Sympathetic Nervous System Activation and Vascular Endothelial Function With Chronic Hypoxia
2020; Lippincott Williams & Wilkins; Volume: 127; Issue: 2 Linguagem: Inglês
10.1161/circresaha.120.317114
ISSN1524-4571
Autores Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoHomeCirculation ResearchVol. 127, No. 2Sympathetic Nervous System Activation and Vascular Endothelial Function With Chronic Hypoxia Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSympathetic Nervous System Activation and Vascular Endothelial Function With Chronic Hypoxia Erik R. Swenson Erik R. SwensonErik R. Swenson Correspondence to: Erik R. Swenson, MD, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, 1660 S Columbian Way, Seattle, WA 98108. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4117-6198 From the Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, VA Puget Sound Health Care System, Seattle. Search for more papers by this author Originally published2 Jul 2020https://doi.org/10.1161/CIRCRESAHA.120.317114Circulation Research. 2020;127:247–248This article is a commentary on the followingGlobal Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric HypoxiaArticle, see p e1Exposure to high altitude with lower inspired oxygen levels evokes an array of acute and chronic changes that allow newcomers to mountainous regions of the world to recreate, work, and even live successfully up to altitudes of 4000 meters.1 Cardiac output acutely increases to maintain tissue oxygen delivery followed by slower nongenomic responses (eg, a progressive rise in ventilation over hours and days). Ultimately, altered gene transcription by HIF (hypoxia-inducible factor) leads to erythropoietin-driven red cell production and changes in intermediary metabolism that enhance oxygen utilization efficiency. The sympathetic nervous system (SNS) through direct innervation and adrenal activation regulates key responses including increasing cardiac output through augmenting heart rate and myocardial contractility and opposing the hypoxia-induced systemic vasodilation.2 In the short term of minutes to hours, the SNS-response to hypoxia resembles the evolutionary flight or fight response that ensures survival in situations of acute stress. With unabating or frequent intermittent stress as occurs with prolonged hypoxic exposure, the consequences of sustained SNS activation become unproductive and harmful. One of these is an increase in systemic vascular resistance leading to hypertension, which is a problem for those remaining at high altitude and in some populations with generational histories in the mountains.Chronic exposure to severe high-altitude hypoxia in some people leads to endothelium-dependent and endothelium-independent impairments in vascular dilation. The altitude-induced vascular dysfunction may parallel that observed in lowland dwellers with cardiopulmonary diseases that cause arterial hypoxemia and tissue hypoxia. As Tymko et al3 in the present issue explore, there are other reasons that this vascular dysfunction might arise. These include the direct oxidative stress of hypoxia, shear stresses with blood pressure elevation, and chronic inflammation associated with many cardiovascular disorders. Other possibilities may involve HIF-1 or 2 gene transcription changes, which are strongly established in the pulmonary circulation4 but much less explored in the systemic circulation. In one study, it was found that normoxic patients with hypertension had different HIF isoform expression in dermal vessels than normotensives5 and in mice with heterozygous deletion of HIF-2, hypertension develops.6 The potential that changes in vascular HIF expression occur with arterial hypoxemia, such as at high altitude, would be of considerable interest, particularly now that HIF-active drugs have been approved for clinical use.7In the Tymko study, the role of the sympathetic nervous system in vascular endothelial dysfunction during chronic exposure to hypobaric hypoxia was elegantly studied in native normotensive lowlanders at low altitude (344 m; Kelowna. British