{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:59:20Z","timestamp":1788350360044,"version":"build-2803163510"},"reference-count":59,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      We examined the interactive influence of hypoxia and exercise, and hypercapnia and exercise,\u00a0on regional cerebral perfusion and sympathetic activation. Twenty healthy young adults (seven women) completed study trials including (1) rest in normoxia (: \u223c96%, : \u223c36\u00a0mmHg), normocapnic hypoxia (: \u223c84%, : \u223c36\u00a0mmHg), and normoxic hypercapnia (: \u223c98%, : \u223c46\u00a0mmHg) and (2) unilateral rhythmic handgrip exercise (45% of maximal voluntary contraction at 1\u00a0Hz for 3\u00a0min) under the same gas conditions. Based on the exercising arm, blood flow in the contralateral internal carotid (ICA\n                      <jats:sub>BF<\/jats:sub>\n                      ) and ipsilateral vertebral (VA\n                      <jats:sub>BF<\/jats:sub>\n                      ) arteries, anterior and posterior cerebral O\n                      <jats:sub>2<\/jats:sub>\n                      delivery (), and muscle sympathetic nerve activity (MSNA) were measured in each trial. During exercise in hypoxia, ICA\n                      <jats:sub>BF<\/jats:sub>\n                      , VA\n                      <jats:sub>BF<\/jats:sub>\n                      , anterior and posterior  were significantly lower, whereas total MSNA was significantly greater, than the sum of the responses evoked by either hypoxia or exercise alone. During exercise in hypercapnia, ICA\n                      <jats:sub>BF<\/jats:sub>\n                      and anterior  were significantly greater, whereas MSNA was lower, than the sum of the responses evoked by either hypercapnia or exercise alone. The VA\n                      <jats:sub>BF<\/jats:sub>\n                      and posterior  responses to hypercapnic exercise were not different from the summated responses. These findings suggest that the brain is hypoperfused and sympathetic outflow potentiated during hypoxic exercise, and that the brain is hyperperfused and sympathetic discharge constrained during hypercapnic exercise. The contrasting consequences for cerebral perfusion and sympathetic activation indicate a potential involvement of Cushing's mechanism in the autonomic control during exercise in healthy humans.\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\/tjp16415-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>\n                            Brain O\n                            <jats:sub>2<\/jats:sub>\n                            \u2010demand and \u2010supply are mismatched, and muscle sympathetic nerve activity (MSNA) is enhanced in humans exercising at high altitude; the link between the two phenomena remains elusive.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We evaluated the isolated and interactive effects of exercise, hypoxia, and hypercapnia on blood flow in the internal carotid (ICA\n                            <jats:sub>BF<\/jats:sub>\n                            ) and vertebral (VA\n                            <jats:sub>BF<\/jats:sub>\n                            ) arteries, and MSNA.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The interaction of hypoxia and exercise was hypo\u2010additive for ICA\n                            <jats:sub>BF<\/jats:sub>\n                            and VA\n                            <jats:sub>BF<\/jats:sub>\n                            and anterior and posterior cerebral O\n                            <jats:sub>2<\/jats:sub>\n                            delivery (), but hyper\u2010additive for MSNA.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            The interaction of hypercapnia and exercise was hyper\u2010additive for ICA\n                            <jats:sub>BF<\/jats:sub>\n                            and anterior , additive for VA\n                            <jats:sub>BF<\/jats:sub>\n                            and posterior , and hypo\u2010additive for MSNA.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These observations indicate that a suboptimal brain perfusion during hypoxic exercise coincides with a potentiated sympathetic outflow, while a (supra\u2010)optimal brain perfusion during hypercapnic exercise coincides with a suppressed sympathetic outflow.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our findings suggest that Cushing's mechanism may play a role in the autonomic control in exercising humans.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp287181","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T12:33:39Z","timestamp":1731155619000},"page":"5103-5119","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Regional cerebral perfusion and sympathetic activation during exercise in hypoxia and hypercapnia: preliminary insight into\u00a0\u2018Cushing's mechanism\u2019"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8853-8451","authenticated-orcid":false,"given":"Hsuan\u2010Yu","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Anesthesiology University of Utah Salt Lake City UT USA"},{"name":"Trauma Services Primary Children's Hospital, Intermountain Health Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanokwan","family":"Bunsawat","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Centre Veterans Affairs Medical Centre Salt Lake City UT USA"},{"name":"Department of Internal Medicine, Division of Geriatrics University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Jarrett","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Centre Veterans Affairs Medical Centre Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L.","family":"Shields","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Centre Veterans Affairs Medical Centre Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela V.","family":"Bisconti","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education, and Clinical Centre Veterans Affairs Medical Centre Salt Lake City UT 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