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PubMed2002

Nitric oxide, inducible nitric oxide synthase and inflammation in veterinary medicine.

Inflammation is a process consisting of a complex of cytological and chemical reactions which occur in and around affected blood vessels and adjacent tissues in response to an injury caused by a physical, chemical or biological insult. Much work has been performed in the past several years investigating inducible nitric oxide synthase (NOS, EC 1.14.13.39) and nitric oxide in inflammation. This has resulted in a rapid increase in knowledge about iNOS and nitric oxide. Nitric oxide formation from inducible NOS is regulated by numerous inflammatory mediators, often with contradictory effects, depending upon the type and duration of the inflammatory insult. Equine medicine appears to have benefited the most from the increased interest in this small, inflammatory mediator. Most of the information on nitric oxide in traditional veterinary species has been produced using models or naturally occurring inflammatory diseases of this species.

Animals↗
PubMed1998

[The role of nitric oxide and nitric oxide synthase in the pathogenesis of asthma].

OBJECTIVE: To investigate the role of nitric oxide (NO) and nitric oxide synthase (NOS) in the pathogenesis of asthma. METHOD: 52 guinea pigs were randomly divided into four groups of 13 each: (1) asthmatic group (Group A): Dunkin-Hartley guinea-pigs were injected celiacly with 1 ml of 10% ovalbumin (OA). After 14 days, the animals were inhaled with an aerosol of 1% OA for 40-60 seconds for 10 days every other day; (2) Corticosteroid prevention group (Group CT): As above, just before the animals were inhaled with an aerosol, 0.5 mg/kg dexamethasone were injected celiacly; (3) N-nitro-L arginine prevention group (Group L): As Group A, just before the animals were inhaled with an aerosol, 0.4 mg/kg LNNA were injected celiacly; (4) Controls (Group C): and nitrate (NO2.-/NO3.-) levels in plasma, nitrite bronchoalveolar lavage fluid (BALF) and lung tissues were examined. At the same time, inducible nitric oxide synthase (iNOS) and constitute nitric oxide synthase (cNOS) activity levels in the lung tissues were examined, and the changes of cNOS in the guinea pig asthma model lung tissues were observed using histochemical detection. RESULT: All groups had no significant alteration of NO2.-/NO3.- in the plasma (P > 0.05). Group A had increased amounts of NO2.-/NO3.- in the BALF and in the lung tissues compared with the other groups (BALF: Group A 10.2 +/- 1.3, Group CT 7.2 +/- 1.1, Group L 7.3 +/- 1.3, Group C 6.2 +/- 0.8 mumol/L respectively, all of P < 0.01; the lung tissues: Group A 0.89 +/- 0.07, Group CT 0.16 +/- 0.09, Group L 0.24 +/- 0.09, Group C 0.18 +/- 0.05 nmol/mg respectively, all of P < 0.01). Group A also showed increased amounts of iNOS levels in the lung tissues than the other groups (Group A 59 +/- 18, Group CT 10 +/- 5, Group L 12 +/- 7, Group C 10 +/- 5 pmol/mg respectively, all of P < 0.01). Group L showed decreased amounts of cNOS levels in the lung tissues than the Group C (0.8 +/- 0.4, 1.2 +/- 0.4 fmol/mg, P < 0.05). While there were no significant alterations in the other groups (P > 0.05). Elevation of iNOS in the lung tissues was correlated with NO2-/NO3- in the BALF and in the lung tissues (r = 0.714, 0.842, respectively, P < 0.05, 0.01 respectively). NADPHd was found to be a histochemical marker reflecting cNOS activity. It was found that there was no marked alteration of cNOS activity in the Group A, Group CT and Group C, but lower in the Group L. CONCLUSION: There is increased production of iNOS in asthmatic guinea pigs, the iNOS produced could cause increased production of NO, and probably cause cytotoxicity and mediate airway hyperresponsiveness. NO and NOS may play an important role in the pathogenesis of asthma.

Animals↗
PubMed2002

The catabolic fate of nitric oxide: the nitric oxide oxidase and peroxynitrite reductase activities of cytochrome oxidase.

