Selective iNOS Inhibition Attenuates Acetylcholine- and Bradykinin-induced Vasoconstriction in Lipopolysaccharide-exposed Rat Lungs 

1999 ◽  
Vol 91 (6) ◽  
pp. 1724-1724 ◽  
Author(s):  
Lars G. Fischer ◽  
Damian J. Horstman ◽  
Klaus Hahnenkamp ◽  
Nancy E. Kechner ◽  
George F. Rich
Keyword(s):  
Nitric Oxide ◽  
Exhaled Nitric Oxide ◽  
Control Group ◽  
Biochemical Engineering ◽  
Inos Inhibitor ◽  
Nos Inhibitor ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Dose Dependent

Background Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. Methods Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. Results Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. Conclusions In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Effects of chronic inhibition of inducible nitric oxide synthase in hyperthyroid rats

2005 ◽  
Vol 288 (6) ◽  
pp. E1252-E1257 ◽  
Author(s):  
Isabel Rodríguez-Gómez ◽  
Rosemary Wangensteen ◽  
Juan Manuel Moreno ◽  
Virginia Chamorro ◽  
Antonio Osuna ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Control Group ◽  
Hemodynamic Variable ◽  
Male Wistar Rats ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

We hypothesized that nitric oxide generated by inducible nitric oxide synthase (iNOS) may contribute to the homeostatic role of this agent in hyperthyroidism and may, therefore, participate in long-term control of blood pressure (BP). The effects of chronic iNOS inhibition by oral aminoguanidine (AG) administration on BP and morphological and renal variables in hyperthyroid rats were analyzed. The following four groups ( n = 8 each) of male Wistar rats were used: control group and groups treated with AG (50 mg·kg−1·day−1, via drinking water), thyroxine (T4, 50 μg·rat−1·day−1), or AG + T4. All treatments were maintained for 3 wk. Tail systolic BP and heart rate (HR) were recorded weekly. Finally, we measured BP (mmHg) and HR in conscious rats and morphological, plasma, and renal variables. T4 administration produced a small BP (125 ± 2, P < 0.05) increase vs. control (115 ± 2) rats. AG administration to normal rats did not modify BP (109 ± 3) or any other hemodynamic variable. However, coadministration of T4 and AG produced a marked increase in BP (140 ± 3, P < 0.01 vs. T4). Pulse pressure and HR were increased in both T4- and T4 + AG -treated groups without differences between them. Plasma NOx (μmol/l) were increased in the T4 group (10.02 ± 0.15, P < 0.05 vs. controls 6.1 ± 0.10), and AG reduced this variable in T4-treated rats (6.81 ± 0.14, P < 0.05 vs. T4) but not in normal rats (5.78 ± 0.20). Renal and ventricular hypertrophy and proteinuria of hyperthyroid rats were unaffected by AG treatment. In conclusion, the results of the present paper indicate that iNOS activity may counterbalance the prohypertensive effects of T4.

scholarly journals Nitric Oxide Is Protective in Listeric Meningoencephalitis of Rats

2001 ◽  
Vol 69 (6) ◽  
pp. 4086-4093 ◽  
Author(s):  
K. A. Remer ◽  
T. W. Jungi ◽  
R. Fatzer ◽  
M. G. Täuber ◽  
S. L. Leib
Keyword(s):  
Nitric Oxide ◽  
Growth Control ◽  
Brain Infection ◽  
Infant Rat ◽  
Inos Inhibitor ◽  
Order Of Magnitude ◽  
Oxide Synthase ◽  
And Control ◽  
Dose Dependent ◽  
The Brain

