Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD).

• Klíčová slova
• COX-2, Cardiovascular diseases, Cyclooxygenase-2 (COX-2), Endothelial NOS (eNOS), Inducible NOS (iNOS), Nitric oxide synthase (NOS), Oxidative stress,
• MeSH
• kardiovaskulární nemoci metabolismus   MeSH
• lidé MeSH
• oxid dusnatý metabolismus   MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého MeSH

Nitric-oxide synthase (NOS) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species. Oxygen is often the overlooked substrate, and the oxygen metabolism catalyzed by NOS has been poorly defined. In this paper we focus on the oxygen stoichiometry and effects of substrate/cofactor binding on the endothelial NOS isoform (eNOS). In the presence of both L-arginine and tetrahydrobiopterin, eNOS is highly coupled (>90%), and the measured stoichiometry of O(2)/NADPH is very close to the theoretical value. We report for the first time that the presence of L-arginine stimulates oxygen uptake by eNOS. The fact that nonhydrolyzable L-arginine analogs are not stimulatory indicates that the occurrence of the coupled reaction, rather than the accelerated uncoupled reaction, is responsible for the L-arginine-dependent stimulation. The presence of 5,6,7,8-tetrahydrobiopterin quenched the uncoupled reactions and resulted in much less reactive oxygen species formation, whereas the presence of redox-incompetent 7,8-dihydrobiopterin demonstrates little quenching effect. These results reveal different mechanisms for oxygen metabolism for eNOS as opposed to nNOS and, perhaps, partially explain their functional differences.

• MeSH
• arginin chemie   metabolismus   MeSH
• biopteriny analogy a deriváty   chemie   metabolismus   MeSH
• katalýza MeSH
• kyslík chemie   metabolismus   MeSH
• lidé MeSH
• nitrosaminy chemie   metabolismus   MeSH
• oxid dusnatý chemie   metabolismus   MeSH
• reaktivní formy kyslíku chemie   metabolismus   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• synthasa oxidu dusnatého, typ I chemie   metabolismus   MeSH
• synthasa oxidu dusnatého, typ III chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• arginin MeSH
• biopteriny MeSH
• kyslík MeSH
• N-nitrosoallyl-2,3-dihydroxypropylamine MeSH Prohlížeč
• nitrosaminy MeSH
• NOS3 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• reaktivní formy kyslíku MeSH
• rekombinantní proteiny MeSH
• sapropterin MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ III MeSH

Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.

• Klíčová slova
• Endophenotypes, NOS1, Nitric oxide, Prepulse inhibition, Schizophrenia, Startle,
• MeSH
• dospělí MeSH
• exony MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• minisatelitní repetice MeSH
• oxid dusnatý fyziologie   MeSH
• prepulsní inhibice genetika   MeSH
• schizofrenie genetika   MeSH
• senzorický gating genetika   MeSH
• synthasa oxidu dusnatého, typ I genetika   MeSH
• úleková reakce genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• NOS1 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ I MeSH

The sympathetic nerve activity (SNA) is augmented in hypertension. SNA is regulated by neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) activity in hypothalamic paraventricular nuclei (PVN) and/or brainstem rostral ventrolateral medulla. High nNOS or eNOS activity within these brain regions lowers the SNA, whereas low cerebral nNOS and/or eNOS activity causes SNA augmentation. We hypothesize that the decreased cerebral nNOS/eNOS activity, which allows the enhancement of SNA, leads to the augmentation of renal eNOS/nNOS activity. Similarly, when the cerebral nNOS/eNOS activity is increased and SNA is suppressed, the renal eNOS/nNOS activity is suppressed as well. The activation of endothelial alpha(2)-adrenoceptors, may be a possible mechanism involved in the proposed regulation. Another possible mechanism might be based on nitric oxide, which acts as a neurotransmitter that tonically activates afferent renal nerves, leading to a decreased nNOS activity in PVN. Furthermore, the importance of the renal nNOS/eNOSactivity during renal denervation is discussed. In conclusion, the presented hypothesis describes the dual organ-specific role of eNOS/nNOS activity in blood pressure regulation and suggests possible connection between cerebral NOS and renal NOS via activation or inhibition of SNA, which is an innovative idea in the concept of pathophysiology of hypertension.