Stimulation of cardiomyocytes to endogenously evolve nitric oxide is shown by microsensor measurements on single cells to lead to transient nitric oxide concentrations of a few hundred nanomolar. At these submicromolar concentrations, no evidence could be found for the expected reaction between nitric oxide generated and the oxymyoglobin present in the cells: nitric oxide + oxymyoglobin --> nitrate + metmyoglobin. No metmyoglobin formation was detected by electron paramagnetic resonance spectroscopy, and microsensor measurements revealed near quantitative conversion of the nitric oxide to nitrite rather than nitrate ion. Moreover, the rate of nitrite formation is shown to be too rapid to be accounted for by non-enzymatic means. The essentially quantitative and rapid catabolism of nitric oxide to nitrite ion can plausibly be explained on the basis of a cycle of reactions catalyzed by cytochrome c oxidase. It is demonstrated with the purified hemoproteins in vitro that the terminal oxidase can outcompete oxymyoglobin for available nitric oxide. It is proposed that under normal physiological and most pathological (non-inflammatory) conditions, reaction with cytochrome c oxidase is the major route by which NO is removed from mitochondria-rich cells.

Animals↗
PubMed2005

Estrogen up-regulates inducible nitric oxide synthase, nitric oxide, and cyclooxygenase-2 in splenocytes activated with T cell stimulants: role of interferon-gamma.

Estrogen is implicated in many autoimmune diseases and is a robust immunomodulator. For example, it regulates interferon (IFN)-gamma, a cytokine believed to up-regulate inducible nitric oxide synthase (iNOS). A notable gap in the literature is a lack of information on the regulation of nitric oxide in immune tissues by estrogen. We now show that activation of splenocytes with T cell stimulants [concanavalin-A (Con-A) or anti-CD3 antibodies] results in copious release of nitric oxide in splenocyte cultures from estrogen-treated but not placebo-treated mice. Moreover, even a low dose of T cell stimulants induced nitric oxide in splenocytes from estrogen-treated, but not placebo-treated, mice. Con-A-activated splenocytes from estrogen-treated mice also have up-regulated iNOS mRNA, iNOS protein, and cyclooxygenase-2 (a nitric oxide-regulated downstream proinflammatory protein) when compared with controls. Our studies suggest that the induction of nitric oxide by activated splenocytes from estrogen-treated mice is mediated in part by IFNgamma. First, blocking costimulatory signals mediated through interactions of CD28 and B7 molecules by CTLA-4Ig markedly decreased not only IFNgamma but also nitric oxide. Second, estrogen treatment of IFNgamma-knockout (IFNgamma(-)/(-)) mice did not induce iNOS protein or nitric oxide. Finally, in vitro addition of recombinant IFNgamma to Con-A-activated splenocytes from IFNgamma((-)/(-)) mice induced iNOS protein primarily in estrogen-treated mice. Overall, this is the first report to show that estrogen treatment up-regulates IFNgamma-inducible-iNOS gene expression, iNOS protein, nitric oxide, and cyclooxygenase-2 as an indirect consequence of activation of T cells. These findings may have wide implications to immunity and inflammatory disorders including female-predominant autoimmune diseases.

Animals↗
PubMed1996

Induction of nitric oxide and nitric oxide synthase mRNA by silica and lipopolysaccharide in PMA-primed THP-1 cells.

Nitric oxide (NO), a nitrogen-free radical, plays an important role in mediating inflammatory reaction and cytotoxicity of tissue. To determine whether NO was involved in silica-induced pulmonary tissue damage, we studied the effects of silica on nitric oxide (NO) production and inducible NO synthase (iNOS) mRNA expression by THP-1 cells, a monocyte-like cell line with properties of the pulmonary alveolar macrophage. Experimental results showed that silica elicited a marked stimulation of nitric oxide production in a time-dependent manner by THP-1 cells in vitro following the priming of these cells with the phorbol ester PMA. Both nitric oxide synthase inhibitor N-monomethyl-L-arginine (NMMA) and xanthine oxidase inhibitor allopurinol can partially suppress silica-induced NO production in PMA-primed THP-1 cells. Northern blot analysis indicated that, after 2 h of silica exposure, PMA-primed THP-1 cells began to express iNOS mRNA, which reached peak expression at 8 h. Endotoxin treatment of these cells produced a similar effect. These results indicated that silica is a potent inducer of NO production in macrophages and its ability to induce tissue damage may partially be attributed to its ability to initiate excessive production of nitric oxide from macrophages.

Allopurinol↗
PubMed2005

Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis.

There is a complex pathophysiologic scenario involving nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the reduction in bioactivity of eNOS with subsequent impaired release of NO. An important mechanism is local enhanced degradation of NO by increased generation of reactive oxygen species and other free radicals, with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Novel molecular approaches have resulted in the development of new strains of mice lacking eNOS. These experimental models will help to understand how to implement NO-based therapies against atherosclerosis. L-arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. The target or goal for new drugs should be the complete restoration of NO-mediated signaling pathways in atherosclerotic arteries.