ABSTRACT The bacterium Listeria monocytogenes causes meningoencephalitis in humans. In rodents, listeriosis is associated with granulomatous lesions in the liver and the spleen, but not with meningoencephalitis. Here, infant rats were infected intracisternally to generate experimental listeric meningoencephalitis. Dose-dependent effects of intracisternal inoculation with L. monocytogeneson survival and activity were noted; 104 L. monocytogenes organisms induced a self-limiting brain infection. Bacteria invaded the basal meninges, chorioid plexus and ependyme, spread to subependymal tissue and hippocampus, and disappeared by day 7. This was paralleled by recruitment and subsequent disappearance of macrophages expressing inducible nitric oxide synthase (iNOS) and nitrotyrosine accumulation, an indication of nitric oxide (NO⋅) production. Treatment with the spin-trapping agent α-phenyl-tert-butyl nitrone (PBN) dramatically increased mortality and led to bacterial numbers in the brain 2 orders of magnitude higher than in control animals. Treatment with the selective iNOS inhibitorl-N 6-(1-iminoethyl)-lysine (L-NIL) increased mortality to a similar extent and led to 1 order of magnitude higher bacterial counts in the brain, compared with controls. The numbers of bacteria that spread to the spleen and liver did not significantly differ among L-NIL-treated, PBN-treated, and control animals. Thus, the infant rat brain is able to mobilize powerful antilisterial mechanisms, and both reactive oxygen and NO⋅ contribute to Listeria growth control.

scholarly journals Benzylidene Barbituric Acid Derivatives Shown Anticonvulsant Activity on Pentylenetetrazole-Induced Seizures in Mice: Involvement of Nitric Oxide Pathway

2018 ◽  
Vol 24 (4) ◽  
pp. 250-256 ◽  
Author(s):  
Shabnam Mahernia ◽  
Niusha Sharifi ◽  
Malihe Hassanzadeh ◽  
Nastaran Rahimi ◽  
Nastaran Pourshadi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Anticonvulsant Activity ◽  
Barbituric Acid ◽  
Compound A ◽  
Oxide Precursor ◽  
Inos Inhibitor ◽  
Barbituric Acid Derivative ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Barbituric Acid Derivatives

ABSTRACT Background: Barbituric acid derivatives have long been used as central nervous system (CNS) suppressants, such as sedatives, hypnotics and anticonvulsants. In addition, previous studies have implicated the involvement of nitric oxide (NO) in the anticonvulsive effects of barbiturates in CNS. Therefore, the purpose of this study was to figure out the effects of a novel class of barbituric acid derivatives on pentylenetetrazole (PTZ)-induced seizures in male mice. Methods: Thirteen synthesized barbituric acid derivatives (a-m) and phenobarbital were administered intraperitoneally (i.p.) 30 min before induction of seizures by PTZ administration. The mechanisms of PTZ-induced seizures in the mice was evaluated using a non-selective nitric oxide synthase (NOS) inhibitor, selective inducible NOS (iNOS) inhibitor, a selective neuronal NOS (nNOS) inhibitor, and NO substrate. Results: Administration of most of the above mentioned derivatives significantly increased the seizures threshold (P<0.001). The most potent derivative (compound a), was chosen in order to investigate the mechanism of action involving in anticonvulsant activity. Administration of a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) and a selective nNOS inhibitor, 7-nitroindazole (7-NI) reversed anticonvulsant activity of compound a. However, injection of the nitric oxide precursor, L-arginine (L-Arg) and a selective iNOS inhibitor, aminoguanidine (AG), did not change anticonvulsant activity of the mentioned compound. Conclusion: These results indicated that the NO system, specifically nNOS may contribute to the anticonvulsant activity of benzylidene barbituric acid derivative a. Therefore, this compound is a good candidate in order to designing new anticonvulsant medications

scholarly journals Therapeutic effects of iNOS inhibition against vitiligo in an animal model

2019 ◽  
Vol 29 (3) ◽  
Author(s):  
Hamid Mansourpour ◽  
Katayoun Ziari ◽  
Sahar Kalantar Motamedi ◽  
Amin Hassan Poor
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Mouse Model ◽  
Therapeutic Effects ◽  
Mice Model ◽  
Inos Inhibitor ◽  
Constitutive Nitric Oxide Synthase ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

