Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat

Lefebvre, Blandine; Godin‐Ribuot, Diane; Joyeux‐Faure, Marie; Caron, Françoise; Bessard, Germain; Lévy, Patrick; Stanke‐Labesque, Françoise

doi:10.1016/j.resp.2005.05.020

Cited by 47 publications

(51 citation statements)

References 31 publications

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“…This is further supported by our previous finding of increased ET-1-dependent vasoconstriction in mesenteric artery of H-IH-exposed rats (2,56). Also, intermittent hypoxia has been shown by others to increase norepinephrine-dependent vasoconstriction (12,39).…”

Section: Discussionsupporting

confidence: 88%

NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Sleep apnea, defined as intermittent respiratory arrest during sleep, is associated with increased incidence of hypertension and peripheral vascular disease. Exposure of rodents to brief periods of intermittent hypercarbia/hypoxia (H-IH) during sleep mimics the cyclical hypoxia-normoxia of sleep apnea. Endothelin-1, an upstream activator of nuclear factor of activated T cells (NFAT), is increased during H-IH. Therefore, we hypothesized that NFATc3 is activated by H-IH and is required for H-IH-induced hypertension. Consistent with this hypothesis, we found that H-IH (20 brief exposures per hour to 5% O2-5% CO2 for 7 h/day) induces systemic hypertension in mice [mean arterial pressure (MAP) ϭ 97 Ϯ 2 vs. 124 Ϯ 2 mmHg, P Ͻ 0.05, n ϭ 5] and increases NFATc3 transcriptional activity in aorta and mesenteric arteries. Cyclosporin A, an NFAT inhibitor, and genetic ablation of NFATc3 [NFATc3 knockout (KO)] prevented NFAT activation. More importantly, H-IHinduced hypertension was attenuated in cyclosporin A-treated mice and prevented in NFATc3 KO mice. MAP was significantly elevated in wild-type mice (⌬ ϭ 23.5 Ϯ 6.1 mmHg), but not in KO mice (⌬ ϭ Ϫ3.9 Ϯ 5.7). These results indicate that H-IH-induced increases in MAP require NFATc3 and that NFATc3 may contribute to the vascular changes associated with H-IH-induced hypertension.nuclear factor of activated T cells; hypercarbic; mouse; endothelin-1; sleep apnea SLEEP APNEA (SA), defined as intermittent respiratory arrest during sleep, affects up to 20% of the adult population. Among the major consequences of SA are decreased O 2 saturation (hypoxia) and increased CO 2 saturation (hypercapnia). In SA patients, incidence of hypertension, peripheral vascular disease, stroke, and sudden cardiac death is increased (for review see Refs. 21 and 44). Thus SA appears to directly initiate vascular changes that predispose individuals to cardiovascular disease.Recently, it was demonstrated that exposure of rodents to periods of intermittent hypoxia with CO 2 supplementation [intermittent hypercarbia/hypoxia (H-IH)] during sleep mimics the cyclical hypoxia-normoxia of SA. In rats exposed to H-IH, blood pressure (34, 35) and circulating endothelin-1 (ET-1) are elevated (35), vasoconstrictor sensitivity to ET-1 is increased (2), and blood pressure is normalized with ET antagonists (35). These studies, together with clinical studies showing increased circulating ET-1 in SA (10, 55), suggest that augmented ET-1 vasoconstriction contributes to SA hypertension. The sustained increased blood pressure observed in SA patients and animal models also appears to involve activation of the sympathetic nervous and renin-angiotensin systems and diminished activity of nitric oxide synthase (for review see Refs. 44 and 52).ET-1 acts through G␣ q -coupled receptors as a Ca 2ϩ -mobilizing agent and as a potent activator of the nuclear factor of activated T cells (NFAT) (1, 25, 57). ANG II, glucose through UTP release, and ␣ 1 -adrenergic agonists are also potent stimuli of NFAT activation (1,25,27,46,57).NFAT...

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Section: Discussionsupporting

confidence: 88%

NFATc3 is required for intermittent hypoxia-induced hypertension

Garcı́a¹,

Duling²,

Alò³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Starting from the early evidence provided by FLETCHER et al [86] that intermittent hypoxia during night resulted in a daytime increase in blood pressure, there have been many reports on intermittent hypoxia effects, mainly on the cardiovascular system. Vascular reactivity has been shown to be altered in rodents [87][88][89][90]. Many biological and pathophysiological changes have been linked to intermittent hypoxia, i.e.…”

Section: Osa Intermittent Hypoxia and Cardiovascular And Metabolic Cmentioning

confidence: 99%

“…alteration in baroreflex activity [91], increase in pulmonary arterial pressure and haematocrit [92], changes in heart structure and function [93], and an alteration in endothelial dependent vasodilation in cerebral and muscular arteries [94]. In addition, an increased response to endothelin (ET)-1 was also demonstrated [89], presumably almost exclusively mediated by ET-A receptors [95]. We recently confirmed the role of the ET-A receptors, overexpressed in the heart during intermittent hypoxia in spontaneously hypertensive rats and responsible for both an increase in blood pressure (BP) and heart sensitivity, to ischaemia [96].…”

Section: Osa Intermittent Hypoxia and Cardiovascular And Metabolic Cmentioning

confidence: 99%

Sleep apnoea syndrome in 2011: current concepts and future directions

Lévy¹,

Tamisier²,

Minville³

et al. 2011

Eur Respir Rev

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“…Starting with the early evidence provided by FLETCHER et al [51] that night-time CIH results in permanent daytime hypertension, there have been many reports on IH effects, mainly on the cardiovascular system. Vascular reactivity has been shown to be altered in various fashions in rodents [52][53][54][55]. A variety of biological and pathophysiological changes have also been demonstrated, i.e.…”

Section: Cellular and Molecular Consequences Of Ihmentioning

confidence: 99%

“…A variety of biological and pathophysiological changes have also been demonstrated, i.e. altered baroreflex activity [56], increased pulmonary arterial pressure and haematocrit [57], changes in heart structure and function [58], altered endothelium-dependent vasodilation in cerebral and muscular arteries [59], and an increased response to endothelin (ET)-1 [54], presumably mediated almost exclusively by ETA receptors [60]. During IH, both blood pressure (BP) and myocardial changes might be critically dependent upon ET-1.…”

Section: Cellular and Molecular Consequences Of Ihmentioning

confidence: 99%

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives

Lévy¹,

Pépin²,

Arnaud³

et al. 2008

European Respiratory Journal

171

111

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There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), CheyneStokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown.In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials.Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality.Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.

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Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat

Cited by 47 publications

References 31 publications

NFATc3 is required for intermittent hypoxia-induced hypertension

NFATc3 is required for intermittent hypoxia-induced hypertension

Sleep apnoea syndrome in 2011: current concepts and future directions

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives

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