ROLE OF ENDOGENOUS NITRIC OXIDE SYNTHASE INHIBITION IN PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN). 464

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

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Role of endogenous nitric oxide synthase inhibitor in gastric mucosal injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y08-003 ◽

2008 ◽

Vol 86 (3) ◽

pp. 97-104 ◽

Cited By ~ 17

Author(s):

Li Wang ◽

Yuan Zhou ◽

Jun Peng ◽

Zhe Zhang ◽

De-Jian Jiang ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mucosal Injury ◽

Gastric Mucosal Injury ◽

Epithelial Cell Line ◽

Tnf Α ◽

Endogenous Nitric Oxide ◽

Injury Models ◽

Oxide Synthase

To explore the role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) in gastric mucosal injury, 3 models of gastric mucosal injury induced by ethanol, indomethacin, or cold stress were used in rats. The cultured human gastric mucosal epithelial cell line GES-1 infected by Helicobacter pylori (Hp) was selected to mimic human gastric mucosal injury. Gastric mucosal ulcer index (UI), levels of ADMA and NO, and activity of dimethylarginine dimethylaminohydrolase (DDAH) were determined in the mucosal injury models; in Hp-infected or ADMA-treated GES-1 cells, levels of ADMA, NO, and TNF-α and activity of DDAH were measured. The results showed that UI and levels of ADMA were markedly increased and accompanied by significantly decreased DDAH activity in the mucosal injury models. Incubation of GES-1 cells with Hp increased levels of TNF-α and ADMA and decreased activity of DDAH. Administration of ADMA also increased levels of TNF-α. The results suggest that ADMA plays an important role in facilitating gastric mucosal injury, an effect which is associated with inhibiting NO synthesis and inducing inflammatory reaction.

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Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat

Journal of Hypertension ◽

10.1097/hjh.0b013e32833e08f1 ◽

2010 ◽

Vol 28 (11) ◽

pp. 2227-2235 ◽

Cited By ~ 48

Author(s):

Xue-Feng Xu ◽

Xiao-Lu Ma ◽

Zheng Shen ◽

Xi-Ling Wu ◽

Fen Cheng ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Nitric Oxide Synthase ◽

Epigenetic Regulation ◽

Endothelial Nitric Oxide Synthase ◽

Persistent Pulmonary Hypertension ◽

Newborn Rat ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00360.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. L1480-L1487 ◽

Cited By ~ 47

Author(s):

Akihito Sasaki ◽

Shouzaburoh Doi ◽

Shuki Mizutani ◽

Hiroshi Azuma

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Pulmonary Hypertension ◽

Nitric Oxide Synthase ◽

Pulmonary Artery ◽

Protein Expression ◽

No Production ◽

Nos Inhibitors ◽

Endogenous Nitric Oxide ◽

Oxide Synthase

Nitric oxide (NO) has been suggested to play a key role in the pathogenesis of pulmonary hypertension (PH). To determine which mechanism exists to affect NO production, we examined the concentration of endogenous nitric oxide synthase (NOS) inhibitors and their catabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) activity and protein expression (DDAH1 and DDAH2) in pulmonary artery endothelial cells (PAECs) of rats given monocrotaline (MCT). We also measured NOS and arginase activities and NOS protein expression. Twenty-four days after MCT administration, PH and right ventricle (RV) hypertrophy were established. Endothelium-dependent, but not endothelium-independent, relaxation and cGMP production were significantly impaired in pulmonary artery specimens of MCT group. The constitutive NOS activity and protein expression in PAECs were significantly reduced in MCT group, whereas the arginase, which shares l-arginine as a common substrate with NOS, activity was significantly enhanced in PAECs of MCT group. The contents of monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA), were increased in PAECs of MCT group. The DDAH activity and DDAH1, but not DDAH2, protein expression were significantly reduced in PAECs of MCT group. These results suggest that the impairment of cGMP production as a marker of NO production is possibly due to the blunted endothelial NOS activity resulting from the downregulation of endothelial NOS protein, accumulation of endogenous NOS inhibitors, and accelerated arginase activity in PAECs of PH rats. The decreased overall DDAH activity accompanied by the downregulation of DDAH1 would bring about the accumulation of endogenous NOS inhibitors.

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