Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1

Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicle-treated control lambs and six PD-156707 (an ET(A) receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 +/- 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET-1, endothelin-converting enzyme-1alpha, and ET(A) and ET(B) receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (-5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET(A) receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.     

The role of nitric oxide in the pathogenesis of multiple sclerosis

Nitric oxide is a free radical gas, NO, of paramount relevance in biology. The enzymes responsible for the synthesis of NO from L-arginine in mammalian tissues are known as nitric oxide synthases (NOS). The inducible NOS (iNOS) is associated with the development of a number of autoimmune diseases. iNOS is induced on monocytes, cells playing a key role in the initiation and progression of the immune response. Induction of the enzyme is effected by proinflammatory cytokines, immunomodulating peptides, and even beta-endorphin through a mechanism involving an increase in cAMP. An excessive production of NO has been implicated in the severe lesions observed in multiple sclerosis (MS). Nitrosation of proteins caused by NO in monocytes may contribute to the formation of new epitopes involved in the autoimmune response. Monocytes/macrophages enhance also their cytotoxic capacity through an increase in NO. iNOS seems to establish a link between neuroendocrine and immune system through beta-endorphin explaining stress-related relapses in MS. One of the causes of demyelination is the lysis of oligodendrocytes by cytotoxic T lymphocytes (CTLs); and T cell response is also known to be modulated by NO.     

The role of nitric oxide in the development of diabetic angiopathy.

Diabetic angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of diabetic angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroangiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term diabetic complications.     

The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives

Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.     

低氧对高原鼠兔和大鼠血液NO 与ET-1的影响

将Wistar大鼠暴露于3 780 m低氧环境,分别于24 h、2 wk及3 wk后采用酶联免疫法和硝酸还原酶法测定血液中的ET~(-1)和NO的含量,计算NO/ET~(-1)值,并与高原鼠兔比较,探讨低氧条件下大鼠与高原鼠兔血液中NO与ET~(-1)含量的变化趋势。结果表明,低氧24 h后,大鼠血液中NO和ET~(-1)的含量显著高于同海拔的高原鼠兔(P<0·01),而NO/ET~(-1)值无显著差异(P>0·05)。随着大鼠在高海拔停留时间的延长,血液中NO含量呈减少趋势,而ET~(-1)则有上升趋势,二者呈显著的负相关(r2=0·2416,P<0·01)。高原鼠兔NO/ET~(-1)值约为大鼠低氧2 wk和3 wk的2倍(P<0·01)。说明不同低氧暴露时间,高原鼠兔和大鼠的NO、ET~(-1)及NO/ET~(-1)值有显著差异,提示NO/ET~(-1)值可以作为有机体是否适应高原低氧环境的一个指标。     

Central role of nitric oxide in the pathogenesis of rheumatoid arthritis and sysemic lupus erythematosus

Nitric oxide (NO) has been shown to regulate T cell functions under physiological conditions, but overproduction of NO may contribute to T lymphocyte dysfunction. NO-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Several studies reported increased endogenous NO synthesis in both SLE and RA, and recent evidence suggests that NO contributes to T cell dysfunction in both autoimmune diseases. The depletion of intracellular glutathione may be a key factor predisposing patients with SLE to mitochondrial dysfunction, characterized by mitochondrial hyperpolarization, ATP depletion and predisposition to death by necrosis. Thus, changes in glutathione metabolism may influence the effect of increased NO production in the pathogenesis of autoimmunity.     

Hypoxia-induced pulmonary endothelin-1 expression is unaltered by nitric oxide.

Nitric oxide (NO) attenuates hypoxia-induced endothelin (ET)-1 expression in cultured umbilical vein endothelial cells. We hypothesized that NO similarly attenuates hypoxia-induced increases in ET-1 expression in the lungs of intact animals and reasoned that potentially reduced ET-1 levels may contribute to the protective effects of NO against the development of pulmonary hypertension during chronic hypoxia. As expected, hypoxic exposure (24 h, 10% O(2)) increased rat lung ET-1 peptide and prepro-ET-1 mRNA levels. Contrary to our hypothesis, inhaled NO (iNO) did not attenuate hypoxia-induced increases in pulmonary ET-1 peptide or prepro-ET-1 mRNA levels. Because of this surprising finding, we also examined the effects of NO on hypoxia-induced increases in ET peptide levels in cultured cell experiments. Consistent with the results of iNO experiments, administration of the NO donor S-nitroso-N-acetyl-penicillamine to cultured bovine pulmonary endothelial cells did not attenuate increases in ET peptide levels resulting from hypoxic (24 h, 3% O(2)) exposure. In additional experiments, we examined the effects of NO on the activity of a cloned ET-1 promoter fragment containing a functional hypoxia inducible factor-1 binding site in reporter gene experiments. Whereas moderate hypoxia (24 h, 3% O(2)) had no effect on ET-1 promoter activity, activity was increased by severe hypoxic (24 h, 0.5% O(2)) exposure. ET-1 promoter activity after S-nitroso-N-acetyl-penicillamine administration during severe hypoxia was greater than that in normoxic controls, although activity was reduced compared with that in hypoxic controls. These findings suggest that hypoxia-induced pulmonary ET-1 expression is unaffected by NO.     

