Sympatho-adrenal activation by chronic intermittent hypoxia

Institute for Integrative Physiology and The Center for Systems Biology of Oxygen Sensing, Biological Sciences Division, University of Chicago, Chicago, Illinois.
Journal of Applied Physiology (Impact Factor: 3.06). 06/2012; 113(8):1304-10. DOI: 10.1152/japplphysiol.00444.2012
Source: PubMed

ABSTRACT Recurrent apnea with chronic intermittent hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by hypoxia-inducible factor-1 and -2, respectively.

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Available from: Ganesh K Kumar, Sep 03, 2014
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    • "Treatment of OSA with continuous positive airway pressure (CPAP) abolished increases in muscle sympathetic nerve activity (Narkiewicz et al., 1999; Imadojemu et al., 2007; Somers et al., 1995) and decreased plasma (Heitmann et al., 2004) and urine (Pinto et al., 2013) catecholamine levels. In rodents, IH increased cervical (Greenberg et al., 1999), renal (Huang et al., 2009), splanchnic (Dick et al., 2007), thoracic (Zoccal et al., 2008) and lumbar (Marcus et al., 2010) sympathetic nerve activity (reviewed in (Prabhakar et al., 2012)), enhanced norepinephrine turnover in sympathetic endings (Gonzalez-Martin et al., 2011), and raised plasma epinephrine and norepinephrine levels (Bao et al., 1997a; Kumar et al., 2006). Kumar et al. (2006) showed that exposure to chronic IH increased norepinephrine and epinephrine efflux from the adrenal medulla ex vivo. "
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    ABSTRACT: Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia.
    Respiratory Physiology & Neurobiology 08/2014; 203. DOI:10.1016/j.resp.2014.08.018 · 1.97 Impact Factor
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    • "A link between neurogenic hypertension and an enhanced carotid body chemoreflex has been more extensively studied in patients and in animal models of sleep apnea (Fletcher et al., 1992; Lesske et al., 1997; Fletcher, 2001; Prabhakar et al., 2001, 2005, 2012; Schultz et al., 2007; Simms et al., 2010; Zoccal and Machado, 2011; Costa-Silva et al., 2012; Moraes et al., 2012a,b; Paton et al., 2013). The peripheral chemoreceptor reflex response has been shown to be significantly enhanced in patients with primary hypertension (Trzebski et al., 1982; Tafil-Klawe et al., 1985a,b; Somers et al., 1988a,b; Sinski et al., 2012) and in animal models of systemic hypertension, e.g., SHRs (Fukuda et al., 1987; Simms et al., 2009; Tan et al., 2010). "
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    ABSTRACT: In this review we focus on the role of orexin in cardio-respiratory functions and its potential link to hypertension. (1) Orexin, cardiovascular function, and hypertension. In normal rats, central administration of orexin can induce significant increases in arterial blood pressure (ABP) and sympathetic nerve activity (SNA), which can be blocked by orexin receptor antagonists. In spontaneously hypertensive rats (SHRs), antagonizing orexin receptors can significantly lower blood pressure under anesthetized or conscious conditions. (2) Orexin, respiratory function, and central chemoreception. The prepro-orexin knockout mouse has a significantly attenuated ventilatory CO2 chemoreflex, and in normal rats, central application of orexin stimulates breathing while blocking orexin receptors decreases the ventilatory CO2 chemoreflex. Interestingly, SHRs have a significantly increased ventilatory CO2 chemoreflex relative to normotensive WKY rats and blocking both orexin receptors can normalize this exaggerated response. (3) Orexin, central chemoreception, and hypertension. SHRs have higher ABP and SNA along with an enhanced ventilatory CO2 chemoreflex. Treating SHRs by blocking both orexin receptors with oral administration of an antagonist, almorexant (Almxt), can normalize the CO2 chemoreflex and significantly lower ABP and SNA. We interpret these results to suggest that the orexin system participates in the pathogenesis and maintenance of high blood pressure in SHRs, and the central chemoreflex may be a causal link to the increased SNA and ABP in SHRs. Modulation of the orexin system could be a potential target in treating some forms of hypertension.
    Frontiers in Neuroscience 02/2014; 8(8):22. DOI:10.3389/fnins.2014.00022 · 3.66 Impact Factor
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    • "Vehicle treated IH rats exhibited significantly increased mean blood pressures (Fig. 8A), which was due to significant elevations in systolic and diastolic blood pressures (P<0.01), and was associated with elevated plasma norepinephrine levels, an index of sympathetic activation (Fig. 8B). Adrenal medulla is a major source of catecholamines, and adrenal medullectomy prevents IH-induced hypertension [29]. Therefore, cytosolic and mitochondrial aconitase activity (index of ROS levels), XO activity and HIF-2α protein expressions were determined in adrenal medullae from vehicle and ALLO treated rats exposed to IH. Adrenal medulla from vehicle treated rats exposed to IH exhibited elevated ROS levels as evidenced by decreased cytosolic and mitochondrial aconitase activity, with concomitant increase in XO activity and decreased HIF-2α protein expression (Fig. 8C–E). "
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    ABSTRACT: Sleep-disordered breathing with recurrent apnea produces chronic intermittent hypoxia (IH). We previously reported that IH leads to down-regulation of HIF-2α protein via a calpain-dependent signaling pathway resulting in oxidative stress. In the present study, we delineated the signaling pathways associated with calpain-dependent HIF-2α degradation in cell cultures and rats subjected to chronic IH. Reactive oxygen species (ROS) scavengers prevented HIF-2α degradation by IH and ROS mimetic decreased HIF-2α protein levels in rat pheochromocytoma PC12 cell cultures, suggesting that ROS mediate IH-induced HIF-2α degradation. IH activated xanthine oxidase (XO) by increased proteolytic conversion of xanthine dehydrogenase to XO. ROS generated by XO activated calpains, which contributed to HIF-2α degradation by IH. Calpain-induced HIF-2α degradation involves C-terminus but not the N-terminus of the HIF-2α protein. Pharmacological blockade as well as genetic knock down of XO prevented IH induced calpain activation and HIF-2α degradation in PC12 cells. Systemic administration of allopurinol to rats prevented IH-induced hypertension, oxidative stress and XO activation in adrenal medulla. These results demonstrate that ROS generated by XO activation mediates IH-induced HIF-2α degradation via activation of calpains.
    PLoS ONE 10/2013; 8(10):e75838. DOI:10.1371/journal.pone.0075838 · 3.23 Impact Factor
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