Nitric oxide (NO) is involved in several biological processes, but its role in human melanogenesis and vitiligo need further studies. Previous studies revealed that exposure to UVA and UVB were capable of the inducing nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, whereas inducible nitric oxide synthase overexpression has been reported to play an important role in hyperpigmentary disorders. The aim of this study was to evaluate iNOS inhibitor aminoguanidine (AG) as a therapeutic agent in our mouse model of vitiligo. In this study, male C57BL/6J Ler-vit/vit mice were purchased to evaluate the effect of iNOS inhibitor (aminoguanidine) (50 and 100 mg/kg) and L-arginine (100 mg/kg) in a mouse model of vitiligo induced by monobenzone 40%. Moreover, we used phototherapy device to treat the mice with NBUVB as a gold standard.The findings revealed that monobenzone was capable of inducing depigmentation after 6 weeks. However, aminoguanidine in combination with monobenzone was decrease the effect of monobenzone, while L-arginine play a key role in promoting the effect of monobenzone (P<0.001). Based on the phototherapy, the efficacy of phototherapy significantly increased by adding L-arginine (P<0.05). Taken together, we suggest that iNOS inhibitor can be a novel treatment for the prevention and treatment of vitiligo by combination of NBUVB therapy, furthermore; NO agents like L-arginine could also increase the effectiveness of phototherapy. Taken together, this pilot study showed significant repigmentation of vitiligous lesions treated with iNOS inhibitor plus NBUVB therapy, where other aspect including expression of an inducible iNOS, NO and TNF levels remained to be evaluated in mice model.

Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever

1996 ◽  
Vol 271 (2) ◽  
pp. R333-R338 ◽  
Author(s):  
T. E. Scammell ◽  
J. K. Elmquist ◽  
C. B. Saper
Keyword(s):  
Nitric Oxide ◽  
Low Dose ◽  
Dependent Manner ◽  
Febrile Response ◽  
Bolus Intravenous Injection ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Higher Doses

The labile gas nitric oxide (NO) mediates a wide variety of thermoregulatory processes including vasomotor control, brown fat thermogenesis, and neuroendocrine regulation. Additionally, during endotoxemia, NO modulates the release of cytokines and hypothalamic peptides. To determine the role of NO in thermoregulation and fever, we intravenously injected the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and measured its effects on body temperature during normal thermoregulation and endotoxemia in awake, unrestrained rats. L-NAME produced a stereoselective, dose-dependent hypothermia that lasted up to 4 h after bolus intravenous injection. Intravenous lipopolysaccharide (LPS) produced fever in a dose-dependent manner, which was preceded by hypothermia at higher doses alpha-LPS. NOS inhibition reduced the febrile response to LPS and produced marked hypothermia with a low dose of LPS. These findings indicate that NO may play an important role in thermoregulation and suggest that NO is required for the production of fever.

scholarly journals Automated Synthesis and Initial Evaluation of (4 ′ -Amino-5 ′ ,8 ′ -difluoro-1 ′ H-spiro[piperidine-4,2 ′ -quinazolin]-1-yl)(4-[18F]fluorophenyl)methanone for PET/MR Imaging of Inducible Nitric Oxide Synthase

