Nitrogen dioxide causes pulmonary arterial relaxation via thiol nitrosation and NO formation.
Micromolar concentrations of nitrogen dioxide (NO2), a key metabolite of nitric oxide (NO) and peroxynitrite (ONOO-), were observed to cause a prolonged relaxation of isolated endothelium-removed rings of bovine pulmonary arteries (BPA) precontracted with 30 mM potassium. Relaxation to NO2 was markedly inhibited by 1 microM hemoglobin (Hb), 10 microM methylene blue (MB), and 10 microM LY-83583. The response to NO2 was enhanced in the presence of 1 mM reduced glutathione (GSH) or cysteine. The addition of NO2 to Krebs bicarbonate buffer (under 95% N2-5% CO2) containing 1 mM GSH or BPA resulted in an increase in NO formation (measured in head space gas). Relaxation to NO2 and NO formation were markedly decreased after GSH depletion by pretreatment of BPA with diethyl maleate. A high-performance liquid chromatography analysis of the products formed immediately after the addition of NO2 to GSH detected a previously isolated (but not identified) potent relaxing agent formed by a reaction of GSH with ONOO-, and this material comigrated with a synthetic product thought to be S-nitro-GSH (GSNO2). Nanomolar concentrations of GSNO2 caused a potent dose-dependent relaxation that was inhibited by Hb, MB, and LY-83583. Therefore NO2 appears to cause a prolonged guanosine 3',5'-cyclic monophosphate-mediated relaxation in BPA via thiol nitration and a subsequent time-dependent release of NO. Thus NO2 (and ONOO-) may function in a tissue hormonelike regulatory role in inflammatory processes in which large amounts of these species are produced.
Davidson
C A
CA
Department of Physiology, New York Medical College, Valhalla 10595, USA.
Kaminski
P M
PM
Wu
M
M
Wolin
M S
MS
D000818:Animals; D002417:Cattle; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D005978:Glutathione; D003545:Cysteine; D009585:Nitrogen Dioxide