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Nitric oxide‐ and nitric oxide donors‐induced relaxation and its modulation by oxidative stress in piglet pulmonary arteries
Author(s) -
LópezLópez José Gustavo,
PérezVizcaíno Francisco,
Cogolludo Angel L,
Ibarra Manuel,
ZaragozáArnáez Francisco,
Tamargo Juan
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704103
Subject(s) - nitric oxide , snap , chemistry , sodium nitroprusside , superoxide dismutase , oxidative stress , xanthine oxidase , endocrinology , myograph , thapsigargin , medicine , pharmacology , biochemistry , enzyme , extracellular , computer graphics (images) , computer science , organic chemistry
Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension while inhaled NO donors have been suggested as an alternative therapy. The differential susceptibility to inactivation by oxidative stress and oxyhaemoglobin of NO and two NO donors, sodium nitroprusside (SNP) and S‐nitroso‐N‐acetyl‐penicillamine (SNAP) were analysed in isolated endothelium‐denuded pulmonary arteries from 2‐week‐old piglets stimulated with U46619. NO, SNAP and SNP relaxed the arteries (pIC 30 =7.73±0.12, 7.26±0.17 and 6.43±0.13, respectively) but NO was not detected electrochemically in the bath after the addition of SNP and only at concentrations at which SNAP produced more than 50% relaxation. The sGC inhibitor ODQ (10 −6 M ) or the sarcoplasmic Ca 2+ ‐ATPase thapsigargin (2×10 −6 M ) markedly inhibited the relaxation induced by NO, SNAP and SNP. Addition of oxyhaemoglobin (3×10 −7 M ) or diethyldithiocarbamate (1 m M ) markedly inhibited NO‐ (pIC 30 =6.88±0.07 and 6.92±0.18, respectively), weakly inhibited SNAP‐ and had no effect on SNP‐induced relaxation. Xanthine oxidase (5 mu ml −1 ) plus hypoxanthine (10 −4 M ) markedly inhibited NO‐ (pIC 30 =6.96±0.12) but not SNAP‐ or SNP‐induced relaxation. Superoxide dismutase (SOD), MnCl 2 , diphenileneiodonium and exposing the luminal surface of the rings outwards (inversion) potentiated the relaxant responses of NO (pIC 30 =8.52±0.16, 8.23±0.11, 8.01±0.11 and 8.20±0.10, respectively). However, SOD did not modify the NO detected by the electrode and had no effect on SNAP‐ or SNP‐induced relaxation. Therefore, the kinetics and local distribution of NO release of NO donors influence the susceptibility to the scavenging effects of oxyhaemoglobin and superoxide.British Journal of Pharmacology (2001) 133 , 615–624; doi: 10.1038/sj.bjp.0704103