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Published ahead of print on June 5, 2003, doi:10.1165/rcmb.2002-0217OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 721-732

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Submitted on October 17, 2002
Revised on June 3, 2003

Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs

Norbert Weissmann1*, Nadine Ebert1, Marit Ahrens1, Hossein A Ghofrani1, Ralph T Schermuly1, Joerg Haenze1, Ludger Fink1, Frank Rose1, Joerg Conzen1, Werner Seeger1, and Friedrich Grimminger1

1 Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany

* To whom correspondence should be addressed. E-mail: Norbert.Weissmann{at}innere.med.uni-giessen.de.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange, however, the underlying mechanism has not yet been fully elucidated. Lung NO generation appears to be involved in this process. Recently, mitochondria have been proposed as oxygen sensors, with HPV-signaling via a hypoxia-induced increase in the generation of reactive oxygen species derived from mitochondrial complex III and escaping through an anion channel into the cytoplasm. In addition, complex II has been suggested to be specifically involved in hypoxia-depended generation of reactive oxygen species in the lung. We investigated the effects of several mitochondrial inhibitors and uncouplers on the strength of HPV and asked for their capacity to mimic HPV during normoxia in isolated buffer-perfused rabbit lungs. Specificity of the agents for HPV was tested by comparison of their effects on non-hypoxia-induced vasoconstriction, elicited by the thromboxane mimetic U46619. Interference with NO metabolism was determined by performing parallel studies with blocked lung NO generation and by measurement of exhaled NO. Rotenone, 3-nitroproprionic acid (3-NPA), and myxothiazol dose-dependently inhibited HPV without being mimics of HPV during normoxia. The inhibitory effect of these agents was only partly specific for HPV by comparison with U46619-induced vasoconstriction. During pre-blocked lung NO synthesis, the selectivity for HPV inhibition was increased for rotenone, but largely lost for myxothiazol. 2-tenoyltrifluoroacetone (TTFA) resulted in an unspecific inhibition of HPV as compared to U46619-induced vasoconstriction. 1-methyl-4-phenylpyridinium iodide (MPP+) and 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO) specifically suppressed HPV and increased normoxic vascular tone. Antimycin A suppressed HPV, an effect being specific in lungs with intact NO synthesis and only partly specific while blocking NO. However, this agent did not mimic HPV during normoxia, as may be expected for interference with the mitochondrial electron transport downstream incomplex III. The uncouplers 2,4-dinitrophenol (DNP, 10-200µM) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, 1-3µM) induced sustained vasoconstriction during normoxia, with enhancement of HPV by DNP at low and suppression of HPV for both agents at high concentrations. The anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) inhibited HPV and U46619-induced vasoconstriction with identical dose-response curves. These findings suggest that mitochondria are in some manner involved in the regulation of HPV in intact rabbit lungs. The hypothesis that enhanced superoxide leak at complex III of mitochondria represents the underlying mechanism of acute HPV is supported by the rotenone and HQNO data, but partly contradicted by the findings with MPP + , antimycin A, DNP, and FCCP. Further studies are mandatory to clarify the link between mitochondrial respiratory chain and hypoxic pulmonary vasoconstriction.




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