Effects of estrous synchronization on response to nitric oxide donors, nitric oxide synthase inhibitors, and endothelin-1 in vitro

Two experiments were conducted to determine the effects of nitric oxide (NO) donors, endothelin-(ET-1), and NO synthase (NOS) inhibitors on bovine luteal function in vitro. In experiment 1, estrus in Brahman cows was synchronized with Synchro-Mate-B (SMB) and day-13-14 corpora luteal slices were weighed, diced and incubated in vitro. Treatments (100 ng/ml) were: vehicle, N[see symbol in text]-nitro-L-arginine-L-methyl ester (L-NAME), N(G)-monomethyl-L-arginine acetate (L-NMMA), diethylenetriamine (DETA), DETA-NONOate, sodium nitroprusside (SNP), or ET-1. In experiment 2, estrus was synchronized with Lutalyse, a Controlled Intravaginal Progesterone Releasing Device (CIDR), or cows were not synchronized. Corpora lutea were collected, weighed, and luteal slices were weighed, diced and incubated in vitro with treatments. Treatments (100ng/ml) were: vehicle, L- NAME, L-NMMA, DETA, DETA-NONOate, sodium nitroprusside, S-nitroso-N-acetylpenicillamine (SNAP) or endothelin-1. Tissues were incubated in M- 199 for 1 h without treatments and for 4 and 8 h in both experiments with treatments in both experiments. Media were analyzed for progesterone, prostaglandins E2 and F2alpha (PGE2, PGF2alpha) by radioimmunoassay (RIA). Hormone data in experiments 1 and 2 were analyzed by 2 x 7 and 3 x 2 x 8 factorial design for analysis of variance (ANOVA), respectively. Luteal weights in experiment 2 were analyzed by a one-way ANOVA. Concentrations of progesterone in media were similar (P > or = 0.05) among treatments within experiments. Concentrations of PGE2 in media in experiment 1 were undetectable in 90 and 57% of the samples at 4 and 8 h, respectively. PGF2alpha increased (P < or = 0.05) with time, but did not differ (P > or = 0.05) among treatments. Secretion of PGF2alpha was not affected by treatments (P > or = 0.05). In experiment 2, luteal weights of the induced estrous cycle were decreased (P < or = 0.05) by Lutalyse. Concentrations of PGE2 and PGF2alpha increased (P < or = 0.05) with time in control of all three synchronization regimens. DETA-NONOate, SNAP, sodium nitroprusside (NO donors) and ET-1 increased (P < or = 0.05) PGE2 except in the CIDR synchronized group (P > or = 0.05). No treatment increased (P > or = 0.05) PGF2alpha in any synchronization regimen. It is concluded that either SMB containing norgestomet or a CIDR containing progesterone alters luteal secretion of PGE2, Lutalyse lowers luteal weights in the induced estrous cycle, and NO or ET-1 given alone are not luteolytic agents. It is suggested that NO and ET-1 could have indirect antiluteolytic/luteotropic effects via increasing PGE2 secretion by luteal tissue rather than being luteolytic.     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelia (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases(NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interest-ingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting theetiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and hasbeen associated with tumour grade, proliferation rate and expression of important signaling componentsassociated with cancer development such as the oestrogen receptor. It appears that high levels of NOSexpression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumorcells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxicallytherefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties.Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis byupregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53,poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understand-ing at the molecular level of the role of NO in cancer will have profound therapeutic implications for thediagnosis and treatment of disease.     

Inducible nitric oxide synthase (iNOS): role in asthma pathogenesis

Asthma is one of the most common chronic inflammatory disorder of the airways of the lungs, affecting more than 300 million people all over the world. Nitric oxide (NO) is endogenously produced in mammalian airways by nitric oxide synthase (NOS) and is known to regulate many aspects of human asthma, including the modulation of airway and vascular smooth muscle tone and the inflammation. Asthmatic patients show an increased expression of inducible nitric oxide synthase (iNOS) in airway epithelial cells and an increased level of NO in exhaled air. Using various NO inhibitors (non-specific or iNOS-specific) and gene knock-out experiments, controversial results have been obtained regarding iNOS's beneficial and deleterious effects in the disease. In the present review, we have attempted to summarize the results of these experiments and also the genetic studies being undertaken to understand the role of iNOS in asthma. It is argued that extensive biochemical, clinical and genetic studies will be required to assess the precise role of NO in the asthma. This may help in designing selective and more potent iNOS inhibitors and NO donors for developing novel therapeutics for the asthma patients.     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic pro     

The role of nitric oxide in cancer

Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interest-ingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties.Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53,poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understand-ing at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.     