Arginine↗
PubMed2004

Novel features of nitric oxide, endothelial nitric oxide synthase, and atherosclerosis.

There is a complex pathophysiologic scenario involving nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the reduction in bioactivity of ENOS with subsequent impaired release of NO. An important mechanism is local enhanced degradation of NO by increased generation of reactive oxygen species and other free radicals, with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Novel molecular approaches have resulted in the development of new strains of mice lacking eNOS. These experimental models will help to understand how to implement NO-based therapies against atherosclerosis. L-arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. The target or goal for new drugs should be the complete restoration of NO-mediated signaling pathways in atherosclerotic arteries.

Animals↗
PubMed2001

Nitric oxide and nitric oxide synthase in Huntington's disease.

Nitric oxide (NO) is a biologically active inorganic molecule produced when the semiessential amino acid l-arginine is converted to l-citrulline and NO via the enzyme nitric oxide synthase (NOS). NO is known to be involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission, neuromodulation, and inflammation, to name only a few. During neuropathological conditions, the production of NO can be either protective or toxic, dependent on the stage of the disease, the isoforms of NOS involved, and the initial pathological event. This paper reviews the properties of NO and NOS and the pathophysiology of Huntington's disease (HD). It discusses ways in which NO and NOS may interact with the protein product of HD and reviews data implicating NOS in the neuropathology of HD. This is followed by a synthesis of current information regarding how NO/NOS may contribute to HD-related pathology and identification of areas for potential future research.

Animals↗
PubMed2005

Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors.

The biosynthesis and release of nitric oxide (NO) and prostaglandins (PGs) share a number of similarities. Two major forms of nitric-oxide synthase (NOS) and cyclooxygenase (COX) enzymes have been identified to date. Under normal circumstances, the constitutive isoforms of these enzymes (constitutive NOS and COX-1) are found in virtually all organs. Their presence accounts for the regulation of several important physiological effects (e.g. antiplatelet activity, vasodilation, and cytoprotection). On the other hand, in inflammatory setting, the inducible isoforms of these enzymes (inducible NOS and COX-2) are detected in a variety of cells, resulting in the production of large amounts of proinflammatory and cytotoxic NO and PGs. The release of NO and PGs by the inducible isoforms of NOS and COX has been associated with the pathological roles of these mediators in disease states as evidenced by the use of selective inhibitors. An important link between the NOS and COX pathways was made in 1993 by Salvemini and coworkers when they demonstrated that the enhanced release of PGs, which follows inflammatory mechanisms, was nearly entirely driven by NO. Such studies raised the possibility that COX enzymes represent important endogenous "receptor" targets for modulating the multifaceted roles of NO. Since then, numerous papers have been published extending the observation across various cellular systems and animal models of disease. Furthermore, other studies have highlighted the importance of such interaction in physiology as well as in the mechanism of action of drugs such as organic nitrates. More importantly, mechanistic studies of how NO switches on/off the PG/COX pathway have been undertaken and additional pathways through which NO modulates prostaglandin production unraveled. On the other hand, NO donors conjugated with COX inhibitors have recently found new interest in the understanding of NO/COX reciprocal interaction and potential clinical use. The purpose of this article is to cover the advances which have occurred over the years, and in particular, to summarize experimental data that outline how the discovery that NO modulates prostaglandin production has impacted and extended our understanding of these two systems in physiopathological events.

Animals↗
PubMed2006

[Effects of paeoniflorin on cerebral energy metabolism, nitric oxide and nitric oxide synthase after cerebral ischemia in mongoliagerbils].

OBJECTIVE: To explore the effects of paeoniflorin on antagonising the delayed neuronal death (DND) induced by cerebral ischemia,and the relation between DND, cerebral tissue energy metabolism, nitric oxide (NO) and nitric oxide synthase (NOS). METHOD: Incomplete cerebral ischemia induced was induced by ligating bilateral arteries carotis communis for 20 min followed by reperfusion 48 h in rats. The indexes including Na(+)-K(+)-ATPase activity, lactic acid content, Ca(2+)-ATPase, Mg(2+)-ATPase activity, NO content and NOS activity were determined in fore brain cortex at 48 h after reperfusion. RESULT: Na(+)-K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase activity were lowered (P < 0.01), NO level was decreased (P < 0.01), NOS activity dropped (P < 0.01) in cerebral tissue at 48h after reperfusion, but lactic acid level had no change. Paeoniflorin could prevent reduction of Na(+)-K(+)-ATPase activity (P < 0.05, P < 0.01), increase NO level (P < 0.01), enhance NOS activity (P < 0.01) at 48h after reperfusion. CONCLUSION: DND induced by ischemia may be concerned with energy metabolism disorder and decrease of NO formation. Paeoniflorin may play the role of antagonising cerebral ischemia by adjusting cerebral energy metabolism and nitric oxide formation.

