Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea

Khayat, Rami; Varadharaj, Saradhadevi; Porter, Kyle; Sow, Angela; Jarjoura, David; Gavrilin, Mikhail A.; Zweíer, Jay L.

doi:10.1093/ajh/hpx174

Cited by 19 publications

(20 citation statements)

References 31 publications

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“…Although no studies have measured endothelial-dependent dilatation after 40 min of IH, longer duration exposure to IH without hypercapnia reduces NO derivatives (Foster et al 2009;Pialoux et al 2011), promotes retrograde shear stress , reduces peak reactive hyperaemia and resting blood flow in the forearm, and increases baseline FVC resistance (Gilmartin et al 2010). After 12 weeks of CPAP therapy in OSA patients without comorbidities, NO expression in microcirculatory vessel walls increased four-fold alongside improved flow-mediated dilatation, which suggests that the absence of IH can improve endothelial function (Khayat et al 2017). However, in healthy young males, 6 h of IH did not reduce flow-mediated dilatation compared to controls .…”

Section: Sympathetic Neurovascular Transductionmentioning

confidence: 98%

“…This response depends on peripheral chemoreceptor afferent activity (Fletcher et al 1992) and afferent-efferent translation within brainstem centers, the median pre-optic nucleus and the subfornical organs (Saxena et al 2015;Shell et al 2019). IH can also reduce nitric oxide (NO) bioavailability (Foster et al 2009;Pialoux et al 2011), contributing to reductions in endothelial function (Gilmartin et al 2010;Khayat et al 2017), as well as reduce vascular sensitivity to exogenous norepinephrine (in animals) (Phillips, 2003). The translation of increases in post-ganglionic muscle sympathetic nerve activity (MSNA) to changes in vascular tone (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men

Stuckless

Vermeulen

Brown

et al. 2020

The Journal of Physiology

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Key pointsr Intermittent hypoxia leads to long-lasting increases in muscle sympathetic nerve activity and blood pressure, contributing to increased risk for hypertension in obstructive sleep apnoea patients.r We determined whether augmented vascular responses to increasing sympathetic vasomotor outflow, termed sympathetic neurovascular transduction (sNVT), accompanied changes in blood pressure following acute intermittent hypercapnic hypoxia in men.r Lower body negative pressure was utilized to induce a range of sympathetic vasoconstrictor firing while measuring beat-by-beat blood pressure and forearm vascular conductance. r IH reduced vascular shear stress and steepened the relationship between diastolic blood pressure and sympathetic discharge frequency, suggesting greater systemic sNVT.r Our results indicate that recurring cycles of acute intermittent hypercapnic hypoxia characteristic of obstructive sleep apnoea could promote hypertension by increasing sNVT.Abstract Acute intermittent hypercapnic hypoxia (IH) induces long-lasting elevations in sympathetic vasomotor outflow and blood pressure in healthy humans. It is unknown whether IH alters sympathetic neurovascular transduction (sNVT), measured as the relationship between sympathetic vasomotor outflow and either forearm vascular conductance (FVC; regional sNVT) or diastolic blood pressure (systemic sNVT). We tested the hypothesis that IH augments sNVT by exposing healthy males to 40 consecutive 1 min breathing cycles, each comprising 40 s of hypercapnic hypoxia (P ETCO 2 : +4 ± 3 mmHg above baseline; P ETO 2 : 48 ± 3 mmHg) and 20 s of Troy J. R. Stuckless is a native of Bayside, Ontario in Canada. He attained his Bachelor of Science in Kinesiology from Queen's University and practiced as a kinesiologist in Calgary before pursuing an Master of Science from the University of British Columbia's Okanagan Campus under the supervision of Dr Glen Foster. His research interests include vascular endothelial cell function and interactions between the autonomic nervous system and cardiovascular health. Troy is currently completing the Doctor of Dental Surgery Program at the University of Toronto.normoxia (n = 9), or a 40 min air-breathing control (n = 7). Before and after the intervention, lower body negative pressure (LBNP; 3 min at -15, -30 and -45 mmHg) was applied to elicit reflex increases in muscle sympathetic nerve activity (MSNA, fibular microneurography) when clamping end-tidal gases at baseline levels. Ventilation, arterial pressure [systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP)], brachial artery blood flow (Q BA ), FVC (Q BA /MAP) and MSNA burst frequency were measured continuously. Following IH, but not control, ventilation [5 L min -1 ; 95% confidence interval (CI) = 1-9] and MAP (5 mmHg; 95% CI = 1-9) were increased, whereas FVC (-0.2 mL min -1 mmHg -1 ; 95% CI = -0.0 to -0.4) and mean shear rate (-21.9 s -1 ; 95% CI = -5.8 to -38.0; all P < 0.05) were reduced. Systemic sNVT was increased following IH (0.25 mmHg burst -1...