• MeSH
• hypertenze enzymologie   patofyziologie   MeSH
• krevní tlak * MeSH
• ledviny enzymologie   inervace   MeSH
• lidé MeSH
• mozek enzymologie   MeSH
• oxid dusnatý metabolismus   MeSH
• sympatický nervový systém patofyziologie   MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ III MeSH

Nitric oxide (NO) is implicated in a wide variety of biological roles. NO is generated from three nitric oxide synthase (NOS) isoforms: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) all of which are found in the lung. While there are no isoform-specific inhibitors of NOS, the recent development and characterization of mice deficient in each of the NOS isoforms has allowed for more comprehensive study of the importance of NO in the lung circulation. Studies in the mouse have identified the role of NO from eNOS in modulating pulmonary vascular tone and in attenuating the development of chronic hypoxic pulmonary hypertension.

• MeSH
• cévy patofyziologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• plicní hypertenze etiologie   patofyziologie   MeSH
• plicní oběh MeSH
• synthasa oxidu dusnatého fyziologie   MeSH
• vazomotorický systém fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• synthasa oxidu dusnatého MeSH

Until now, the expression and possible role of nitric oxide and nitrogen related oxidants in the human dry eye have not been investigated. Therefore, we examined immunohistochemically nitric oxide synthase isomers (NOS), enzymes generated nitric oxide, nitrotyrosine, a cytotoxic byproduct of nitric oxide and malondialdehyde, a byproduct of lipid peroxidation, in conjunctival epithelium of patients with dry eye, Sjögren's syndrome (SS). Moreover, in conjunctival epithelium of patients with dry eye (SS) the immunohistochemical staining of some pro-inflammatory cytokines was demonstrated: mature interleukin-1 beta (IL-1beta), interleukin 6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-alpha). Conjunctival epithelial cells were obtained by the method of impression cytology. Normal eyes served as controls. In contrast to the normal eyes where endothelial nitric oxide synthase (NOS3) as well as inducible nitric oxide synthase (NOS2) were only slightly expressed in conjunctival epithelium, in dry eye both NOS (mainly NOS2) were gradually expressed along the severity of dry eye symptoms which was in accord with pro-inflammatory cytokine immunodetection (IL-1beta, IL-6, IL-8, TNF-alpha) in dry eye conjunctival cytology samples. This was in contrast to normal eyes where the staining of pro-inflammatory cytokines was weak or completely absent. Peroxynitrite formation (demonstrated by nitrotyrosine residues) and lipid peroxidation (evaluated by increased malondialdehyde staining) were also found in conjunctival epithelium of dry eye with highly pronounced symptoms of dryness. In conclusion, results point to the suggestion that reactive nitrogen species are involved in the pathogenesis or self-propagation of autoimmune dry eye (SS).

• MeSH
• biologické modely MeSH
• dospělí MeSH
• dusík metabolismus   MeSH
• epitel metabolismus   MeSH
• imunohistochemie MeSH
• konjunktiva metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• oxid dusnatý metabolismus   MeSH
• oxidancia metabolismus   MeSH
• Sjögrenův syndrom metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dusík MeSH
• oxid dusnatý MeSH
• oxidancia MeSH
• synthasa oxidu dusnatého MeSH
• TNF-alfa MeSH

In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects both in vitro and in vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted.