Columbia, Canada) and then again 14 to 21 days after arriving at 4300 m in Cerro de Pasco, Peru. Two groups of native highlanders living in Cerro de Pasco were also studied, those well adapted and with only mild and appropriate polycythemia (mean Hb 18.7 g/dL) and those with excessive erythrocytosis (mean Hb 22.5 g/dL) and chronic mountain sickness, an illness afflicting 10% to 20 % of the population in parts of the Andes.3 Chronic mountain sickness is defined as a Hb >21 g/dL along with symptoms of headache, breathlessness, paresthesia, tinnitus, and sleep disturbances and signs of superficial venous dilations and cyanosis. Sympathetic nerve activity recorded from a sympathetic nerve bundle in the radial nerve, along with heart rate, blood pressure, brachial artery diameter, and blood flow velocity by ultrasonography were measured at rest and during intraarterial graded infusions of either acetylcholine (Ach) to assess endothelium-dependent vasodilation or sodium nitroprusside (SNP) to assess endothelial-independent vasodilation. To measure the contribution of sympathetic nerve activity activation, combined alpha and β adrenergic blockade was accomplished by intraarterial infusion of phentolamine and propranolol. Although it was anticipated that heightened alpha adrenergic activity would be most responsible for impaired endothelial function, the authors also blocked β adrenergic activity to eliminate any possible norepinephrine-mediated β adrenergic vasodilation.In the healthy lowlanders, several weeks of hypoxia (mean PaO2, 56 mm Hg; mean SaO2, 89.7%; mean PaCO2, 27.0 mm Hg) led to a mild elevation in mean blood pressure (89–94 mm Hg) and heart rate (65–75/minute). These changes were largely mediated by sympathetic nerve activity as confirmed by microneurography demonstrating a >2-fold increase in burst frequency and incidence. Chronic hypoxia in the lowlanders reduced endothelium-dependent vasodilation by 25% to 50%, but not endothelium-independent vasodilation. Adrenergic blockade fully restored endothelium-dependent vasodilation at high altitude to low altitude values. In the highlanders with excessive erythrocytosis, sympathetic activity by microneurography was higher than normal highlanders, but surprisingly not blood pressure. Adrenergic blockade restored endothelium-dependent vasodilation in those with excessive erythrocytosis to that of normal highlanders.It should be noted that there were age differences between the lowlanders (younger by about 20 years) and in the average SaO2 between the highlanders with and without excessive erythrocytosis (5% higher in healthy highlanders) that might confound the absolute differences in vascular responses but probably not enough to dilute the strength of the findings and their implications. Although there is no doubt of a large role of the activated SNS in chronic hypoxia-associated endothelial dysfunction, other contributors including differences in nonendothelial related nitric oxide metabolism, such as circulating concentrations of endogenous NO synthase inhibitors (eg, asymmetrical dimethylarginine), red cell-mediated hypoxic release of NO via nitrite reduction or bioequivalents of NO (eg, nitrosothiols), ATP, and vascular-generated reactive oxygen species and hydrogen sulfide will need to be explored. Another factor not controlled for in this study are differences in ventilation and changes in CO2 and acid-base balance between groups and altitudes, as is often the case in too much of hypoxia research.8 The SNS is altered by hypercapnia and ventilation itself9 and ideally these should be measured and controlled (eg, clamped with end-tidal forcing). It would be useful in the future to explore the extent to which the elevated red cell mass and concentration plays in the endothelial dysfunction of those with chronic mountain sickness, because it is known that phlebotomy in these patients improves vascular function, improves ventilation and arterial oxygenation, and reduces symptoms,10 some of which may derive from less red cell-mediated NO scavenging.11These findings of Tymko