Animals↗
PubMed2001

Aspirin dose dependently inhibits the interleukin-1 beta-stimulated increase in inducible nitric oxide synthase, nitric oxide, and prostaglandin E(2) production in rat ovarian dispersates cultured in vitro.

OBJECTIVE: Determine if aspirin inhibits the IL-1 beta-stimulated expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO), and prostaglandin E(2) (PGE(2)) in rat ovarian dispersates cultured in vitro. DESIGN: Prospective, controlled in vitro study. SETTING: Academic research laboratory. ANIMALS: Ovaries collected from immature rats. INTERVENTION(S): Ovaries were collected from immature rats and enzymatically dispersed. Ovarian dispersates were placed into plates containing media alone or media supplemented with IL-1 beta (100 U/mL) and varying concentrations of aspirin (0, 1, 3, 5 and 10 mM). Ovarian dispersates were cultured in a humidified environment of 5% CO(2) in air at 37 degrees C for 24 or 48 hours. MAIN OUTCOME MEASURE(S): Twenty-four- and 48-hour iNOS, nitrite (a stable metabolite of NO), and PGE(2) levels were determined from ovarian dispersates cultured in vitro. RESULT(S): Administration of IL-1 beta increased nitrite and PGE(2) levels over that observed in the control group after culture of ovarian dispersates for 24 and 48 hours. Aspirin dose dependently reduced the IL-1 beta-stimulated increase in nitrite production from ovarian dispersates after culture for 24 and 48 hours. Aspirin completely (24 hours) or dose dependently (48 hours) prevented the IL-beta-stimulated increase in PGE(2.) Coadministration of IL-1 beta and aspirin (10 mM) attenuates IL-1 beta-stimulated iNOS expression after culture for 24 and 48 hours. CONCLUSION(S): Aspirin significantly inhibits the IL-1 beta-stimulated expression of iNOS, NO, and PGE(2) in ovarian dispersates cultured in vitro.

Animals↗
PubMed1999

Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization.

Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca2+/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and arginases for L-arginine utilization, and by potent inhibition of arginase activity by N(omega)-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.

Animals↗
PubMed1996

[Study of nitric oxide synthases, nitric oxide and tumor necrosis factor in different types of ascites].

The purpose of this study was to elucidate the clinical significance of nitric oxide synthases (NOS), nitric oxide (NO) and tumor necrosis factor (TNF) in different types of ascites. NOS, NO and TNF in ascitic transudates of 21 patients with liver cirrhosis, ascitic exudate of 32 patients with liver cirrhosis and carcinogenesic ascites of 19 patients were measured by Griess, ELISA and colorimetric methods. Compares to the value in ascitic transudate of 21 patients with liver cirrhosis, NOS (7.32 +/- 3.13 nmol.min-1.g-1), NO (15.4 +/- 7.6 mumol/L) and TNF (331.7 +/- 121.2 mumol/L) in ascitic exudate of 32 patients with liver cirrhosis were significantly higher (P < 0.01). The NO (10.7 +/- 3.2 mumol/L) and TNF (185.6 +/- 84.1 mumol/L) in carcinogenesic ascites of 19 patients were between those in ascitic exudates and those in ascitic transudates of patients with liver cirrhosis (P < 0.05 or 0.01). The NOS activity was highest in carcinogenesic ascites. The decrease of 24h urine volume in patients with cirrhosis was relative to the increase of NO level in ascites. Those suggested that measurements of NOS, NO and TNF in ascites are helpful in differential diagnosis of ascites. The separation between NO level and NOS activity in ascites indicates that the ascites is carcinogenesis.

Adolescent↗
PubMed2006

[Effect of nitric oxide and nitric oxide synthase on sensorineural hearing loss secondary to secretory otitis media].