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Skye Hsin-Hsien Yeh ◽  
Wen-Sheng Huang ◽  
Chuang-Hsin Chiu ◽  
Chuan-Lin Chen ◽  
Hui-Ting Chen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mr Imaging ◽  
Area Under The Curve ◽  
Volume Of Distribution ◽  
Control Group ◽  
Inos Inhibitor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background. Inducible nitric oxide synthase (iNOS) plays a crucial role in neuroinflammation, especially microglial activity, and may potentially represent a useful biomarker of neuroinflammation. In this study, we carefully defined a strategic plan to develop iNOS-targeted molecular PET imaging using (4 ′ -amino-5 ′ ,8 ′ -difluoro-1 ′ H-spiro[piperidine-4,2 ′ -quinazolin]-1-yl)(4-fluorophenyl)methanone ([18F]FBAT) as a tracer in a mouse model of lipopolysaccharide- (LPS-) induced brain inflammation. Methods. An in vitro model, murine microglial BV2 cell line, was used to assess the uptake of [18F]FBAT in response to iNOS induction at the cellular level. In vivo whole-body dynamic PET/MR imaging was acquired in LPS-treated (5 mg/kg) and control mice. Standard uptake value (SUV), total volume of distribution ( V t ), and area under the curve (AUC) based on the [18F]FBAT PET signals were determined. The expression of iNOS was confirmed by immunohistochemistry (IHC) of brain tissues. Results. At the end of synthesis, the yield of [18F]FBAT was 2.2–3.1% (EOS), radiochemical purity was >99%, and molar radioactivity was 125–137 GBq/μmol. In vitro, [18F]FBAT rapidly and progressively accumulated in murine microglial BV2 cells exposed to LPS; however, [18F]FBAT accumulation was inhibited by aminoguanidine, a selective iNOS inhibitor. In vivo biodistribution studies of [18F]FBAT showed a significant increase in the liver and kidney on LPS-treated mice. At 3 h postinjection of LPS, in vivo, the [18F]FBAT accumulation ratios at 30 min post intravenous (i.v.) radiotracer injection for the whole brain, cortex, cerebellum, and brainstem were 2.16 ± 0.18 , 1.53 ± 0.25 , 1.41 ± 0.21 , and 1.90 ± 0.12 , respectively, compared to those of mice not injected with LPS. The mean area under the curve (AUC0-30min), total volume of distribution ( V t , mL/cm3), and K i (influx rate) of [18F]FBAT were 1.9 ± 0.21 - and 1.4 ± 0.22 -fold higher in the 3 h LPS group, respectively, than in the control group. In the pharmacokinetic two-compartment model, the whole brain K i of [18F]FBAT was significantly higher in mice injected with LPS compared to the control group. Aminoguanidine, selective iNOS inhibitor, pretreatment significantly reduced the AUC0-30min and V t values in LPS-induced mice. Quantitative analysis of immunohistochemically stained brain sections confirmed iNOS was preferentially upregulated in the cerebellum and cortex of mice injected with LPS. Conclusion. An automated robotic method was established for radiosynthesis of [18F]FBAT, and the preliminary in vitro and in vivo results demonstrated the feasibility of detecting iNOS activity/expression in LPS-treated neuroinflammation by noninvasive imaging with [18F]FBAT PET/MRI.

Fetal cerebral and peripheral circulatory responses to hypoxia after nitric oxide synthase inhibition

2001 ◽  
Vol 281 (2) ◽  
pp. R381-R390 ◽  
Author(s):  
Andrew P. Harris ◽  
Sabah Helou ◽  
Christine A. Gleason ◽  
Richard J. Traystman ◽  
Raymond C. Koehler
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Treated Group ◽  
Arterial Oxygen ◽  
Control Group ◽  
Fetal Sheep ◽  
Arterial Oxygen Content ◽  
Arterial Blood ◽  
Nos Inhibitor ◽  
Oxide Synthase

The increase in cerebral blood flow (CBF) during hypoxia in fetal sheep at 0.6 gestation is less than the increase at 0.9 gestation when normalized for differences in baseline CBF and oxygen consumption. Nitric oxide (NO) synthase (NOS) catalytic activity increases threefold during this period of development. We tested the hypothesis that administration of the NOS inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) decreases the CBF response to systemic hypoxia selectively at 0.9 gestation. We also tested whether any peripheral vasoconstriction during hypoxia is potentiated byl-NAME at 0.9 gestation. Administration ofl-NAME increased arterial blood pressure and decreased microsphere-determined CBF during normoxia in fetal sheep at both 0.6 and 0.9 gestation. With subsequent reduction of arterial oxygen content by ∼50%, the percent increase in forebrain CBF in a control group (57 ± 11%; ± SE) and l-NAME-treated group (51 ± 6%) was similar at 0.6 gestation. Likewise, at 0.9 gestation, the increase in CBF was similar in control (90 ± 25%) andl-NAME (80 ± 28%) groups. At 0.9 gestation,l-NAME treatment attenuated the increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia. We conclude that NO exerts a basal vasodilatory influence in brain as early as 0.6 gestation in fetal sheep but is not an important mechanism for hypoxic vasodilation in brain at either 0.6 or 0.9 gestation. Thus the developmental increase in NOS catalytic capacity does not appear to be responsible for developmental increases in the CBF response to hypoxia during this period. In contrast, NO modulates the vascular response to hypoxia in heart and gastrointestinal tract.

