Hypoxic vasoconstriction in intact lungs: a role for NADPH oxidase-derivedH2O2?

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventil ation. Controversy exists whether decreased or increased reactive oxygen sp ecies may elicit HPV and from which source such oxygen metabolites are deri ved. In rabbit lungs, we detected transcripts of a nonphagocytic NADPH oxid ase subunit homologous to mitogenic oxidase-1 (Mox1) or NADPH oxidase homol og 1 (NOH-1L). In perfused rabbit lungs, we employed 1) a new NADPH oxidase inhibitor [4-( 2-aminoethyl)benzenesulfonyl fluoride (AEBSF; 100-600 mu M) ] and 2) the superoxide dismutase (SOD) inhibitors diethyldithiocarbamic ac id (DETC; 100 mu M to 10 mM) and triethylenetetramine (TETA; 1-25 mM). Spec ificity of these agents for HPV was investigated by comparison with U-46619 -induced vasoconstrictions. AEBSF induced a transient increase in pulmonary arterial pressure with increased strength of HPV. Subsequent to this initi al response, normoxic pulmonary arterial pressure was not affected and HPV was specifically suppressed. Whereas DETC turned out to act in a nonspecifi c fashion, TETA suppressed HPV specifically. These findings provide evidenc e of a role for a nonphagocytic NAD(P)H oxidase with superoxide and SOD-rel ated hydrogen peroxide formation in HPV. Because HPV was inhibited but not mimicked by the inhibitors, increased rather than decreased superoxide and/ or hydrogen peroxide formation is suggested as the hypoxia-provoked signali ng event.