OBJECTIVE: To evaluate the effect of nitric oxide synthase (NOS) and nitric oxide(NO) on sensorineural hearing loss (SNHL) secondary to secretory otitis media (SOM). METHOD: Samples of middle ear effusion were collected at the time of tympanocentesis from 16 cases of SOM with SNHL(group A) and 16 cases of SOM without SNHL(group B). And the concentration of NO and NOS activity in middle ear effusion were detected by colorimetric assay (Griess method). RESULT: The concentration of NO in group A (181.19 +/- 44.31) micromol/L was significantly higher than that in group B (137.00 +/- 40.67) micromol/L (P < 0.01). The NOS activity in group A (97.69 +/- 29.62)U was also significantly higher than that in group B (75.50 +/- 26.99)U (P < 0.05). CONCLUSION: Excess generation of NO in middle ear effusion which synthesized by NOS may hurt inner ear directly by its cytotoxic action or enhance local inflammatory reaction with other inflammatory factors. This study suggests that NO play a significant role in the process and pathogenesis of SNHL secondary to SOM.

Adult↗
PubMed2001

Role of nitric oxide and nitric oxide synthases in experimental models of denervation and reinnervation.

Nitric oxide (NO) is a short-living free molecule synthesized by three different isoforms of nitric oxide synthases (NOS)-neuronal NOS, endothelial NOS, and inducible NOS-associated with neuromuscular transmission, muscle contractility, mitochondrial respiration, and carbohydrate metabolism in skeletal muscle. Neuronal NOS is constitutively expressed at the muscle fiber sarcolemma linked to the dystrophin-glycoprotein complex and concentrated at the neuromuscular endplate. There is increasing evidence that altered expression of neuronal NOS plays a role in muscle fiber damage in neuromuscular diseases such as dystrophinopathies and denervating disorders. Although there have been some previous conflicting results on the neuronal NOS expression pattern in denervated muscle fibers, it is now well established that denervation is associated with a down-regulation and disappearance of sarcolemmal neuronal NOS at synaptic/extrasynaptic or both sites. As NO has been shown to induce collapse and growth arrest on neuronal growth cones, down-regulation of sarcolemmal neuronal NOS may contribute to axonal regeneration and attraction to muscle fibers aiming at the formation of new motor endplates providing reinnervation and reconstitution of NOS expression. As NO serves as a retrograde messenger, it may trigger structural downstream events responsible for neuromuscular synaptogenesis and preventing polyneural innervation. Nevertheless, decreased NO production in denervation reduces the cytoprotective scavenger function of NO for superoxide anions promoting oxidative stress that is likely to be involved in muscle fiber damage and death. However, the multifaced role of NOS and NO under physiological and pathological conditions remains poorly understood on the basis of the current knowledge.

Animals↗
PubMed1999

Involvement of nitric oxide and nitric oxide synthase activity in anticonvulsive action.

The anticonvulsant drug Diazepam (DIA-2 mg/kg b. wt), the nitric oxide (NO) donor L-Arginine (L-Arg-2000 mg/kg b. wt) and the putative nitric oxide synthase (NOS) inhibitor N(G)-Nitro-L-Arginine methyl ester (L-NAME-50 mg/kg b. wt) were used to determine the role of endogenous NO on convulsions induced by picrotoxin (PCT-5 mg/kg b. wt) in rats. Rats given a convulsant dose of PCT (5 mg/kg b. wt) had convulsion and it suppresses the NOS activity and NO concentration in brain regions. The anticonvulsant L-Arg alone significantly increases the NO concentration and NOS activity in brain regions, but not diazepam. Whereas DIA, along with L-Arg, enhances the NO and NOS activity when compared to L-Arg alone. The combination of both OIA and L-Arg completely suppressed the convulsions. L-NAME alone had no effect to produce convulsions but it completely decreased NO concentration and NOS activity and potentiated the PCT convulsions. This was reverted by pre- and post treatment of DIA plus L-Arg indicating, the increased NO concentration and NOS activity in brain regions suppresses convulsions.

Animals↗
PubMed2000

Nitric oxide protects nitric oxide synthase function from hydroxyl radical-induced inhibition.

The interdependent relationships among nitric oxide synthase (NOS), its coenzyme, cofactors and nitric oxide (NO(free radical) were studied using electron paramagnetic resonance spectroscopy. It was found that superoxide-dependent hydroxyl free radical (OH(free radical), derived from NOS coenzyme and cofactors, inhibits NOS activity, and that endogenous NO(free radical) generated by NOS scavenges OH(free radical) and protects NOS function. These results reveal a new role for NO(free radical) that may be important in NOS function and cellular free radical homeostasis.

Coenzymes↗