The dichotomous role of nitric oxide in the pathogenesis of accelerated atherosclerosis associated with systemic lupus erythematosus

Atherosclerosis is an inflammatory disorder, and the inflammation associated with systemic lupus erythematosus (SLE) accelerates the development of atherosclerosis. Nitric oxide (NO) is an important mediator of inflammation including the inflammation associated with atherosclerosis and SLE. Endothelial nitric oxide synthase (NOS3)-mediated constitutive expression of NO promotes endothelial integrity and normal vascular function. In contrast, inducible nitric oxide synthase- (NOS2) mediated expression of NO promotes endothelial dysfunction and atherogenesis. Statins appear to have anti-inflammatory properties and reverse many of the deleterious effects associated with NO metabolism in atherosclerosis. Statins augment NOS3 expression and inhibit the induction of NOS2. Therefore, the balance between normal vascular function and atherogenesis may be mediated by differences in the quantity, location, and timing of NO production within vessel walls.     

植物中一氧化氮的生理作用

No是一种易扩散的生物活性分子,是生物体内重要的信号分子。植物细胞通过NO合酶,硝酸还原酶,或非生化反应途径产生NO。NO参与植物生长发育调控和对生物和非生物胁迫的应答反应。主要通过讨论No的产生,对植物生长发育的影响及在抗逆反应中的信号调节来阐述No在植物中的作用。     

Regulatory role of nitric oxide on the cardiac Na, K-ATPase in hypertension

The present study was focused on regulatory role of nitric oxide on functional properties of the cardiac Na, K-ATPase in three various animal models of hypertension: spontaneously hypertensive male rats (SHR) with increased activity of nitric oxide synthase (NOS) by 60 % (Sh1), SHR with decreased activity of NOS by 40 % (Sh2) and rats with hypertension induced by L-NAME (40 mg/kg/day) with depressed activity of NOS by 72 % (LN). Studying the utilization of energy substrate we observed higher Na, K-ATPase activity in the whole concentration range of ATP in Sh1 and decreased activity in Sh2 and LN. Evaluation of kinetic parameters revealed an increase of Vmax value by 37 % in Sh1 and decrease by 30 % in Sh2 and 17 % in LN. The KM value remained unchanged in Sh2 and LN, but was lower by 38 % in Sh1 indicating increased affinity of the ATP binding site, as compared to controls. During the activation with Na+ we observed increased Vmax by 64 % and increased KNa by 106 % in Sh1. In Sh2 we found decreased Vmax by 40 % and increased KNa by 38 %. In LN, the enzyme showed unchanged Vmax with increased KNa by 50 %. The above data indicate a positive role of increased activity of NOS in improved utilization of ATP as well as enhanced binding of Na+ by the cardiac Na, K-ATPase.     

The physiological role of nitric oxide

The review is devoted to exposition of a physiological role of a nitric oxide (NO), free radical gas, in various physiological functions. The number of those NO involvements is extremely high: bacteriocidal, cytotoxic and antitumor leukocyte effects, a relaxation of smooth-muscle cells of both vessels and gastrointestinal tract, the name just a few. The scheme of NO formation in various biological systems and its targets were shown and neuromodulator functions of NO in a brain were analyzed by the review presented. The findings of own researches on a role of NO in function of neuro-muscular synapse were included by the authors.     

Mechanisms of salt-sensitive hypertension: role of inducible nitric oxide synthase

The goal of this study was to determine the role of inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, renal excretory, and hormonal changes that occur in Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats during changes in Na intake. Thirty-two R and S rats, equipped with indwelling arterial and venous catheters, were subjected to low (0.87 mmol/day) or high (20.6 mmol/day) Na intake, and selective iNOS inhibition was achieved with intravenous aminoguanidine (AG, 12.3 mg. kg(-1). h(-1)). After 5 days of AG, mean arterial pressure increased to 121 +/- 3% control in the R-high Na AG rats compared with 98 +/- 1% control (P < 0.05) in the R-high Na alone rats, and S-high Na rats increased their arterial pressure to 123 +/- 3% control compared with 110 +/- 2% control (P < 0.05) in S-high Na alone rats. AG caused no significant changes in renal hemodynamics, urinary Na or H(2)O excretion, plasma renin activity, or cerebellar Ca-dependent NOS activity. The data suggest that nitric oxide produced by iNOS normally helps to prevent salt-sensitive hypertension in the Dahl R rat and decreases salt sensitivity in the Dahl S rat.