Noah Jouett

Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.

What is the central question of this study? The central question of this study was to investigate the interaction of mild exposures to O2 and CO2 on chemoreflex control of SNA and the modulation of lung volume and respiratory phase on this interaction. What is the main finding and its importance? We demonstrate that the synergistic interaction of oxygen‐ and carbon dioxide‐chemosensitive control of the sympathetic nervous system with hypoxia and hypercapnia exists at very mild excitatory stimuli, is significantly overridden by lung inflation and does not extend to inhibitory modulation by hypocapnia in healthy subjects. These findings demonstrate the important inhibitory modulation of sympathetic nerve activity by lung inflation mechanisms in healthy individuals even in the presence of strong sympathoexcitatory stimuli.

Systolic pressure response to voluntary apnea predicts sympathetic tone in obstructive sleep apnea as a clinically useful index.

The present investigation tested the hypotheses that systolic arterial pressure (SAP) responses to voluntary apnea (a) serve as a surrogate of sympathetic nerve activity (SNA), (b) can distinguish Obstructive Sleep Apnea (OSA) patients from control subjects and (c) can document autonomic effects of treatment. 9 OSA and 10 control subjects were recruited in a laboratory study; 44 OSA subjects and 78 control subjects were recruited in a clinical study; and 21 untreated OSA subjects and 14 well-treated OSA subjects were recruited into a treatment study. Each subject performed hypoxic and room air voluntary apneas in triplicate. Muscle SNA (MSNA) and continuous AP were measured during each apnea in the laboratory study, while systolic arterial pressure (SAP) responses were measured continuously and by standard auscultation in the clinical and treatment studies. OSA subjects exhibited increased mean arterial pressure (MAP), SAP and MSNA responses to hypoxic apnea (all P<0.01) and the SAP response highly correlated with the MSNA response (R(2)=0.72, P<0.001). Clinical assessment confirmed that OSA subjects exhibited markedly elevated SAP responses (P<0.01), while treated OSA subjects had a decreased SAP response to apnea (P<0.04) compared to poorly treated subjects. These data indicate that (a) OSA subjects exhibit increased pressor and MSNA responses to apnea, and that (b) voluntary apnea may be a clinically useful assessment tool of autonomic dysregulation and treatment efficacy in OSA.

Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise‐induced increases in muscle sympathetic nerve activity

The arterial baroreflexs operating point pressure is reset upwards and rightwards from rest in direct relation to the increases in dynamic exercise intensity. The intraneural pathways and signalling mechanisms that lead to upwards and rightwards resetting of the operating point pressure, and hence the increases in central sympathetic outflow during exercise, remain to be identified. We tested the hypothesis that the central production of angiotensin II during dynamic exercise mediates the increases in sympathetic outflow and, therefore, the arterial baroreflex operating point pressure resetting during acute and prolonged dynamic exercise. The results identify that perindopril, a centrally acting angiotensin converting enzyme inhibitor, markedly attenuates the central sympathetic outflow during acute and prolonged dynamic exercise.

Losartan reduces the immediate and sustained increases in muscle sympathetic nerve activity after hyperacute intermittent hypoxia

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 1) SNA discharge and 2) 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 P < 0.01) and MAP (baseline: 89.2 ± 3.3, IHT: 92.62 ± 3.1, post-IHT: 93.83 ± 3.1 mmHg, all P < 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 P < 0.001) and MAP (baseline: 81.9 ± 2.6, IHT: 81.1 ± 2.8, post-IHT: 81.3 ± 3.0 mmHg, all P > 0.70). This investigation confirms the role of angiotensin II type 1a receptors in the immediate and persistent sympathoexcitatory and pressor responses to IHT.NEW & NOTEWORTHY 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.

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects

What is the central question of this study? This study evaluated the following central question: does N‐acetylcysteine (N‐AC), an antioxidant that readily penetrates the blood–brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N‐AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N‐AC, have therapeutic potential in obstructive sleep apnoea.

Rapid‐eye‐movement sleep‐predominant central sleep apnea relieved by positive airway pressure: a case report

Central Sleep Apnea (CSA) is characterized by intermittent apneas and hypopneas during sleep that result from absent central respiratory drive. CSA occurs almost exclusively during non‐rapid‐eye‐movement (NREM) sleep due to enhanced neuronal ventilatory drive during REM sleep that makes central apneas highly unlikely to form. A 45‐year‐old obese African American female presented with co‐existing Obstructive Sleep Apnea (OSA) and CSA, not in the form of mixed or complex sleep apnea. Peculiarly, her CSA occurred only during rapid‐eye‐movement (REM) sleep, which is exceedingly rare. The patients CSA was resolved when appropriate positive airway pressure (PAP) was prescribed. Our patient remains stable and has reported significant benefit from PAP usage. We offer possible neuro‐physiological mechanisms herein, including enhanced loop gain and/or malfunction or malformation of the pre‐Botzinger nucleus or other neurological process, that could explain the unique findings of this case.