NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventil ation but may also result in chronic pulmonary hypertension. It has not bee n clarified whether acute HPV and the response to prolonged alveolar hypoxi a are triggered by identical mechanisms. We characterized the vascular resp onse to sustained hypoxic ventilation (3% O-2 for 120-180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pr essure (PAP). Persistent PAP elevation was observed after termination of hy poxia. Total blockage of lung nitric oxide (NO) formation by N-G-monomethyl -L-arginine caused a two- to threefold amplification of acute HPV, the sust ained pressor response, and the loss of posthypoxic relaxation. This amplif ication was only moderate when NO formation was partially blocked by the in ducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenet etramine reduced the initial vasoconstrictor response, the prolonged PAP in crease, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the lat e vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implic ated in the prolonged pressor response and the posthypoxic loss of vasorela xation in perfused rabbit lungs undergoing 2-3 h of hypoxic ventilation.