Published online before print August 2, 2001, doi: 10.1161/hh1601.094983
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Role for Endothelin-1–Induced Superoxide and Peroxynitrite Production in Rebound Pulmonary Hypertension Associated With Inhaled Nitric Oxide Therapy
From the Department of Pediatrics (S.W., S.M.B.) and Molecular Pharmacology (S.M.B.), Northwestern University Medical School, Chicago, Ill; and Department of Cardiothoracic Surgery (D.M.M.), Pediatrics (J.R.F.) and the Cardiovascular Research Institute (J.R.F.), University of California, San Francisco, San Francisco, Calif.
Correspondence to Stephen M. Black, PhD, Research Director–Division of Neonatology, Northwestern University Medical School, Ward 12-191, 303 E Chicago Ave, Chicago, IL 60611-3008. E-mail steveblack{at}northwestern.edu
Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO. We have also demonstrated that inhaled NO elevates plasma endothelin-1 (ET-1) levels and that pretreatment with PD156707, an ETA receptor antagonist, blocks the rebound hypertension. The objectives of this study were to further elucidate the role of ET-1 in the rebound pulmonary hypertension upon acute withdrawal of inhaled NO. Inhaled NO (40 ppm) delivered to thirteen 4-week-old lambs decreased NOS activity by 36.2% in control lambs (P<0.05), whereas NOS activity was preserved in PD156707-treated lambs. When primary cultures of pulmonary artery smooth muscle cells were exposed to ET-1, superoxide production increased by 33% (P<0.05). This increase was blocked by a preincubation with PD156707. Furthermore, cotreatment of cells with ET-1 and NO increased peroxynitrite levels by 26% (P<0.05), whereas preincubation of purified human endothelial nitric oxide synthase (eNOS) protein with peroxynitrite generated a nitrated enzyme with 50% activity relative to control (P<0.05). Western blot analysis of peripheral lung extracts obtained after 24 hours of inhaled NO revealed a 90% reduction in 3-nitrotyrosine residues (P<0.05) in PD156707-treated lambs. The nitration of eNOS was also reduced by 40% in PD156707-treated lambs (P<0.05). These data suggest that the reduction of NOS activity associated with inhaled NO therapy may involve ETA receptor–mediated superoxide production. ETA receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during inhaled NO therapy.
Key Words: nitric oxide • rebound pulmonary hypertension • receptor blockade • superoxide • peroxynitrite
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