et al3 provide solid evidence that chronic hypoxia via SNS activation impairs vascular function be it of several weeks in lowlanders or much longer in highlanders with excessive erythrocytosis. The implications of these results and the evidence that much of the vascular endothelial dysfunction of chronic hypoxia can be ameliorated with pharmacological adrenergic blockade raises the possibility of benefits with available alpha blockers started at low doses to improve cardiovascular health outcomes in patients with cardiopulmonary disease and those with chronic mountain sickness at high altitude.DisclosuresNone.FootnotesFor Disclosures, see page 248.Correspondence to: Erik R. Swenson, MD, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, 1660 S Columbian Way, Seattle, WA 98108. Email erik.[email protected]govReferences1. Swenson ER, Bärtsch P, eds. High altitude.Human Adaptation to Hypoxia. New York: Springer; 2014: 1–496.Google Scholar2. Bärtsch P, Gibbs JS. Effect of altitude on the heart and the lungs.Circulation. 2007; 116:2191–2202. doi: 10.1161/CIRCULATIONAHA.106.650796LinkGoogle Scholar3. Tymko MM, Lawley JS, Ainslie PN, Hansen AB, Hofstaetter F, Rainer S, Amin S, Moralez G, Gasho C, Vizcardo-Galindo GA, et al. Global reach 2018: heightened α-adrenergic signaling impairs endothelial function during chronic exposure to hypobaric hypoxia.Circ Res. 2020; 127:e1–e13. doi: 10.1161/CIRCRESAHA.119.316053LinkGoogle Scholar4. Shimoda LA, Laurie SS. HIF and pulmonary vascular responses to hypoxia.J Appl Physiol (1985). 2014; 116:867–874. doi: 10.1152/japplphysiol.00643.2013CrossrefMedlineGoogle Scholar5. Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, et al. HIF isoforms in the skin differentially regulate systemic arterial pressure.Proc Natl Acad Sci U S A. 2013; 110:17570–17575. doi: 10.1073/pnas.1306942110CrossrefMedlineGoogle Scholar6. Peng YJ, Nanduri J, Khan SA, Yuan G, Wang N, Kinsman B, Vaddi DR, Kumar GK, Garcia JA, Semenza GL, et al. Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension.Proc Natl Acad Sci U S A. 2011; 108:3065–3070. doi: 10.1073/pnas.1100064108CrossrefMedlineGoogle Scholar7. Li ZL, Tu Y, Liu BC. Treatment of renal anemia with roxadustat: advantages and achievement.Kidney Dis (Basel). 2020; 6:65–73. doi: 10.1159/000504850CrossrefMedlineGoogle Scholar8. Swenson ER. Hypoxia and its acid-base consequences: from mountains to malignancy.Adv Exp Med Biol. 2016; 903:301–323. doi: 10.1007/978-1-4899-7678-9_21CrossrefMedlineGoogle Scholar9. Jouett NP, Watenpaugh DE, Dunlap ME, Smith ML. Interactive effects of hypoxia, hypercapnia and lung volume on sympathetic nerve activity in humans.Exp Physiol. 2015; 100:1018–1029. doi: 10.1113/EP085092CrossrefMedlineGoogle Scholar10. Winslow RM, Monge CC, Brown EG, Klein HG, Sarnquist F, Winslow NJ, McKneally SS. Effects of hemodilution on O2 transport in high-altitude polycythemia.J Appl Physiol (1985). 1985; 59:1495–1502. doi: 10.1152/jappl.1985.59.5.1495CrossrefMedlineGoogle Scholar11. Deem S, Swenson ER, Alberts MK, Hedges RG, Bishop MJ. Red-blood-cell augmentation of hypoxic pulmonary vasoconstriction: hematocrit dependence and the importance of nitric oxide.Am J Respir Crit Care Med. 1998; 157:1181–1186. doi: 10.1164/ajrccm.157.4.9707165CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hansen A, Moralez G, Amin S, Simspon L, Hofstaetter F, Anholm J, Gasho C, Stembridge M, Dawkins T, Tymko M, Ainslie P, Villafuerte F, Romero S, Hearon C and Lawley J (2021) Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia, The Journal of Physiology, 10.1113/JP281730, 599:17, (4021-4044), Online publication date: 1-Sep-2021. Related articlesGlobal Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric HypoxiaMichael M. Tymko, et al. Circulation Research. 2020;127:e1-e13 July 3, 2020Vol 127, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.120.317114PMID: 32614721 Originally publishedJuly 2, 2020 Keywordsendothelium, vascularEditorialshypertensionsympathetic nervous systemhypoxiaPDF download Advertisement
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