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1 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
2 Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA; the International Heart Institute, University of Montana, Missoula, MT, USA
3 New York University, New York, NY, USA
4 Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA
5 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: OishiP{at}peds.ucsf.edu.
Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase activity (NOS) and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data is lacking. The objectives of this study were to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 hours of inhaled NO (40 ppm) decreased NOS activity by 40% (p<0.05), and increased ET-1 levels by 64% (p<0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P<0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than two-fold (p<0.05) following 24 hours of inhaled NO therapy. However, in lambs treated with polyethylene glycol conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, eNOS nitration was 18-fold higher (p<0.05) in control lambs than in PEG-SOD treated lambs, following 24 hours of inhaled NO. These data suggest that superoxide and peroxynitrite, participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.
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