title: Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans.
abstract: Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P< 0.01), a finding explained by a lower [Formula: see text] (P< 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n= 6) had no effect on CBF compared with placebo (n= 6) when end-tidal gases were comparable (P> 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHYThe signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada; ryanleohoiland@gmail.com.
authors.forename: Ryan L
authors.identifier: http://orcid.org/0000-0002-5657-0059
authors.initials: RL
authors.lastname: Hoiland
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Bain
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Tymko
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Mathew G
authors.initials: MG
authors.lastname: Rieger
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Connor A
authors.initials: CA
authors.lastname: Howe
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Willie
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Hansen
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Flück
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Wildfong
authors.affiliation: Cardiff Centre for Exercise and Health, Cardiff Metropolitan University, Cardiff, United Kingdom; and.
authors.forename: Mike
authors.initials: M
authors.lastname: Stembridge
authors.affiliation: VA Loma Linda Healthcare System and Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: Prajan
authors.initials: P
authors.lastname: Subedi
authors.affiliation: VA Loma Linda Healthcare System and Loma Linda University School of Medicine, Loma Linda, California.
authors.forename: James
authors.initials: J
authors.lastname: Anholm
authors.affiliation: Centre for Heart, Lung and Vascular Health, University of British Columbia, Okanagan Campus, School of Health and Exercise Sciences, Kelowna, British Columbia, Canada.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Ainslie
mesh_terms: D000064:Acclimatization / Q000187:drug effects / Q000502:physiology; D000328:Adult; D000531:Altitude; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D002245:Carbon Dioxide / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D010100:Oxygen / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists / Q000008:administration & dosage; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013806:Theophylline / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D002245:Carbon Dioxide; D013806:Theophylline; D010100:Oxygen
keywords: adenosine; cerebral blood flow; high-altitude; transcranial Doppler; ultrasound