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Section: Sympathetic Neurovascular Transductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men

Stuckless

Vermeulen

Brown

et al. 2020

The Journal of Physiology

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“…Therefore, another goal was to test the hypothesis that allopurinol and losartan, drugs that prevent CIH-induced endothelial dysfunction in rats (Dopp et al, 2011;Marcus et al, 2012), alter vasodilatory responses to hypoxia in humans with OSA. Given that chemoreflex hypersensitivity and vascular dysfunction are putative contributors to OSA-associated hypertension (Del Rio, Moya, & Iturriaga, 2014;Fletcher et al, 1992a;Khayat et al, 2018;Prabhakar, 2016), we evaluated the effects of allopurinol and losartan on blood pressure. This research was registered at clinicaltrials.gov (NCT01637623) before recruitment of subjects.…”

Section: New Findingsmentioning

confidence: 99%

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

Morgan

Teodorescu

Pegelow

et al. 2018

Experimental Physiology

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Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT R) blockade. Both AT R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.

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“…Intermittent hypoxemia has been shown to activate RAA system (33,34). There is also vascular dysfunction and stimulation of systemic inflammation induced by an increase in oxidative stress, reduced production of endothelium-dependent vasodilator, such as nitric oxide (35)(36)(37).…”

Section: Sleep Apnea Syndromementioning

confidence: 99%

Cardiovascular Complications Of Acromegaly

et al. 2018

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Acromegaly is associated with increased mortality and decreased life expectancy. Cardiovascular disease is the principal cause of premature mortality in patients with acromegaly, accounting for about 60% of deaths. GH and/or IGF-I exert direct cardiac effects: enhance cardiac contractility, stimulate cardiomyocyte growth, influence calcium influx in cardiomyocytes. Cardiac remodelling is influenced by hypertension and insulin resistance. Among cardiovascular risk factors arterial hypertension, reported in 35% of patients with acromegaly, ranks among most important negative prognostic factors for mortality. Hypertension plays significant role in the development of cardiac hypertrophy, especially in older acromegalic patients and diastolic blood pressure is best predictive factor for cardiac hypertrophy. Therefore, early and aggressive hypertension treatment is essential for prognosis in acromegaly. Other important risk factors are: valvular defects, arrhythmias, endothelial dysfunction, heart failure, lipid abnormalities and coronary artery disease. Numerous studies suggest that patients with acromegaly are under threat of arrhythmias, especially those with structural heart abnormalities. Congestive heart failure as end-stage acromegalic cardiomyopathy occurs usually in older patients, with long-term uncontrolled disease and other cardiovascular and metabolic complications. Relation between acromegaly and coronary artery disease is controversial as it seems to be connected rather with classical cardiovascular risk factors than GH and IGF-1 overexpresion.

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Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea

Abstract: In OSA patients with no to minimal CVD risk, VED is associated with upregulation of AT-1 expression that is reversible with CPAP. Endothelial oxidative stress was reversible with ARB. RAS activation may play an important role in the development of early CVD risk in OSA patients.

Cited by 19 publications

References 31 publications

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

Cardiovascular Complications Of Acromegaly

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