Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture

2001 ◽  
Vol 13 (6) ◽  
pp. 411 ◽  
Author(s):  
Virginia Novaro ◽  
Alejandro Colman-Lerner ◽  
Felipe Vadillo Ortega ◽  
Alicia Jawerbaum ◽  
Dante Paz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Embryo Implantation ◽  
No Production ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
No Donors ◽  
Multinucleated Cells ◽  
Nos Inhibitors ◽  
Spermine Nonoate

The process of embryo implantation requires extensive remodelling of the endometrial extracellular matrix, a function largely performed by matrix-degrading metalloproteinases (MMPs). In the present study, we used trophoblast cells isolated from human term placentas to study the regulation of MMPs by nitric oxide (NO). Using a combination of zymography, Western blot and indirect immunofluorescence, we showed that MMP-2 and MMP-9 are increased during the conversion from low-motile cytotrophoblast cells to the highly motile and differentiated syncytiotrophoblast multinucleated cells. We also observed an increase in NO production and NO synthase (NOS) expression during this cellular differentiation process. In addition, we demonstrated a positive regulatory role of NO on the activity and protein expression of MMP-2 and MMP-9, because NO donors (NOC-18 and spermine-NONOate) or the NOS substrate (L-arginine) stimulate, whereas NOS inhibitors (NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine) reduce the expression and gelatinolytic activity of MMP-2 and MMP-9 in isolated trophoblast cells. Taken together, these results suggest that, in differentiating trophoblasts, NO regulates the induction of matrix-degrading proteases required for invasion during embryo implantation.

Obligatory role of NO in glutamate-dependent hyperemia evoked from cerebellar parallel fibers

1997 ◽  
Vol 272 (4) ◽  
pp. R1155-R1161 ◽  
Author(s):  
G. Yang ◽  
C. Iadecola
Keyword(s):  
Cerebellar Cortex ◽  
Ringer Solution ◽  
No Production ◽  
Parallel Fibers ◽  
No Donors ◽  
Cyclic Monophosphate ◽  
Doppler Probe ◽  
Nos Inhibitors ◽  
Nos Inhibitor

Electrical stimulation of cerebellar parallel fibers (PF) increases cerebellar blood flow (BFcrb), a response that is attenuated by glutamate receptor antagonists and NO synthase (NOS) inhibitors. We investigated whether administration of NO donors could counteract attenuation by NOS inhibitors of vasodilation produced by PF stimulation. In halothane-anesthetized rats the cerebellar cortex was exposed and superfused with Ringer solution. PF were stimulated with microelectrodes (100 microA, 30 Hz), and BFcrb was recorded by a laser-Doppler probe. During Ringer superfusion, PF stimulation increased BFcrb by 56 +/- 7% and hypercapnia by 72 +/- 5% (n = 5). Superfusion with the nonselective NOS inhibitor N-nitro-L-arginine (L-NNA, 1 mM) reduced resting BFcrb and attenuated the response to PF stimulation (-47 +/- 5%) and hypercapnia (-46 +/- 7%; PCO2 = 50-60 mmHg). After L-NNA, superfusion with the NO donors 3-morpholinosydnonimine (100 microM, n = 5) or S-nitroso-N-acetyl-penicillamine (5 microM, n = 5) reestablished resting BFcrb (P > 0.05 vs. before L-NNA) and reversed L-NNA-induced attenuation of the response to hypercapnia (P > 0.05 vs. before L-NNA) but not PF stimulation (P > 0.05 vs. after L-NNA). Similar results were obtained when NOS activity was inhibited with the inhibitor of neuronal NOS 7-nitroindazole (50 mg/kg i.p.). Like NO donors, the guanosine 3',5'-cyclic monophosphate analog 8-bromoguanosine 3',5'-cyclic monophosphate (n = 5), administered after L-NNA, restored resting BFcrb and counteracted inhibition of the response to hypercapnia but not PF stimulation. In contrast to NO donors and 8-bromoguanosine 3',5'-cyclic monophosphate, the NO-independent vasodilator papaverine (100 microM, n = 5) had no effect on attenuation of responses to PF stimulation or hypercapnia. Thus NO donors are unable to reverse the effect of NOS inhibition on vasodilation produced by PF stimulation. The data support the hypothesis that the vascular response to PF stimulation, at variance with hypercapnia, requires NOS activation and NO production. Thus NO plays an obligatory role in vasodilation produced by increased functional activity in cerebellar cortex.

scholarly journals Role of the Platelets and Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review from Bench to Bedside

