Obstructive sleep apnea: Plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure

Jordan, Wolfgang; Reinbacher, A; Cohrs, Stefan; Grunewald, R. Willi; Mayer, Geert; Rüther, Eckart; Rodenbeck, Andrea

doi:10.1016/j.peptides.2005.02.012

Cited by 49 publications

(32 citation statements)

References 35 publications

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“…Previous reports in these patients have yielded conflicting results [29, 30]. It is likely that the discrepancy between results is in part due to the differences in patient characteristics.…”

Section: Discussionmentioning

confidence: 90%

“…Former studies that have reported elevated ET-1 levels studied severer OSAS [42, 43]. On the other hand, Jordan et al [30] found increased plasma levels of the ET-1 precursor (but not of ET-1 itself), and suggested that, perhaps, cross-reactivity between different forms of endothelins explain the variable results of ET-1 published so far in OSAS.…”

Section: Discussionmentioning

confidence: 99%

“…However, the potential role of the confounding factors mentioned above was not specifically considered. On the other hand, ET-1, a potent vasoconstrictor produced by endothelial cells, has also been implicated in the pathogenesis of endothelial dysfunction and CV disease [27, 28], but studies in patients with OSAS have yielded conflicting results [29, 30]. …”

Section: Introductionmentioning

confidence: 99%

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Increased Plasma Levels of Asymmetric Dimethylarginine and Soluble CD40 Ligand in Patients with Sleep Apnea

Barceló

Peña²,

Ayllón³

et al. 2008

Respiration

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Background: Cardiovascular (CV) diseases are a leading cause of mortality and they are frequent in patients with the obstructive sleep apnea syndrome (OSAS). Objectives: In this study we investigated if OSAS influences CV function independently of other CV risk factors frequently present in these patients (e.g. obesity, high blood pressure). Methods: We compared plasma markers of endothelial dysfunction, asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1), and atherosclerosis progression (soluble fraction of the CD40 ligand, sCD40L) in OSAS patients with (n = 23) and without (n = 18) concurrent CV risk factors, as well as in healthy subjects (n = 23). Results: Plasma ADMA (p < 0.01) and sCD40L (p < 0.05) were abnormally increased in patients with OSAS versus healthy controls, but they were not influenced by the presence or absence of CV risk factors in OSAS. ET-1 levels were not different between the three groups of subjects studied. Conclusions: OSAS is associated with endothelial injury and atherosclerosis progression independently of other CV risk factors.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased Plasma Levels of Asymmetric Dimethylarginine and Soluble CD40 Ligand in Patients with Sleep Apnea

Barceló

Peña²,

Ayllón³

et al. 2008

Respiration

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“…A role for ET-1 in sleep apnea-associated cardiovascular disease is further suggested by increased circulating plasma ET-1 (32,44), which is reversed when apneic episodes are prevented with continuous positive airway pressure (17). Previously, we have shown that in rats with simulated sleep apnea, circulating plasma ET-1 increases in parallel with increases in arterial pressure and that blocking ET-1 receptors lowers MAP in these rats (20).…”

