{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:23:16Z","timestamp":1787016196317,"version":"build-2736575974"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      High altitude\u2010induced hypoxaemia is often associated with peripheral vascular dysfunction. However, the basic mechanism(s) underlying high\u2010altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high altitude. Ten young healthy lowlanders were tested at sea level (344\u00a0m) and following 4\u20136 days at high altitude (4300\u00a0m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain\u2010gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP) and a co\u2010infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was \u223c30% lower at high altitude than at sea level (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.048). There was no difference in the response to SNP at high altitude (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.860). At sea level, the co\u2010infusion of ACh+VitC had no influence on the FBF dose response (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.268); however, at high altitude ACh+VitC resulted in an average increase in the FBF dose response by \u223c20% (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.019). At high altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxaemia (R\n                      <jats:sup>2<\/jats:sup>\n                      = 0.60,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.008 and R\n                      <jats:sup>2<\/jats:sup>\n                      = 0.63,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high altitude are in part attributable to oxidative stress, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high\u2010altitude sojourns, with important implications for understanding the aetiology of high altitude\u2010related vascular dysfunction.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp14879-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Vascular dysfunction has been demonstrated in lowlanders at high altitude (&gt;4000\u00a0m). However, the extent of impairment and the delineation of contributing mechanisms have remained unclear.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Using the gold\u2010standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4\u20136 days after rapid ascent to 4300\u00a0m.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The total forearm blood flow response to acetylcholine at high altitude was decreased by \u223c30%. Co\u2010infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by \u223c20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxaemia.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These data extend our basic understanding of vascular (mal)adaptation to high\u2010altitude sojourns, with important implications for understanding the aetiology of high altitude\u2010related changes in endothelial\u2010mediated vasodilatory function.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp282281","type":"journal-article","created":{"date-parts":[[2021,11,7]],"date-time":"2021-11-07T01:14:32Z","timestamp":1636247672000},"page":"1373-1383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["GLOBAL REACH 2018: intra\u2010arterial vitamin C improves endothelial\u2010dependent vasodilatory function in humans at high altitude"],"prefix":"10.1113","volume":"600","author":[{"given":"Rachel M.","family":"Stone","sequence":"first","affiliation":[{"name":"Faculty of Human Kinetics University of Windsor  Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Ainslie","sequence":"additional","affiliation":[{"name":"Kelowna, Centre for Heart Lung and Vascular Health University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1667-294X","authenticated-orcid":false,"given":"Joshua C.","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Kelowna, Centre for Heart Lung and Vascular Health University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Akins","sequence":"additional","affiliation":[{"name":"University of Texas  Arlington Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5989-3961","authenticated-orcid":false,"given":"David B.","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Tymko","sequence":"additional","affiliation":[{"name":"University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"DeSouza","sequence":"additional","affiliation":[{"name":"University of Colorado  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7910-6921","authenticated-orcid":false,"given":"Anthony R.","family":"Bain","sequence":"additional","affiliation":[{"name":"Faculty of 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