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
Maciej Bladowski ◽  
Jakub Gawrys ◽  
Damian Gajecki ◽  
Ewa Szahidewicz-Krupska ◽  
Anna Sawicz-Bladowska ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Endothelial Damage ◽  
Guanosine Monophosphate ◽  
No Production ◽  
Nos Inhibitors ◽  
No Bioavailability

Ischemic stroke remains the fifth cause of death, as reported worldwide annually. Endothelial dysfunction (ED) manifesting with lower nitric oxide (NO) bioavailability leads to increased vascular tone, inflammation, and platelet activation and remains among the major contributors to cardiovascular diseases (CVD). Moreover, temporal fluctuations in the NO bioavailability during ischemic stroke point to its key role in the cerebral blood flow (CBF) regulation, and some data suggest that they may be responsible for the maintenance of CBF within the ischemic penumbra in order to reduce infarct size. Several years ago, the inhibitory role of the platelet NO production on a thrombus formation has been discovered, which initiated the era of extensive studies on the platelet-derived nitric oxide (PDNO) as a platelet negative feedback regulator. Very recently, Radziwon-Balicka et al. discovered two subpopulations of human platelets, based on the expression of the endothelial nitric oxide synthase (eNOS-positive or eNOS-negative platelets, respectively). The e-NOS-negative ones fail to produce NO, which attenuates their cyclic guanosine monophosphate (cGMP) signaling pathway and—as result—promotes adhesion and aggregation while the e-NOS-positive ones limit thrombus formation. Asymmetric dimethylarginine (ADMA), a competitive NOS inhibitor, is an independent cardiovascular risk factor, and its expression alongside with the enzymes responsible for its synthesis and degradation was recently shown also in platelets. Overproduction of ADMA in this compartment may increase platelet activation and cause endothelial damage, additionally to that induced by its plasma pool. All the recent discoveries of diverse eNOS expression in platelets and its role in regulation of thrombus formation together with studies on the NOS inhibitors have opened a new chapter in translational medicine investigating the onset of acute cardiovascular events of ischemic origin. This translative review briefly summarizes the role of platelets and NO biotransformation in the pathogenesis and clinical course of ischemic stroke.

Endothelin-1 stimulates NO production and inhibits cAMP accumulation in rat inner medullary collecting duct through independent pathways

2006 ◽  
Vol 290 (6) ◽  
pp. F1315-F1319 ◽  
Author(s):  
Peter K. Stricklett ◽  
Alisa K. Hughes ◽  
Donald E. Kohan
Keyword(s):  
Collecting Duct ◽  
Cell Suspensions ◽  
No Production ◽  
Camp Accumulation ◽  
No Donors ◽  
Endothelin 1 ◽  
Inner Medullary Collecting Duct ◽  
Nos Inhibitors ◽  
Medullary Collecting Duct ◽  
Spermine Nonoate

Endothelin-1 (ET-1) inhibition of vasopressin (AVP)-stimulated cAMP accumulation in the collecting duct has been hypothesized to be mediated, at least in part, by nitric oxide (NO). To examine this, the effect of ET-1 on NO production by acutely isolated rat inner medullary collecting duct (IMCD) cell suspensions and the role of NO in mediating ET-1 effects on AVP-stimulated cAMP accumulation were studied. ET-1 dose dependently (first evident at 100 pM ET-1) increased IMCD NO production as determined by DAF-FM fluorescence. ETB receptor (BQ-788), but not ETA receptor (BQ-123), antagonism blocked this effect. Nonspecific NO synthase (NOS) inhibitors [ NG-nitro-l-arginine methyl ester (l-NAME) or NG-monomethyl-l-arginine] or NOS-1 inhibitors (SMTC or VNIO) inhibited the ET-1 response, whereas NOS-2 or NOS-3 inhibitors (l-NAA or 1400W) were ineffective. ET-1 also increased cGMP accumulation. ET-1 caused a 35% reduction in AVP-stimulated cAMP levels; however, this response was not affected by l-NAME or SMTC. The addition of l-arginine, NADPH, tetrahydrobiopterin, or tempol (to reduce superoxide-dependent conversion of NO to peroxynitrate) did not affect the response. NO donors (SNAP or spermine NONOate), at concentrations that stimulated DAF-FM fluorescence and increased cGMP levels, did not alter AVP-stimulated cAMP accumulation in the IMCD cell suspensions. In conclusion, ET-1 stimulates IMCD NO production through activation of the ETB receptor and NOS-1. However, neither ET-1-mediated NO production nor NO donors inhibit AVP-stimulated cAMP accumulation, indicating that NO does not mediate ET-1 inhibition of cAMP production by the IMCD.

