Effect of isosorbide dinitrate on nitric oxide synthase under hypoxia

Citation
Hb. Jiang et al., Effect of isosorbide dinitrate on nitric oxide synthase under hypoxia, PHARMACOL, 62(1), 2001, pp. 10-16
Citations number
28
Categorie Soggetti
Pharmacology & Toxicology
Journal title
PHARMACOLOGY
ISSN journal
00317012 → ACNP
Volume
62
Issue
1
Year of publication
2001
Pages
10 - 16
Database
ISI
SICI code
0031-7012(2001)62:1<10:EOIDON>2.0.ZU;2-0
Abstract
Nitric oxide synthase (NOS) catalyzes nitric oxide (NO) formation from L-ar ginine in the presence of molecular oxygen and NADPH. NO is involved in the regulation of microvasculature. Isosorbide dinitrate (ISDN) and glyceryl t rinitrate (GTN) have been widely used as vasodilators to treat acute myocar dial ischemia, their biological effects being due to the release of NO. In this investigation, the effects of ISDN and GTN on NOS activity in the pres ence or absence of oxyhemoglobin under hypoxia and normoxia were studied. T he apparent K-m values for molecular oxygen were 21.6 +/- 1.5 and 9.4 +/- 1 .3 mu mol/l for nNOS and eNOS, respectively. ISDN liberated NO in a concent ration- and pH-dependent manner, but no differences between hypoxia and nor moxia were observed. The NO release from ISDN was also measured directly by an electron spin resonance spectral method with N-(dithiocarboxy)sarcosine -Fe complex as a NO-trapping agent. ISDN increased nNOS and eNOS activities in the presence of 30 mu mol/l oxyhemoglobin under hypoxia, while it did n ot affect nNOS and eNOS activities under normoxia. In the absence of oxyhem oglobin, ISDN inhibited nNOS and eNOS activities under both hypoxic and nor moxic experimental conditions. The rate of oxygen release from oxyhemoglobi n under hypoxia was increased 3 times in the presence of 1 mmol/l ISDN. In contrast to ISDN, GTN could not release NO spontaneously, and it also did n ot affect nNOS and eNOS activities in the absence or presence of 30 mu mol/ l oxyhemoglobin under both hypoxic and normoxic conditions. These results i ndicated that the NO release from ISDN is different from that of GTN, and t he increase of NOS activity by ISDN in the presence of oxyhemoglobin under hypoxia is ascribed to the increase in molecular oxygen concentration. Copy right (C) 2001 S. Karger AG, Basel.