Nitric oxide modulates the cardiovascular effects elicited by acetylcholine in the NTS of awake rats

2008 ◽  
Vol 295 (6) ◽  
pp. R1774-R1781 ◽  
Author(s):  
Liana Gouveia da Silva ◽  
Ana Carolina Rodrigues Dias ◽  
Elaina Furlan ◽  
Eduardo Colombari
Keyword(s):  
Nitric Oxide ◽  
Cardiovascular Effects ◽  
Cardiovascular Reflexes ◽  
Induced Hypotension ◽  
Acetylcholine Chloride ◽  
Nos Inhibitor ◽  
Inhibition Control ◽  
Oxide Synthase ◽  
Dose Dependent ◽  
Awake Rats

Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 ± 5 mmHg before l-NAME to 9 ± 4 mmHg, 10 min after l-NAME, and HR fell by 100 ± 26 bpm before l-NAME to 20 ± 10 bpm, 10 min after l-NAME (both P < 0.05). Microinjection of the selective inhibitor of neuronal nitric oxide synthase (nNOS), 1-(2-trifluoromethylphenyl) imidazole (TRIM; 13.3 nmol in 100 nl), in the NTS also reduced responses to ACh: MAP fell from 42 ± 3 mmHg before TRIM to 27 ± 6 mmHg, 10 min after TRIM ( P < 0.05). TRIM also tended to reduce ACh-induced bradycardia, but this effect was not statistically significant. ACh-induced hypotension and bradycardia returned to control levels 30–45 min after NOS inhibition. Control injections with d-NAME and saline did not affect resting values or the response to ACh. In conclusion, injection of ACh into the NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.

Search for Potential Inducible Nitric Oxide Synthase Inhibitors with Favorable ADMET Profiles for the Therapy of Helicobacter pylori Infections

2020 ◽  
Vol 19 (30) ◽  
pp. 2795-2804 ◽  
Author(s):  
Ricardo Pereira Rodrigues ◽  
Juliana Santa Ardisson ◽  
Rita de Cássia Ribeiro Gonçalves ◽  
Tiago Branquinho Oliveira ◽  
Vinicius Barreto da Silva ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Helicobacter Pylori ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Crucial Role ◽  
Chemical Space ◽  
Target Selection ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Inducible Nitric Oxide

Background: Helicobacter pylori is a gram-negative bacterium related to chronic gastritis, peptic ulcer and gastric carcinoma. During its infection process, promotes excessive inflammatory response, increasing the release of reactive species and inducing the production of pro-inflammatory mediators. Inducible Nitric Oxide Synthase (iNOS) plays a crucial role in the gastric carcinogenesis process and a key mediator of inflammation and host defense systems, which is expressed in macrophages induced by inflammatory stimuli. In chronic diseases such as Helicobacter pylori infections, the overproduction of NO due to the prolonged induction of iNOS is of major concern. Objective: In this sense, the search for potential iNOS inhibitors is a valuable strategy in the overall process of Helicobacter pylori pathogeny. Method: In silico techniques were applied in the search of interesting compounds against Inducible Nitric Oxide Synthase enzyme in a chemical space of natural products and derivatives from the Analyticon Discovery databases. Results: The five compounds with the best iNOS inhibition profile were selected for activity and toxicity predictions. Compound 9 (CAS 88198-99-6) displayed significant potential for iNOS inhibition, forming hydrogen bonds with residues from the active site and an ionic interaction with heme. This compound also displayed good bioavailability and absence of toxicity/or from its probable metabolites. Conclusion: The top-ranked compounds from the virtual screening workflow show promising results regarding the iNOS inhibition profile. The results evidenced the importance of the ionic bonding during docking selection, playing a crucial role in binding and positioning during ligand-target selection for iNOS.

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