Electronic versions

  • Ryan L Hoiland
    University of British Columbia
  • David B MacLeod
    Duke University Medical Center
  • Benjamin S Stacey
    University of South Wales
  • Hannah G Caldwell
    University of British Columbia, Okanagan
  • Connor A Howe
    University of British Columbia, Okanagan
  • Daniela Nowak-Flück
    University of British Columbia, Okanagan
  • Jay Mjr Carr
    University of British Columbia, Okanagan
  • Michael M Tymko
    University of British Columbia, Okanagan
  • Geoff B Coombs
    School of Health and Exercise SciencesUniversity of British Columbia, Okanagan
  • Alexander Patrician
    University of British Columbia, Okanagan
  • Joshua C Tremblay
    University of British Columbia, Okanagan
  • Michelle Van Mierlo
    University of Twente
  • Chris Gasho
    Loma Linda University School of Medicine
  • Mike Stembridge
    Cardiff Metropolitan University
  • Mypinder S Sekhon
    International Collaboration on Repair Discoveries
  • Damian M Bailey
    University of South Wales
  • Philip N Ainslie
    University of British Columbia, Okanagan

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite (NO2-) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and NO2-. Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not NO2-, while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.

Keywords

  • Humans, Nitric Oxide/metabolism, Vasodilation/physiology, Hypoxia, Hemoglobins/metabolism, Signal Transduction/physiology, Oxygen/metabolism, S-Nitrosothiols
Original languageEnglish
Pages (from-to)1519-1531
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume43
Issue number9
Early online date12 Apr 2023
DOIs
Publication statusPublished - Sept 2023
Externally publishedYes
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