Role of nitric oxide synthase isoforms in glucose-stimulated insulin release

2002 ◽  
Vol 283 (1) ◽  
pp. C296-C304 ◽  
Author(s):  
Ragnar Henningsson ◽  
Albert Salehi ◽  
Ingmar Lundquist
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Insulin Release ◽  
Type Ii Diabetes Mellitus ◽  
No Production ◽  
No Donor ◽  
Nos Inhibitors ◽  
Constitutive Nitric Oxide Synthase ◽  
Oxide Synthase

The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of l-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus.

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

1997 ◽  
Vol 273 (3) ◽  
pp. L504-L512 ◽  
Author(s):  
Y. C. Huang ◽  
P. W. Fisher ◽  
E. Nozik-Grayck ◽  
C. A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Average Rate ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
No Production ◽  
Protective Effects ◽  
Lung Weight ◽  
Edema Formation ◽  
No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases

2005 ◽  
Vol 289 (6) ◽  
pp. F1324-F1332 ◽  
Author(s):  
Manish M. Tiwari ◽  
Robert W. Brock ◽  
Judit K. Megyesi ◽  
Gur P. Kaushal ◽  
Philip R. Mayeux
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Blood Flow ◽  
Saline Group ◽  
No Production ◽  
Capillary Perfusion ◽  
Peritubular Capillary ◽  
Synthase Inhibitor ◽  
Peritubular Capillary Perfusion

Acute renal failure (ARF) is a frequent and serious complication of endotoxemia caused by lipopolysaccharide (LPS) and contributes significantly to mortality. The present studies were undertaken to examine the roles of nitric oxide (NO) and caspase activation on renal peritubular blood flow and apoptosis in a murine model of LPS-induced ARF. Male C57BL/6 mice treated with LPS ( Escherichia coli) at a dose of 10 mg/kg developed ARF at 18 h. Renal failure was associated with a significant decrease in peritubular capillary perfusion. Vessels with no flow increased from 7 ± 3% in the saline group to 30 ± 4% in the LPS group ( P < 0.01). Both the inducible NO synthase inhibitor l- N6-1-iminoethyl-lysine (l-NIL) and the nonselective caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD) prevented renal failure and reversed perfusion deficits. Renal failure was also associated with an increase in renal caspase-3 activity and an increase in renal apoptosis. Both l-NIL and Z-VAD prevented these changes. LPS caused an increase in NO production that was blocked by l-NIL but not by Z-VAD. Taken together, these data suggest NO-mediated activation of renal caspases and the resulting disruption in peritubular blood flow are an important mechanism of LPS-induced ARF.

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen

2000 ◽  
Vol 88 (4) ◽  
pp. 1381-1389 ◽  
Author(s):  
Ivan T. Demchenko ◽  
Albert E. Boso ◽  
Thomas J. O'Neill ◽  
Peter B. Bennett ◽  
Claude A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Methyl Ester ◽  
No Production ◽  
No Donors ◽  
Mk 801 ◽  
Neuronal Excitation ◽  
Synthase Inhibitor ◽  
Electroencephalogram Eeg

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO2 exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO2, but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.

Nitrate reductases and hemoglobins control nitrogen-fixing symbiosis by regulating nitric oxide accumulation

2020 ◽  
Author(s):  
Antoine Berger ◽  
Alexandre Boscari ◽  
Alain Puppo ◽  
Renaud Brouquisse
Keyword(s):  
Nitric Oxide ◽  
Defense Responses ◽  
Nodule Formation ◽  
No Production ◽  
Degradation Pathways ◽  
Atmospheric Nitrogen ◽  
Metabolic Intermediate ◽  
Hypoxic Environment ◽  
Nitrate Reductases

Abstract The interaction between legumes and rhizobia leads to the establishment of a symbiotic relationship between plant and bacteria. This is characterized by the formation of a new organ, the nodule, which facilitates the fixation of atmospheric nitrogen (N2) by nitrogenase through the creation of a hypoxic environment. Nitric oxide (NO) accumulates at each stage of the symbiotic process. NO is involved in defense responses, nodule organogenesis and development, nitrogen fixation metabolism, and senescence induction. During symbiosis, either successively or simultaneously, NO regulates gene expression, modulates enzyme activities, and acts as a metabolic intermediate in energy regeneration processes via phytoglobin-NO respiration and the bacterial denitrification pathway. Due to the transition from normoxia to hypoxia during nodule formation, and the progressive presence of the bacterial partner in the growing nodules, NO production and degradation pathways change during the symbiotic process. This review analyzes the different source and degradation pathways of NO, and highlights the role of nitrate reductases and hemoproteins of both the plant and bacterial partners in the control of NO accumulation.

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