Abstract 3663: Characterization of Cerebrovascular Parameters using MRI in Endothelial Nitric Oxide Synthase Knockout Mice

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Ji-Yeon Suh ◽  
Shunning Huang ◽  
Dmitriy N Atochin ◽  
Jeong Kon Kim ◽  
WH Shim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Exchange Rate ◽  
Water Permeability ◽  
Water Exchange ◽  
No Synthase ◽  
Systemic Hypertension ◽  
No Production ◽  
Wild Type ◽  
Water Exchange Rate ◽  
Before And After

Endothelial-derived nitric oxide (NO) is important for properly regulating vascular tone and maintaining blood pressure. Mice lacking endothelial NO synthase (eNOS), i.e. loss of endothelial NO production, have systemic hypertension and develop larger cerebral infarction upon cerebral ischemia. Given that constitutively produced NO is necessary for a normal endothelial function, we posit that cerebrovascular characters in eNOS KO mice brain may differ in structure and physiology. In this study, we aim to establish MRI-derived vascular parameters such as cerebral blood volume (CBV), water exchange index (WEI), and vessel size index (VSI) using two different MRI intravascular contrast agents (Gd-PGC (Protected graft copolymer bearing covalently linked Gd- DTPA residues) and SPION (superparamagnetic iron oxide nanoparticle)). We also investigated whether perivascular aquaporine (AQP) proteins, which play a central role in the pathophysiology of many diseases, are differently expressed in eNOS KO mice. Flip angle dependence of the MRI signal intensity on transvascular water exchange rate was used to quantify CBV and WEI before and after intravenous administration of Gd-PGC using wild type mice (C57BL/6, n=8) and eNOS KO mice (n=5). 2D T2 and T2* maps were also acquired before and after SPION administration for measurements of cerebral VSI. As results, eNOS KO mice have lower VSI than that that in wild type mice ( Fig. A ). The CBV of eNOS KO mice is not significantly different from that of wild type mice ( Fig. B ). Furthermore, baseline WEI significantly increased in the eNOS KO mice, indicating higher BBB water permeability. However, both AQP1 and AQP4 were less expressed in eNOS KO mice than those in wild type mice ( Fig. D ). These suggest that the loss of eNOS contribute to the decrease of the vessel diameter and increase of water permeability under a baseline physiological condition. However, expression of AQP proteins forming vascular water channels is not involved with the observed water exchange rate increase across the BBB in eNOS KO mice. The study warrants future investigations to elucidate the relationship between NO synthase and the BBB integrity and its involvement with ischemic damage.

Excessive NO production dose not account for the inhibition of hepatic gluconeogenesis in endotoxemia

1996 ◽  
Vol 271 (4) ◽  
pp. G621-G628 ◽  
Author(s):  
J. Ou ◽  
L. Molina ◽  
Y. M. Kim ◽  
T. R. Billiar
Keyword(s):  
No Synthase ◽  
No Production ◽  
Wild Type ◽  
Gapdh Activity ◽  
Nos Inhibitors ◽  
Before And After ◽  
Gluconeogenic Substrates ◽  
Fasted Rats

The pattern of inhibition of gluconeogenesis in hepatocytes was compared between endotoxemia in vivo and nitric oxide (NO) exposure in vitro. Fasted rats were injected with lipopolysaccharide (LPS; 12 mg/kg) or with vehicle alone. After 2-24 h, hepatocytes were isolated, placed in suspension, and incubated for 1 h with various gluconeogenic substrates that enter at different sites of the gluconeogenic pathway. Hepatocytes from LPS-treated rats exhibited up to a 50% decrease in gluconeogenesis for substrates that enter proximal to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) beginning at 6 h, followed by a nadir at 12 h after LPS. Although hepatocytes exposed to exogenous NO (S-nitroso-N-acetylpenicillamine) also exhibited a depressed gluconeogenesis, the pattern was not the same with inhibition in gluconeogenesis for substrates that enter the pathway both before and after GAPDH. Furthermore, when rats injected with LPS were subjected to a constant portal infusion (Alzet pump) of the NO synthase (NOS) inhibitors, NG-monomethyl-L-arginine or aminoguanidine, no changes in the LPS-induced gluconeogenesis suppression were seen. In addition, no difference in LPS-induced inhibition of gluconeogenesis was detected when hepatocytes from inducible NO synthase (NOS-2) knockout mice were compared with cells obtained from wild-type mice. Minimal decreases in GAPDH activity were measured in hepatocytes from the LPS-treated rats, whereas the activity of phosphoenol pyruvate carboxykinase (PEPCK) declined up to 40%, independent of NO synthesis. These data indicate that NO does not account for the inhibition of gluconeogenesis in endotoxemia, and they provide support for NO-independent reduction in PEPCK activity as a more plausible explanation.