• MeSH
• arginin chemie   MeSH
• inhibitory enzymů chemie   farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• racionální návrh léčiv MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• arginin MeSH
• inhibitory enzymů MeSH
• synthasa oxidu dusnatého MeSH

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

• MeSH
• aminochinoliny chemie   farmakokinetika   farmakologie   MeSH
• Caco-2 buňky MeSH
• fenylethery chemie   farmakokinetika   farmakologie   MeSH
• inhibitory enzymů chemie   farmakokinetika   farmakologie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminochinoliny MeSH
• fenylethery MeSH
• inhibitory enzymů MeSH
• phenyl ether MeSH Prohlížeč
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého, typ III MeSH
• synthasa oxidu dusnatého MeSH

Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. There is no vaccine against human leishmaniasis and the treatment of the disease would benefit from a broader spectrum and a higher efficacy of leishmanicidal compounds. We analyzed the leishmanicidal activity and the mechanism of action of the calcium ionophore, calcimycin. L. major promastigotes were coincubated with calcimycin and the viability of the cells was assessed using resazurin assay. Calcimycin displayed dose-dependent effect with IC50 = 0.16 μM. Analysis of propidium iodide/LDS-751 stained promastigotes revealed that lower concentrations of calcimycin had cytostatic effect and higher concentrations had cytotoxic effect. To establish the mechanism of action of calcimycin, which is known to stimulate activity of mammalian constitutive nitric oxide synthase (NOS), we coincubated L. major promastigotes with calcimycin and selective NOS inhibitors ARL-17477 or L-NNA. Addition of these inhibitors substantially decreased the toxicity of calcimycin to Leishmania promastigotes. In doing so, we demonstrated for the first time that calcimycin has a direct leishmanicidal effect on L. major promastigotes. Also, we showed that Leishmania constitutive Ca2+/calmodulin-dependent nitric oxide synthase is involved in the parasite cell death. These data suggest activation of Leishmania nitric oxide synthase as a new therapeutic approach.

• MeSH
• aktivace enzymů MeSH
• calcimycin farmakologie   MeSH
• Leishmania major enzymologie   MeSH
• leishmanióza kožní farmakoterapie   enzymologie   MeSH
• protozoální proteiny metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• vápníkové ionofory farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• calcimycin MeSH
• protozoální proteiny MeSH
• synthasa oxidu dusnatého MeSH
• vápníkové ionofory MeSH

The development of the cauda equina syndrome in the dog and the involvement of spinal nitric oxide synthase immunoreactivity (NOS-IR) and catalytic nitric oxide synthase (cNOS) activity were studied in a pain model caused by multiple cauda equina constrictions. Increased NOS-IR was found two days post-constriction in neurons of the deep dorsal horn and in large, mostly bipolar neurons located in the internal basal nucleus of Cajal seen along the medial border of the dorsal horn. Concomitantly, NOS-IR was detected in small neurons close to the medioventral border of the ventral horn. High NOS-IR appeared in a dense sacral vascular body close to the Lissauer tract in S1-S3 segments. Somatic and fiber-like NOS-IR appeared at five days post-constriction in the Lissauer tract and in the lateral and medial collateral pathways arising from the Lissauer tract. Both pathways were accompanied by a dense punctate NOS immunopositive staining. Simultaneously, the internal basal nucleus of Cajal and neuropil of this nucleus exhibited high NOS-IR. A significant decrease in the number of small NOS immunoreactive somata was noted in laminae I-II of L6-S2 segments at five days post-constriction while, at the same time, the number of NOS immunoreactive neurons located in laminae VIII and IX was significantly increased. Moreover, high immunopositivity in the sacral vascular body persisted along with a highly expressed NOS-IR staining of vessels supplying the dorsal sacral gray commissure and dorsal horn in S1-S3 segments. cNOS activity, based on a radioassay of compartmentalized gray and white matter regions of lower lumbar segments and non-compartmentalized gray and white matter of S1-S3 segments, proved to be highly variable for both post-constriction periods.

• MeSH
• arginin metabolismus   MeSH
• citrulin metabolismus   MeSH
• imunohistochemie MeSH
• katalýza MeSH
• mícha enzymologie   MeSH
• NADPH-dehydrogenasa metabolismus   MeSH
• polyradikulopatie enzymologie   MeSH
• psi MeSH
• radioimunoanalýza MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• arginin MeSH
• citrulin MeSH
• NADPH-dehydrogenasa MeSH
• synthasa oxidu dusnatého, typ I MeSH
• synthasa oxidu dusnatého MeSH