{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:13:06Z","timestamp":1790665986617,"version":"4.1.0"},"reference-count":108,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"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":[[2021,7]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We investigated the influence of arterial PCO<jats:sub>2<\/jats:sub> (PaCO<jats:sub>2<\/jats:sub>) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050\u00a0m.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>At sea level and high altitude, we assessed stepwise alterations in PaCO<jats:sub>2<\/jats:sub> following metabolic acidosis (via 2\u00a0days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>] (i.e. buffering capacity) were effectively altered.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The cerebrovascular responses to changes in arterial [H<jats:sup>+<\/jats:sup>]\/pH were consistent with the altered relationship between PaCO<jats:sub>2<\/jats:sub> and [H<jats:sup>+<\/jats:sup>]\/pH following ACZ at high altitude (i.e. leftward <jats:italic>x<\/jats:italic>\u2010intercept shifts).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO<jats:sub>2<\/jats:sub> was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO<jats:sub>2<\/jats:sub> rather than <jats:italic>arterial<\/jats:italic> pH.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Alterations in acid\u2010base balance with progressive acclimatization to high altitude have been well\u2010established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050\u00a0m; involving: (1) resting acid\u2010base balance (control); (2) following metabolic acidosis via 2\u00a0days of oral acetazolamide at 250\u00a0mg every 8 h (ACZ; pH: \u0394 \u20100.07 \u00b1 0.04 and base excess: \u0394 \u20105.7 \u00b1 1.9 mEq\u22c5l<jats:sup>\u20131<\/jats:sup>, trial effects: <jats:italic>P<\/jats:italic> &lt; 0.001 and <jats:italic>P<\/jats:italic> &lt; 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>; pH: \u0394 \u20100.01 \u00b1 0.04 and base excess: \u0394 \u20101.5 \u00b1 2.1 mEq\u22c5l<jats:sup>\u20131<\/jats:sup>, trial effects: <jats:italic>P<\/jats:italic> = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO<jats:sub>2<\/jats:sub> (PaCO<jats:sub>2<\/jats:sub>), i.e. cerebrovascular CO<jats:sub>2<\/jats:sub> reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. \u0394 \u20103.4 \u00b1 2.3 mmHg PaCO<jats:sub>2<\/jats:sub>, trial effect: <jats:italic>P<\/jats:italic> &lt; 0.001) was sufficient to offset any elevations in CBF induced via the ACZ\u2010mediated metabolic acidosis. Between trials at high altitude, we observed consistent <jats:italic>leftward<\/jats:italic> shifts in both the PaCO<jats:sub>2<\/jats:sub>\u2010pH and CBV\u2010pH responses across the CO<jats:sub>2<\/jats:sub> reactivity tests with experimentally <jats:italic>reduced<\/jats:italic> arterial pH via ACZ. When indexed against PaCO<jats:sub>2<\/jats:sub> \u2013 rather than pH \u2013 the absolute CBV and sensitivity of CBV\u2010PaCO<jats:sub>2<\/jats:sub> was unchanged between trials at high altitude. Taken together, following acclimatization, CO<jats:sub>2<\/jats:sub>\u2010mediated changes in cerebrovascular tone rather than <jats:italic>arterial<\/jats:italic> [H<jats:sup>+<\/jats:sup>]\/pH is integral to CBF regulation at high altitude.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp281446","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T10:46:03Z","timestamp":1622198763000},"page":"3513-3530","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regulation of cerebral blood flow by arterial PCO<sub>2<\/sub> independent of metabolic acidosis at 5050\u00a0m"],"prefix":"10.1113","volume":"599","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6072-7277","authenticated-orcid":false,"given":"Hannah G.","family":"Caldwell","sequence":"first","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Integrative Physiology Laboratory Department of Kinesiology and Nutrition University of Illinois Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nia C.S.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-0059","authenticated-orcid":false,"given":"Ryan L.","family":"Hoiland","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Pharmacology and Therapeutics Vancouver General Hospital, West 12th Avenue, University of British Columbia  Vancouver British Columbia 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UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0818-6420","authenticated-orcid":false,"given":"Michael","family":"Stembridge","sequence":"additional","affiliation":[{"name":"Cardiff School of Sport and Health Sciences Cardiff Metropolitan University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith R.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Peninsula Sleep Clinic  Sydney New South Wales Australia"},{"name":"Department of Medicine University of Sydney  Sydney New South Wales Australia"}],"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":"Human Pharmacology and Physiology Lab Department of Anesthesiology Duke University Medical Center  Durham North Carolina 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