Protective roles of nitric oxide and testosterone in endotoxemia: evidence from NOS-2-deficient mice

1998 ◽  
Vol 275 (6) ◽  
pp. H2211-H2218 ◽  
Author(s):  
Victor E. Laubach ◽  
Patricia L. Foley ◽  
Kim S. Shockey ◽  
Curtis G. Tribble ◽  
Irving L. Kron
Keyword(s):  
Nitric Oxide ◽  
Sex Hormones ◽  
Protective Role ◽  
Multiple Organ ◽  
No Synthase ◽  
Serum Enzymes ◽  
No Production ◽  
Multiple Organ Dysfunction ◽  
Wild Type ◽  
Deficient Mice

Lipopolysaccharide (LPS)-induced septic shock, which triggers nitric oxide (NO) overproduction, multiple organ dysfunction, and death, can be affected by gender and sex hormones. We hypothesized that NO is beneficial during endotoxemia and that this beneficial effect is influenced by sex hormones. C57BL/6 wild-type (WT) mice and congenic inducible NO synthase knockout (KO) mice were injected with LPS, and mortality was recorded for 4 days. After 5 mg/kg LPS, female KO mice had significantly higher mortality than WT. After 12.5 mg/kg LPS, both male and female KO mice had significantly higher mortality than WT. Ovariectomy did not alter mortality, but orchiectomy dramatically increased mortality in KO mice. After 5 mg/kg LPS, exogenous testosterone completely prevented the increased mortality in KO female and orchiectomized KO male mice. WT survival was not affected by exogenous testosterone. After 12.5 mg/kg LPS, exogenous testosterone significantly improved survival of female KO mice. Serum enzymes and organ edema, which may not correlate with mortality, were significantly and similarly increased in both WT and KO endotoxemic mice; however, edema was not observed in KO hearts. Thus, NO plays a protective role in endotoxemia while having differential effects on different organs. Importantly, testosterone is beneficial in endotoxemia when NO production is deficient, and may be therapeutic in certain septic patients.

scholarly journals The Effect of the Nitric Oxide Synthase Inhibitor L-NMMA on Basal CBF and Vasoneuronal Coupling in Man: A PET Study

1999 ◽  
Vol 19 (6) ◽  
pp. 673-678 ◽  
Author(s):  
Richard P. White ◽  
Claire Hindley ◽  
Peter M. Bloomfield ◽  
Vincent J. Cunningham ◽  
Patrick Vallance ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Animal Models ◽  
No Synthase ◽  
No Production ◽  
Finger Movements ◽  
Nitric Oxide Synthase Inhibitor ◽  
Positron Emission ◽  
Animal Data ◽  
Before And After ◽  
Synthase Inhibitor

