Impact of mitochondria and NADPH oxidases on acute and sustained hypoxic pulmonary vasoconstriction.
Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.
Weissmann
Norbert
N
University Giessen Lung Centre (UGLC), Medical Clinic II/V, Justus-Liebig-University Giessen, Klinikstrasse 36, 35392 Giessen, Germany. Norbert.Weissmann@UGLC.de
Zeller
Stefanie
S
Schäfer
Rolf U
RU
Turowski
Carmen
C
Ay
Mahmut
M
Quanz
Karin
K
Ghofrani
Hossein A
HA
Schermuly
Ralph T
RT
Fink
Ludger
L
Seeger
Werner
W
Grimminger
Friedrich
F
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D042967:Electron Transport Complex I / Q000502:physiology; D042963:Electron Transport Complex II / Q000502:physiology; D014450:Electron Transport Complex III / Q000502:physiology; D003576:Electron Transport Complex IV / Q000502:physiology; D005260:Female; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010100:Oxygen / Q000502:physiology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D011659:Pulmonary Gas Exchange; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D014662:Vasoconstrictor Agents; D013481:Superoxides; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D042963:Electron Transport Complex II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D010100:Oxygen