursts/min, P = 0.01) and burst incidence (PL: 35 ± 2 bursts/100HB vs. N‐AC: 25 ± 2 bursts/100HB, P = 0.003). However, N‐AC did not alter EPR spectrum amplitude during IHT compared to placebo (PL: 2.2 × 105 ± 0.6 × 105arbitrary units (AU) vs. N‐AC: 2.7 × 105 ± 0.6 × 105 AU, P = 0.49) in venous blood. Moreover, IHT did not increase ROS concentrations in the peripheral circulation as measured by EPR (P > 0.91). The (a) lack of effect for N‐AC on EPR amplitude and (b) lack of an increase in ROS after IHT are probably indicative of little ROS blood‐brain barrier penetrability/spillover and/or extremely short chemical half‐life of ROS. These data indicate that N‐AC reduces MSNA in response to IHT either centrally by interacting with the central nervous system or peripherally by reducing afferent sensory activity emanating from the peripheral chemoreceptors. This investigation opens the possibility to develop antioxidant‐based pharmacotherapeutics to inhibit the sympathoexcitation associated with OSA and improve the cardiovascular disease burden in this patient population.Support or Funding InformationNational Institute of General Medical Sciences, Grant# P30GM103335National Heart Lung and Blood Institute, Grant #HL106431