Nitric oxide (NO) regulates basal CBF. In a number of animal models NO has been implicated in the mediation of the regional changes in CBF (rCBF) that accompany neuronal activation (vasoneuronal coupling). However, some results in animal models have failed to confirm this finding, and the validity of extrapolation to man from animal data is uncertain. To determine the contribution of NO to basal global CBF and activation-induced changes in rCBF, the authors have performed quantitative H215O positron emission tomography (PET) studies before and after administration of the non-isoform-specific NO synthase inhibitor, NG-monomethyl-l-arginine (L-NMMA), in 10 healthy male volunteers. Learning a novel sequence of finger movements was used as a paradigm to induce regional frontal cortex activation. The effect of NO synthase inhibition on the magnitude and pattern of activation was determined. Resting global CBF fell from 33.3 ± 5.3 mL·100 g−1·min−1 at rest before L-NMMA, to 26.5 ± 7.7 mL·100 g−1·min−1 after L-NMMA ( P = 0.001). This fall was reversed by l-arginine administration. Learning sequential finger movements induced increases in rCBF in the left motor, right prefrontal, and bilateral premotor cortices. After NO synthase inhibition with L-NMMA, there was no change in this pattern of activation and no reduction in the magnitude of rCBF responses at the foci of maximal stimulation before and after L-NMMA. These findings confirm that NO production contributes to basal CBF regulation in man, but show that systemic NO synthase inhibition with L-NMMA does not impair regional vasoneuronal coupling.

Simulation of the Changes of Flow Fields by Ecological Islands in Wohushan Reservoir

2013 ◽  
Vol 405-408 ◽  
pp. 2190-2193
Author(s):  
Ming Hui Niu ◽  
Zheng He Xu ◽  
Ke Kong
Keyword(s):  
Water Quality ◽  
Exchange Rate ◽  
Recovery Time ◽  
Water Exchange ◽  
Vertical Direction ◽  
Quality Model ◽  
Water Exchange Rate ◽  
Before And After ◽  
Speed Up ◽  
Field Velocity

Based on the MIKE21 software, the water quality model to simulate flow field, velocity, and proliferation of pollutants before and after ecological islands is established in Wohushan Reservoir. It consists of mass equations and momentum equations. The results indicate ecological islands can ease the phenomenon of reservoir circulation and speed up the water exchange rate in the vertical direction that shortens the recovery time of water. The study provides a strong guarantee for water resources regulation, management and protection of Wohushan Reservoir.

scholarly journals NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1

2015 ◽  
Vol 212 (10) ◽  
pp. 1725-1738 ◽  
Author(s):  
Mirza Saqib Baig ◽  
Sofia V. Zaichick ◽  
Mao Mao ◽  
Andre L. de Abreu ◽  
Farnaz R. Bakhshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Transcriptional Activity ◽  
Cytokine Production ◽  
Critical Role ◽  
No Synthase ◽  
Cytokine Signaling ◽  
No Production ◽  
Wild Type ◽  
Suppressor Of Cytokine Signaling ◽  
Gram Negative

The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1−/− mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1−/− macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1−/− macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1−/− cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role for NOS1-derived NO in regulating TLR4-mediated inflammatory gene transcription, as well as the intensity and duration of the resulting host immune response.

Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

2021 ◽  
Author(s):  
Hadis Shakeri ◽  
Jente R.A. Boen ◽  
Sofie De Moudt ◽  
Jhana O. Hendrickx ◽  
Arthur J.A. Leloup ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Fibrosis ◽  
Separate Experiment ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Paracrine Factor ◽  
Renal Hypertrophy ◽  
Neuregulin 1 ◽  
Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

Decrease in ambient [Cl-] stimulates nitric oxide release from cultured rat mesangial cells

1994 ◽  
Vol 267 (1) ◽  
pp. F190-F195 ◽  
Author(s):  
H. Tsukahara ◽  
Y. Krivenko ◽  
L. C. Moore ◽  
M. S. Goligorsky
Keyword(s):  
Nitric Oxide ◽  
Mesangial Cells ◽  
Ionic Composition ◽  
Juxtaglomerular Apparatus ◽  
Cytosolic Calcium ◽  
No Synthase ◽  
Tubuloglomerular Feedback ◽  
No Production ◽  
Rapid Reduction ◽  
No Release

