title: High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability.
abstract: High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A(·-)), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv(D)) resulting in a net transpulmonary loss of ascorbate, α-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv(D) and net output of A(·-) and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability.
authors.affiliation: Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, South Wales, UK. dbailey1@glam.ac.uk
authors.forename: Damian M
authors.initials: DM
authors.lastname: Bailey
authors.forename: Christoph
authors.initials: C
authors.lastname: Dehnert
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Luks
authors.forename: Elmar
authors.initials: E
authors.lastname: Menold
authors.forename: Christian
authors.initials: C
authors.lastname: Castell
authors.forename: Guido
authors.initials: G
authors.lastname: Schendler
authors.forename: Vitalie
authors.initials: V
authors.lastname: Faoro
authors.forename: Mariusz
authors.initials: M
authors.lastname: Gutowski
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Evans
authors.forename: Sarah
authors.initials: S
authors.lastname: Taudorf
authors.forename: Philip E
authors.initials: PE
authors.lastname: James
authors.forename: J
authors.initials: J
authors.lastname: McEneny
authors.forename: Ian S
authors.initials: IS
authors.lastname: Young
authors.forename: Erik R
authors.initials: ER
authors.lastname: Swenson
authors.forename: Heimo
authors.initials: H
authors.lastname: Mairbäurl
authors.forename: Peter
authors.initials: P
authors.lastname: Bärtsch
authors.forename: Marc M
authors.initials: MM
authors.lastname: Berger
mesh_terms: D000328:Adult; D000532:Altitude Sickness / Q000188:drug therapy / Q000503:physiopathology; D000959:Antihypertensive Agents / Q000627:therapeutic use; D005260:Female; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism*; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D008168:Lung / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009543:Nifedipine / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000627:therapeutic use; D011659:Pulmonary Gas Exchange / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D005609:Free Radicals; D009569:Nitric Oxide; D009543:Nifedipine; D010100:Oxygen