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confidence: 96%

Reactive oxygen species contribute to sleep apnea-induced hypertension in rats

Brindeiro¹,

Silva²,

Allahdadi³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

103

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In clinical studies, sleep apnea is associated with hypertension, oxidative stress, and increased circulating endothelin-1 (ET-1). We previously developed a model of sleep apnea by exposing rats to eucapnic intermittent hypoxia (IH-C) during sleep, which increases both blood pressure and plasma levels of ET-1. Because similar protocols in mice increase tissue and plasma markers of oxidative stress, we hypothesized that IH-C generation of reactive oxygen species (ROS) contributes to the development of ET-1-dependent hypertension in IH-C rats. To test this, male Sprague-Dawley rats were instrumented with indwelling blood pressure telemeters and drank either plain water or water containing the superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, 1 mM). Mean arterial pressure (MAP) and heart rate (HR) were recorded for 3 control days and 14 treatment days with rats exposed 7 h/day to IH-C or air/air cycling (Sham). On day 14, MAP in IH-C rats treated with Tempol (107 ± 2.29 mmHg) was significantly lower than in untreated IH-C rats (118 ± 9 mmHg, P < 0.05). Tempol did not affect blood pressure in sham-operated rats (Tempol = 101 ± 3, water = 101 ± 2 mmHg). Immunoreactive ET-1 was greater in plasma from IH-C rats compared with plasma from shamoperated rats but was not different from Sham in Tempol-treated IH-C rats. Small mesenteric arteries from IH-C rats but not Tempol-treated IH-C rats had increased superoxide levels as measured by ferric cytochrome c reduction, lucigenin signaling, and dihydroethidium fluorescence. The data show that IH-C increases ET-1 production and vascular ROS levels and that scavenging superoxide prevents both. Thus oxidative stress appears to contribute to increases in ET-1 production and elevated arterial pressure in this rat model of sleep apnea-induced hypertension. Keywords Tempol; endothelinThe repeated episodes of cessation of breathing that occur during sleep apnea have been linked to the increased generation of reactive oxygen species (ROS) with an associated increase in cardiovascular morbidity (1). Since it is estimated that up to one in five adults in Western countries suffer from sleep apnea (36), this condition appears to be a significant cause of cardiovascular disease. Several longitudinal studies of sleep apnea patients conclude that the greatest health risk of sleep apnea is the increased incidence of cardiovascular disease (24,42), with the most consistent alteration being increased mean arterial pressure (MAP) (26,30). Thus almost 50% of people suffering from sleep apnea also suffer from hypertension (13), and it is of great relevance to better understand the role of oxidative stress in sleep apnea-associated hypertension.Repeated apneic episodes are reported to increase oxidative stress in sleep apnea patients (16,21), in animal models of sleep apnea (31, 41), and in cultured cells exposed to cyclical hypoxia (43). However, debate continues on the consequences of this elevated oxidative stress. One potential consequence is an incr...

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“…endothelin (ET)-1 (29,42), a potent vasoconstrictor and mitogenic peptide implicated in the development of many forms of arterial hypertension (1). Furthermore, the synthesis of ET-1 is increased by hypoxia, shear stress, oxidative stress, and catecholamines, which are elevated in E-IH-exposed rats and sleep apnea (42,47).…”

mentioning

confidence: 99%

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

Allahdadi

Cherng²,

Pai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Allahdadi KJ, Cherng TW, Pai H, Silva AQ, Walker BR, Nelin LD, Kanagy NL. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia. Am J Physiol Heart Circ Physiol 295: H434-H440, 2008. First published May 30, 2008 doi:10.1152/ajpheart.91477.2007.-We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ETA) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 Ϯ 2 to 137 Ϯ 4 mmHg; P Ͻ 0.005) but did not change in sham-exposed rats. The ETA receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol ⅐ kg Ϫ1 ⅐ day Ϫ1 sc for 14 days) prevented E-IHinduced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ETA receptor antagonist BQ-123 (10 M) but not by the ET type B (ET B) receptor antagonist BQ-788 (100 M). ETA receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ETB receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ETA receptors appears to elevate blood pressure in E-IHexposed rats. sleep apnea; BQ-123; BQ-788; mitochondrial ribonucleic acid OBSTRUCTIVE SLEEP APNEA is characterized by repeated upper airway obstruction during sleep and affects between 5% and 20% of the population (32). This syndrome of sleep-disordered breathing leads to episodic hypoxia and sleep deprivation. Recent epidemiological studies reveal that sleep apnea and other forms of sleep-disordered breathing increase the risk for hypertension and associated metabolic disorders (24). However, the mechanisms whereby sleep apnea and the associated eucapnic intermittent hypoxia (E-IH) cause systemic hypertension remain incompletely understood. Recent studies show that patients with sleep apnea have increased circulating levels of endothelin (ET)-1 (29, 42), a potent vasoconstrictor and mitogenic peptide implicated in the development of many forms of arterial hypertension (1). Furthermore, the synthesis of ET-1 is increased by hypoxia, shear stress, oxidative stress, and catecholamines, which are elevated in E-IH-exposed rats and sleep apnea (42, 47). We have previously described that both blood pressure and plasma ET-1 levels are incre...

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Obstructive sleep apnea: Plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure

Cited by 49 publications

References 35 publications

Increased Plasma Levels of Asymmetric Dimethylarginine and Soluble CD40 Ligand in Patients with Sleep Apnea

Increased Plasma Levels of Asymmetric Dimethylarginine and Soluble CD40 Ligand in Patients with Sleep Apnea

Reactive oxygen species contribute to sleep apnea-induced hypertension in rats

Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

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