AJP - Lung Cellular and Molecular Physiology, Vol 268, Issue 5 747-L752, Copyright © 1995 by American Physiological Society
Effects of NADPH oxidase inhibitors on hypoxic vasoconstriction in buffer-perfused rabbit lungs
F. Grimminger, N. Weissmann, R. Spriestersbach, E. Becker, S. Rosseau and W. Seeger
Department of Internal Medicine, Justus Leibig University, Giessen, Germany.
The involvement of NADPH oxidase in hypoxic pulmonary vasoconstriction
(HPV) was investigated in buffer-perfused rabbit lungs, employing the
inhibitors diphenyleneiodonium (DPI) and apocynin. Responses to the
vasoconstrictors U-46619 and angiotensin II (ANG II) were used to test
specificity. Lung nitric oxide (NO) generation was assessed by on-line
monitoring of NO exhalation (chemiluminescence), and the efficacy of DPI
and apocynin on the NADPH oxidase-dependent O2- generation was quantified
in alveolar macrophages by fluorescent-activated cell sorter technique. In
a concentration range between 1 and 5 mM, apocynin inhibited macrophage
respiratory burst and HPV but similarly suppressed U-46619-induced
vasoconstrictor responses. DPI inhibited macrophage O2- generation in
concentrations > or = 0.5 microM. At doses between 0.5 and 1.5 microM,
DPI blocked lung NO generation, thereby increasing HPV. At higher doses (4
microM), in contrast, DPI fully blocked the hypoxia-induced pressor
responses, whereas the vasoconstrictor responses to U-46619 and [Asn1,
Val5] ANG II were not diminished. In the presence of
NG-monomethyl-L-arginine, used to block lung NO generation throughout, DPI
exhibited only the monophasic selective inhibition of HPV. We conclude that
apocynin lacks specificity for HPV, but DPI, in addition to inhibiting lung
NO generation, causes selective blockade of the hypoxia-induced
vasoconstriction. This finding supports the hypothesis that an NADPH
oxidase is involved in hypoxia sensing or specific signal transduction
events underlying HPV.
