Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats

Dopp, John M.; Philippi, Nathan R.; Marcus, Noah J.; Olson, E. B.; Bird, Cynthia E.; Moran, John J.; Mueller, Scott W.; Morgan, Barbara J.

doi:10.1159/000329341

Cited by 55 publications

(39 citation statements)

References 113 publications

(96 reference statements)

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“…These doses of allopurinol and losartan were shown in previous studies to reduce urinary uric acid excretion and block the arterial pressure rise caused by angiotensin II infusion (Dopp et al, 2011; Marcus et al, 2012). Because of the limited solubility of allopurinol in water, the daily doses of allopurinol and the allopurinol plus losartan combination were prepared as 1% w/v methylcellulose suspensions and given by oral gavage.…”

Section: Methodsmentioning

confidence: 93%

“…Multiple studies using blockers of ROS formation and ROS scavengers have demonstrated a crucial role for ROS in CIH-induced alterations in vascular function, blood pressure, carotid body sensory activity, and chemoreflex control of ventilation (Del Rio et al, 2010; Dopp et al, 2011; Lim et al, 2014; Marcus et al, 2010; Marcus et al, 2012; Peng et al, 2013; Peng et al, 2009; Peng and Prabhakar, 2003). The present study demonstrates, in the intact unanesthetized rat, that oxidative stress plays a crucial role in the ventilatory and metabolic adaptations elicited by CIH exposure.…”

Section: Discussionmentioning

confidence: 99%

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Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

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Section: Methodsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Morgan

Bates

Río

et al. 2016

Respiratory Physiology & Neurobiology

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“…The other explanation of benefitial allopurinol effect considers the effects on vascular endothelial function. Xanthine oxidase plays a key role in mediating intermittent hypoxia-induced vascular dysfunction and administration of allopurinol might prevent it (32). The investigations on animal models in the most cases also confirmed the beneficial effect of allopurinol after induction of myocardial infarction (4) with reducing myocardial damage, better recovery of ventricular function, better preservation of cellular ATP levels and mitochondrial ATP generation during ischemia and prevention of the decrease in left ventricular pressure.…”

Section: Uric Acid and Oxidative Stressmentioning

confidence: 99%

Uric acid as one of the important factors in multifactorial disorders – facts and controversies

Marinković²,

2012

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With considering serum concentration of the uric acid in humans we are observing hyperuricemia and possible gout development. Many epidemiological studies have shown the relationship between the uric acid and diff erent disorders such are obesity, metabolic syndrome, hypertension and coronary artery disease. Clinicians and investigators recognized serum uric acid concentration as very important diagnostic and prognostic factor of many multifactorial disorders. This review presented few clinical conditions which are not directly related to uric acid, but the concentrations of uric acid might have a great impact in observing, monitoring, prognosis and therapy of such disorders. Uric acid is recognized as a marker of oxidative stress. Production of the uric acid includes enzyme xanthine oxidase which is involved in producing of radical-oxigen species (ROS). As by-products ROS have a signifi cant role in the increased vascular oxidative stress and might be involved in atherogenesis. Uric acid may inhibit endothelial function by inhibition of nitric oxide-function under conditions of oxidative stress. Down regulation of nitric oxide and induction of endothelial dysfunction might also be involved in pathogenesis of hypertension. The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in acute myocardial infarction (AMI) patients and stroke. Nephrolithiasis of uric acid origin is signifi cantly more common among patients with the metabolic syndrome and obesity. On contrary to this, uric acid also acts is an ''antioxidant'' , a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms.

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“…Indeed, OSA has been considered as an oxidative stress disorder [29]. It has further been confirmed that chronic intermittent hypoxia leads to important oxidative stress in various tissues [30][31][32][33][34]. The role of reactive oxygen species (ROS) in regulating HIF-1 activity is at least as important as hypoxia per se.…”

Section: What Are the Mechanisms Linking Sleep Apnoea And Cancer Devementioning

confidence: 99%

Sleep apnoea and cancer: the new challenge

Lévy

Godin‐Ribuot

Pépin

2014

European Respiratory Journal

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@ERSpublications Epidemiological studies suggest that excess mortality in OSA patients is partly related to a higher risk of cancer http://ow.ly/vBNY5Obstructive sleep apnoea (OSA) is a well-known public health problem owing to its high prevalence and the numerous consequences of the disorder, including excessive daytime somnolence, cognitive impairment and consequently traffic accidents [1]. There is an excess in cardiovascular mortality that has been repeatedly reported in longitudinal cohorts, in both general and clinical populations. Despite many confounding factors, including age, sex and obesity, evidence has accumulated over the past 25 years regarding strong associations between OSA, cardiovascular diseases i.e. hypertension [2], coronary artery disease, cerebrovascular disease, heart rate and conduction disorders, and excess mortality. Through a complex interaction between obesity, metabolism, sleep and sleep apnoea, metabolism seems to be altered by OSA [3], although it remains uncertain whether treating OSA may improve blood glucose control, lipid metabolism [4] or adipose tissue distribution [5]. More recently, it has been suspected that the excess in mortality in OSA could not only be attributed to cardiometabolic consequences but also to cancer. Cancer has been found to be associated with sleep disordered breathing (SDB) in two large observational studies [6,7]. This had been previously suspected through proof-of-concept animal studies that demonstrated an association between intermittent hypoxia, a major consequence of SDB, carcinogenesis and acceleration of tumour growth [8]. Intermittent hypoxia is a particular condition with relatively specific cellular effects [9], including changes in host immune responses that could favour cancer progression [10]. The relationship between SDB and cancer has been studied in animal [8,11,12] and clinical studies; they suggest that SDB, mainly through intermittent hypoxia, is likely to be associated with an increase in growth rate [8], incidence [6] and mortality [7] of cancer. In addition, sleep fragmentation, another hallmark of sleep apnoea, has also been demonstrated to promote tumour progression in animal models through recruitment of tumourassociated macrophages and Toll-like receptor 4 signalling pathways [13].In this issue of the European Respiratory Journal (ERJ), analysed the relationship between the severity of SDB and the aggressiveness factors of cutaneous malignant melanoma (CMM). They performed a multicentre observational study in 82 consecutive patients diagnosed with CMM, of whom 56 patients were finally included in the study. Measurements of melanoma aggressiveness included: tumour mitotic rate, Breslow Index, presence of ulceration, stage of disease and growth rate of melanoma. The severity of SDB, i.e. apnoea/hypopnoea index (AHI) and desaturation indexes, was correlated with melanoma aggressiveness markers. There are several limitations in this study. Age is a major confounder since, as mentioned by the authors, it will both favour melanom...

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Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats

Cited by 55 publications

References 113 publications

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

Uric acid as one of the important factors in multifactorial disorders – facts and controversies

Sleep apnoea and cancer: the new challenge

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