It has been hypothesized that fluctuations of the ionic composition in the interstitium of juxtaglomerular apparatus (JGA) modulate the function of extraglomerular mesangial cells (MC), thereby participating in tubuloglomerular feedback (TGF) signal transmission. We examined the effects of isosmotic reductions in ambient sodium concentration ([Na+]) and [Cl-] on cytosolic calcium concentration ([Ca2+]i) in cultured rat MC. Rapid reduction of [Na+] or [Cl-] in the bath induced a concentration-dependent rise in [Ca2+]i. MC are much more sensitive to decreases in ambient [Cl-] than to [Na+]; a decrease in [Cl-] as small as 14 mM was sufficient to elicit a detectable [Ca2]i response. These observations suggest that MC can be readily stimulated by modest perturbations of extracellular [Cl-]. Next, we examined whether activation of MC by lowered ambient [Cl-] influences cellular nitric oxide (NO) production. Using an amperometric NO sensor, we found that a 13 mM decrease in ambient [Cl-] caused a rapid, Ca2+/calmodulin-dependent rise in NO release from MC. This response was not inhibitable by dexamethasone, indicating the involvement of the constitutive rather than the inducible type of NO synthase in MC. In addition, the NO release was blunted by indomethacin pretreatment, suggesting that a metabolite(s) of cyclooxygenase regulates the activation of NO synthase in MC. Our findings that small perturbations in external [Cl-] stimulate MC to release NO, a highly diffusible and rapidly acting vasodilator, provide a possible mechanism to explain the transmission of the signal for the TGF response within the JGA.

Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

1994 ◽  
Vol 267 (1) ◽  
pp. R84-R88 ◽  
Author(s):  
M. Huang ◽  
M. L. Leblanc ◽  
R. L. Hester
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Cardiac Output ◽  
No Synthase ◽  
Before And After ◽  
Regional Hemodynamics ◽  
Autonomic Blockade ◽  
Infusion Of Norepinephrine ◽  
Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

2007 ◽  
Vol 293 (2) ◽  
pp. R707-R713 ◽  
Author(s):  
Sharyn M. Fitzgerald ◽  
Barbara K. Kemp-Harper ◽  
Helena C. Parkington ◽  
Geoffrey A. Head ◽  
Roger G. Evans
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Pressure ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
No Production ◽  
Wild Type ◽  
Early Diabetes ◽  
Diabetes In Mice ◽  
Vehicle Treatment

We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of Nω-nitro-l-arginine methyl ester (l-NAME; 100 mg·kg−1·day−1 in drinking water; 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered; the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells

2004 ◽  
Vol 287 (1) ◽  
pp. L60-L68 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Tamara L. Young ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
No Production ◽  
Urea Production ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Regular Medium ◽  
Necrosis Factor

Nitric oxide (NO) is produced by NO synthase (NOS) from l-arginine (l-Arg). Alternatively, l-Arg can be metabolized by arginase to produce l-ornithine and urea. Arginase (AR) exists in two isoforms, ARI and ARII. We hypothesized that inhibiting AR with l-valine (l-Val) would increase NO production in bovine pulmonary arterial endothelial cells (bPAEC). bPAEC were grown to confluence in either regular medium (EGM; control) or EGM with lipopolysaccharide and tumor necrosis factor-α (L/T) added. Treatment of bPAEC with L/T resulted in greater ARI protein expression and ARII mRNA expression than in control bPAEC. Addition of l-Val to the medium led to a concentration-dependent decrease in urea production and a concentration-dependent increase in NO production in both control and L/T-treated bPAEC. In a second set of experiments, control and L/T bPAEC were grown in EGM, EGM with 30 mM l-Val, EGM with 10 mM l-Arg, or EGM with both 10 mM l-Arg and 30 mM l-Val. In both control and L/T bPAEC, treatment with l-Val decreased urea production and increased NO production. Treatment with l-Arg increased both urea and NO production. The addition of the combination l-Arg and l-Val decreased urea production compared with the addition of l-Arg alone and increased NO production compared with l-Val alone. These data suggest that competition for intracellular l-Arg by AR may be involved in the regulation of NOS activity in control bPAEC and in response to L/T treatment.

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