Nitric oxide- and nitric oxide donors-induced relaxation and its modulation by oxidative stress in piglet pulmonary arteries

1 Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary h ypertension while inhaled NO donors have been suggested as an alternative t herapy. The differential susceptibility to inactivation by oxidative stress and oxyhaemoglobin of NO and two NO donors, sodium nitroprusside (S NP) a nd S-nitroso-N-acetyl-penicillamine (SNAP) were ana lysed in isolated endot helium-denuded pulmonary arteries from 2-week-old piglets stimulated with U 46619. 2 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 electrochemicall y in the bath after the addition of SNP and only at concentrations at which SNAP produced more than 50% relaxation. 3 The sGC inhibitor ODQ (10(-6) M) or the sarcoplasmic Ca2+-ATPase thapsiga rgin (2 x 10(-6) M) markedly inhibited the relaxation induced by NO, SNAP a nd SNP. 4 Addition of oxyhaemoglobin (3 x 10(7) M) or diethyldithiocarbamate (1 mM) markedly inhibited NO- (pIC(30) = 6.88 +/- 0.07 and 6.92 +/- 0.18, respect ively), weakly inhibited SNAP- and had no effect on SNP-induced relaxation. Xanthine oxidase (5 mu ml(-1)) plus hypoxanthine (10(-4) M) markedly inhib ited NO- (pIC(30) = 6.96 +/- 0.12) but not SNAP- or SNP-induced relaxation. 5 Superoxide dismutase (SOD), MnCl2, diphenileneiodonium and exposing the l uminal surface of the rings outwards (inversion) potentiated the relaxant r esponses 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-indnced relaxation. 6 Therefore, the kinetics and local distribution of NO release of NO donors influence the susceptibility to the scavenging effects of oxyhaemoglobin a nd superoxide.