Sympathetic Chemoreflex Responses in Obstructive Sleep Apnea and Effects of Continuous Positive Airway Pressure Therapy

Imadojemu, Virginia A.; Mawji, Zubina; Kunselman, Allen R.; Gray, Kristen S.; Hogeman, Cynthia S.; Leuenberger, Urs A.

doi:10.1378/chest.06-2580

Cited by 135 publications

(112 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several studies have found autonomic abnormalities in OSA that are attenuated with CPAP therapy. 57,65 During sleep in OSA, intermittent hypoxia and recurrent arousals stimulate sympathetic responses by mechanisms that include chemoreflex and baroreflex changes, vasoconstrictor effects of nocturnal endothelin release and endothelial dysfunction. 66,67 Sympathetic activation increases hepatic glycogenolysis and gluconeogenesis.…”

Section: Compromised Metabolism Insulin Resistance and Type 2 Diabetesmentioning

confidence: 99%

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

Seetho

Wilding

2014

Chron Respir Dis

View full text Add to dashboard Cite

Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss.

show abstract

Section: Compromised Metabolism Insulin Resistance and Type 2 Diabetesmentioning

confidence: 99%

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

Seetho

Wilding

2014

Chron Respir Dis

View full text Add to dashboard Cite

show abstract

“…Physiological stressors such as exercise, the cold pressor test, and hypoxia elicit robust increases in MSNA (5,7,15,22,53). Resting levels of MSNA have been shown to be elevated with chronic disease (14,17,23,24,28), and decreases in basal MSNA have been shown following medical therapy (50). Studies have reported an exaggerated MSNA response to physiological stress such as isometric exercise (30) and hypoxia (17) in chronic disease compared with healthy controls.…”

Section: Cihr Author Manuscriptmentioning

confidence: 99%

Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing

DeBeck

Petersen

Jones

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Previous research has suggested a relationship between low-frequency power of heart rate variability (HRV; LF in normalized units, LFnu) and muscle sympathetic nerve activity (MSNA). However, investigations have not systematically controlled for breathing, which can modulate both HRV and MSNA. Accordingly, the aims of this experiment were to investigate the possibility of parallel responses in MSNA and HRV (LFnu) to selected acute stressors and the effect of controlled breathing. After data were obtained at rest, 12 healthy males (28 ± 5 yr) performed isometric handgrip exercise (30% maximal voluntary contraction) and the cold pressor test in random order, and were then exposed to hypoxia (inspired fraction of O 2 = 0.105) for 7 min, during randomly assigned spontaneous and controlled breathing conditions (20 breaths/min, constant tidal volume, isocapnic). MSNA was recorded from the peroneal nerve, whereas HRV was calculated from ECG. At rest, controlled breathing did not alter MSNA but decreased LFnu (P < 0.05 for all) relative to spontaneous breathing. MSNA increased in response to all stressors regardless of breathing. LFnu increased with exercise during both breathing conditions. During cold pressor, LFnu decreased when breathing was spontaneous, whereas in the controlled breathing condition, LFnu was unchanged from baseline. Hypoxia elicited increases in LFnu when breathing was controlled, but not during spontaneous breathing. The parallel changes observed during exercise and controlled breathing during hypoxia suggest that LFnu may be an indication of sympathetic outflow in select conditions. However, since MSNA and LFnu did not change in parallel with all stressors, a cautious approach to the use of LFnu as a marker of sympathetic activity is warranted. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptconsidered the gold-standard measurement of global sympathetic outflow to skeletal muscle (51). Physiological stressors such as exercise, the cold pressor test, and hypoxia elicit robust increases in MSNA (5,7,15,22,53). Resting levels of MSNA have been shown to be elevated with chronic disease (14,17,23,24,28), and decreases in basal MSNA have been shown following medical therapy (50). Studies have reported an exaggerated MSNA response to physiological stress such as isometric exercise (30) and hypoxia (17) in chronic disease compared with healthy controls. In contrast, patients display an MSNA response similar to that of healthy individuals to the cold pressor test (17,29). Importantly, because of the invasiveness and technical complexity associated with this technique, microneurography is generally not practical for repeated measurements or large clinical studies.Heart rate variability (HRV) uses the changes of beat-to-beat heart rate to assess autonomic control of the heart (1). Mathematical transformations of the time between each beat are used in a variety of clinical settings, including risk stratification in cardiac patients and assessment of diabetic neuropathy (47a). Spe...

show abstract

“…Our study is first to demonstrate that an increase in cardiorespiratory sensitivity to hypoxia after AIH is mediated by orexin-A. Enhanced chemoreflex sensitivity is pathogenic to neurogenic hypertension in obstructive sleep apnea (Leuenberger et al, 2005;Imadojemu et al, 2007;Xing and Pilowsky, 2010;Paton et al, 2013). Repetitive hypoxia causes a cumulative elevation in chemoreflexmediated sympathoexcitatory response, gradually increasing the excitatory response for every succeeding stimulus during AIH or chronic intermittent hypoxia.…”

Section: Discussionmentioning

confidence: 64%

“…Prolongation of intermittent hypoxia from an acute to a chronic intermittent hypoxia protocol (intermittent hypoxia for days or weeks) severely exacerbates sympathetic activity, eventually leading to the development of neurogenic hypertension over time in animals (Fletcher et al, 1992a,b;Xing and Pilowsky, 2010) and humans (Caples et al, 2005). Second, AIH and chronic intermittent hypoxia also cause a gradual increase in peripheral chemoreceptor sensitivity to hypoxia (Poon and Siniaia, 2000), another pathophysiologic feature in neurogenic hypertension (Cutler et al, 2004a,b;Leuenberger et al, 2005;Imadojemu et al, 2007). It is now widely accepted that mechanistic understanding of the molecular targets that attenuate or block sympathetic hyperactivity is vital for preventing cardiovascular complications from sympathetic long-term facilitation.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Kim

Pilowsky

Farnham

2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n 5 58). A spinally infused subthreshold dose of orexin-A (intermittent; 10 pmol Â 10) produced long-term enhancement in SNA (41.4% 6 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (100 pmol; 7.3% 6 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% 6 4.5% for Almorexant at 30 mg•kg 21 and 18.5% 6 1.2% for 75 mg•kg 21), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.

show abstract

Sympathetic Chemoreflex Responses in Obstructive Sleep Apnea and Effects of Continuous Positive Airway Pressure Therapy

Cited by 135 publications

References 39 publications

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Contact Info

Product

Resources

About