{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T12:51:45Z","timestamp":1784119905723,"version":"3.55.0"},"reference-count":67,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100013921","name":"Wilderness Medical Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013921","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1F32HL137285\u20100"],"award-info":[{"award-number":["1F32HL137285\u20100"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Chronic exposure to hypoxia (high\u2010altitude, HA; &gt;4000\u00a0m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) at sea\u2010level (SL; 344 m) and following 21\u201328\u00a0days at HA (\u223c4300\u00a0m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF\/MAP), and arterial and venous blood sampling (O<jats:sub>2<\/jats:sub> delivery () and uptake ()) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local \u03b1\u2010 and \u03b2\u2010adrenergic blockade (intra\u2010arterial phentolamine and propranolol). HA reduced \u0394FBF (25% MVC: SL: 138.3\u00a0\u00b1\u00a047.6 <jats:italic>vs<\/jats:italic>. HA: 113.4\u00a0\u00b1\u00a037.1\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.022) and \u0394 (25% MVC: SL: 20.3\u00a0\u00b1\u00a07.5 <jats:italic>vs<\/jats:italic>. HA: 14.3\u00a0\u00b1\u00a06.2\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SL<jats:sub>\u03b1\u2013\u03b2 blockade<\/jats:sub>: 164.1\u00a0\u00b1\u00a071.7 <jats:italic>vs<\/jats:italic>. HA<jats:sub>\u03b1\u2013\u03b2 blockade<\/jats:sub>: 185.4\u00a0\u00b1\u00a066.6\u00a0ml\u00a0min<jats:sup>\u22121<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.947) but resulted in an exaggerated relationship between  and  (\/ slope: SL: 1.32; HA: slope: 1.86; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15161-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Exposure to chronic hypoxia (altitude, &gt;4000\u00a0m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In healthy male lowlanders exposed to chronic hypoxia (21\u201328\u00a0days; \u223c4300\u00a0m), local adrenoreceptor blockade (combined \u03b1\u2010 and \u03b2\u2010adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282972","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T23:39:42Z","timestamp":1656027582000},"page":"3483-3495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high\u2010altitude"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6747-3708","authenticated-orcid":false,"given":"Alexander B.","family":"Hansen","sequence":"first","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0654-2383","authenticated-orcid":false,"given":"Gilbert","family":"Moralez","sequence":"additional","affiliation":[{"name":"Department of Applied Clinical Research University of Texas Southwestern Medical Center  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin B.","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Hofst\u00e4tter","sequence":"additional","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0357-6561","authenticated-orcid":false,"given":"Lydia L.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Gasho","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Pulmonary and Critical Care University of Loma Linda  Loma Linda CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Tymko","sequence":"additional","affiliation":[{"name":"Physical Activity and Diabetes Laboratory Faculty of Kinesiology Sport and Recreation University of Alberta  Edmonton Alberta Canada"},{"name":"Centre of Heart, Lung, and Vascular Health, School of Health and Exercise Sciences University of British Columbia \u2013 Okanagan  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Ainslie","sequence":"additional","affiliation":[{"name":"Centre of Heart, Lung, and Vascular Health, School of Health and Exercise Sciences University of British Columbia \u2013 Okanagan  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2166-7966","authenticated-orcid":false,"given":"Justin S.","family":"Lawley","sequence":"additional","affiliation":[{"name":"Department of Sport Science University of Innsbruck  Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Christopher M.","family":"Hearon","sequence":"additional","affiliation":[{"name":"Department of Applied Clinical Research University of Texas Southwestern Medical Center  Dallas TX USA"},{"name":"Institute for Exercise and Environmental Medicine Texas Health Presbyterian Dallas  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.113936"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-979077"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1958.13.1.75"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.65.6.2592"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00323.2001"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0b013e3181729dd3"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j..2003.t01-1-00379.x"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00156.2002"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00155.2002"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.162271"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1976.40.5.658"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000470"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00212.2014"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301675"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000028819.64790.BE"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.015297"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1976.sp011584"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2000.89.3.1189"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1989.66.5.2454"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1987.63.2.521"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP281730"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00208.2020"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.031765"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00387.x"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1974.36.3.362"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272829"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP276998"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1113\/eph8802513"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2012.066092"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-218206"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2013"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1992.263.4.H1078"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1966.21.2.609"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106554"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-2862(89)90040-X"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00649.2019"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.239780"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.146035"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/sms.12976"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.106765"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1139\/h01-010"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1991.70.5.1963"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00321.2017"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.90410.2008"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.91060.2008"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13696"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.317.7165.1063"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.278358"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.65.6.2545"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1968.25.4.400"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1995.tb09935.x"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1080\/10739680590895028"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP279694"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP282281"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.64.4.1309"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00183.2018"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.90.5.1855"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00597.2020"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.12780"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP088350"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.316053"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00757.2021"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112841"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00033.2021"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1991.70.3.1129"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01016.2008"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.6.H2636"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282972","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP282972","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP282972","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T12:36:20Z","timestamp":1692880580000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP282972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,12]]},"references-count":67,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1113\/JP282972"],"URL":"https:\/\/doi.org\/10.1113\/jp282972","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,12]]},"assertion":[{"value":"2022-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}