NO synthases are widely distributed in the lung and are extensively involve
d in the central of airway and vascular homeostasis, It is recognized, howe
ver, that the O-2-rich environment of the lung may predispose NO toward tox
icity. These Janus faces of NO are manifest in recent clinical trials with
inhaled NO gas, which has shown therapeutic benefit in some patient populat
ions but increased morbidity in others. In the airways and circulation of h
umans, most NO bioactivity is packaged in the form of S-nitro-sothiols (SNO
s), which are relatively resistant to toxic reactions with O-2/O-2(-). This
finding has led to the proposition that channeling of NO into SNOs may pro
vide a natural defense against lung toxicity. The means to selectively mani
pulate the SNO pool, however, has not been previously possible. Here we rep
ort on a gas, O-nitrosoethanol (ENO), which does not react with Oz or relea
se NO and which markedly increases the concentration of indigenous species
of SNO within airway lining fluid. Inhalation of ENO provided immediate rel
ief from hypoxic pulmonary vasoconstriction without affecting systemic hemo
dynamics. Further, in a porcine model of lung injury, there was no rebound
in cardiopulmonary hemodynamics or fall in oxygenation on stopping the drug
(as seen with NO gas), and additionally ENO protected against a decline in
cardiac output. Our data suggest that SNOs within the lung serve in matchi
ng ventilation to perfusion, and can be manipulated for therapeutic gain. T
hus, ENO may be of particular benefit to patients with pulmonary hypertensi
on, hypoxemia, and/or right heart failure, and may offer a new therapeutic
approach in disorders such as asthma and cystic fibrosis, where the airways
may be depleted of SNOs.