Role of endogenous nitric oxide in progression of atherosclerosis in apolipoprotein E-deficient mice

2000 ◽  
Vol 278 (5) ◽  
pp. H1679-H1685 ◽  
Author(s):  
Katalin Kauser ◽  
Valdeci da Cunha ◽  
Richard Fitch ◽  
Cornell Mallari ◽  
Gabor M. Rubanyi
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Apolipoprotein E ◽  
Lesion Size ◽  
Significant Inhibition ◽  
Arterial Blood ◽  
Endogenous Nitric Oxide ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

This study investigated the role of endogenous nitric oxide (NO) in the progression of atherosclerosis in apolipoprotein E-deficient [apoE-knockout (KO)] mice. Mice were treated with N ω-nitro-l-arginine methyl ester (l-NAME) an inhibitor of nitric oxide synthase (NOS) or with the NOS substrate l-arginine for 8 wk.l-NAME treatment resulted in a significant inhibition of NO-mediated vascular responses and a significant increase in the atherosclerotic plaque/surface area in the aorta of apoE-KO mice.l-arginine treatment had no influence on endothelial function and did not alter lesion size. Mean arterial blood pressure and serum lipid levels were not altered by the treatments. At the beginning of the study impairment in endothelial function was only apparent in the case of N G-nitro-l-arginine-induced, NO-mediated contraction, whereas ACh-induced, NO-mediated relaxation was not different between age-matched apoE-KO and C57Bl/6J mice. After the 8-wk treatment with the NOS inhibitor, both NO-mediated responses were significantly inhibited. The acceleration in lesion size concomitant to the severely impaired NO-mediated responses indicates that lack of endogenous NO is an important progression factor of atherosclerosis in the apoE-KO mouse.

Exercise training improves endogenous nitric oxide mechanisms within the paraventricular nucleus in rats with heart failure

2005 ◽  
Vol 288 (5) ◽  
pp. H2332-H2341 ◽  
Author(s):  
Hong Zheng ◽  
Yi-Fan Li ◽  
Kurt G. Cornish ◽  
Irving H. Zucker ◽  
Kaushik P. Patel
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Exercise Training ◽  
Paraventricular Nucleus ◽  
No Donor ◽  
Protein Levels ◽  
Arterial Blood ◽  
Endogenous Nitric Oxide ◽  
Dose Dependent

Previously, we have demonstrated that an altered endogenous nitric oxide (NO) mechanism within the paraventricular nucleus (PVN) contributes to increased renal sympathetic nerve activity (RSNA) in heart failure (HF) rats. The goal of this study was to examine the effect of exercise training (ExT) in improving the endogenous NO mechanism within the PVN involved in the regulation of RSNA in rats with HF. ExT significantly restored the decreased number of neuronal NO synthase (nNOS)-positive neurons in the PVN (129 ± 17 vs. 99 ± 6). nNOS mRNA expression and protein levels in the PVN were also significantly increased in HF-ExT rats compared with HF-sedentary rats. To examine the functional role of NO within the PVN, an inhibitor of NOS, NG-monomethyl-l-arginine, was microinjected into the PVN. Dose-dependent increases in RSNA, arterial blood pressure (BP), and heart rate (HR) were produced in all rats. There was a blunted increase in these parameters in HF rats compared with the sham-operated rats. ExT significantly augmented RSNA responses in rats with HF (33% vs. 20% at the highest dose), thus normalizing the responses. The NO donor sodium nitroprusside, microinjected into the PVN, produced dose-dependent decreases in RSNA, BP, and HR in both sham and HF rats. ExT significantly improved the blunted decrease in RSNA in HF rats (36% vs. 17% at the highest dose). In conclusion, our data indicate that ExT improves the altered NO mechanism within the PVN and restores NO-mediated changes in RSNA in rats with HF.

Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice

2010 ◽  
Vol 119 (3) ◽  
pp. 131-142 ◽  
Author(s):  
Tim S. Schmidt ◽  
Eileen McNeill ◽  
Gillian Douglas ◽  
Mark J. Crabtree ◽  
Ashley B. Hale ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Apolipoprotein E ◽  
Knockout Mice ◽  
Immune Cell ◽  
Vascular Inflammation ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Apolipoprotein E Knockout Mice ◽  
Apoe Ko

BH4 (tetrahydrobiopterin) supplementation improves endothelial function in models of vascular disease by maintaining eNOS (endothelial nitric oxide synthase) coupling and NO (nitric oxide) bioavailability. However, the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE-KO (apolipoprotein E-knockout) mice. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs. Plasma BH4 levels returned to baseline by 8 h after oral dosing, but remained markedly increased in aorta at 24 h. Daily oral BH4 supplementation in ApoE-KO mice from 8 weeks of age, for a period of 8 or 12 weeks, had no effect on plasma lipids or haemodynamic parameters, but significantly reduced aortic root atherosclerosis compared with placebo-treated animals. BH4 supplementation significantly reduced VCAM-1 (vascular cell adhesion molecule 1) mRNA levels in aortic endothelial cells, markedly reduced the infiltration of T-cells, macrophages and monocytes into plaques, and reduced T-cell infiltration in the adjacent adventitia, but importantly had no effect on circulating leucocytes. GCH (GTP cyclohydrolase I)-transgenic mice, with a specific increase in endothelial BH4 levels, exhibited a similar reduction in vascular immune cell infiltration compared with BH4-deficient controls, suggesting that BH4 reduces vascular inflammation via endothelial cell signalling. In conclusion, BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis.

Role of endogenous nitric oxide (NO) and NO synthases in healing of indomethacin-induced intestinal ulcers in rats

Life Sciences ◽  
2007 ◽  
Vol 80 (4) ◽  
pp. 329-336 ◽  
Author(s):  
Koji Takeuchi ◽  
Ryo Hatazawa ◽  
Mayu Tanigami ◽  
Akiko Tanaka ◽  
Ryoko Ohno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endogenous Nitric Oxide ◽  
Intestinal Ulcers

Nitric oxide: a new role in intensive care

2020 ◽  
Vol 22 (1) ◽  
pp. 72-79
Author(s):  
Alexandra Lee ◽  
◽  
Warwick Butt ◽  
◽  
◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Potential Role ◽  
Nitric Oxide Donors ◽  
Ischaemia Reperfusion Injury ◽  
Surface Receptors ◽  
The Past ◽  
Ischaemia Reperfusion ◽  
Human Experiments ◽  
Endogenous Nitric Oxide

Inhaled nitric oxide has been used for 30 years to improve oxygenation and decrease pulmonary vascular resistance. In the past 15 years, there has been increased understanding of the role of endogenous nitric oxide on cell surface receptors, mitochondria, and intracellular processes involving calcium and superoxide radicals. This has led to several animal and human experiments revealing a potential role for administered nitric oxide or nitric oxide donors in patients with systemic inflammatory response syndrome or ischaemia–reperfusion injury, and in patients for whom exposure of blood to artificial surfaces has occurred.

scholarly journals The role of TLR-4 in the immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum

2019 ◽  
Vol 13 (11) ◽  
pp. 1057-1061
Author(s):  
Muhammad Adamu Abbas ◽  
Rapeah Suppian
Keyword(s):  
Nitric Oxide ◽  
Plasmodium Falciparum ◽  
Inflammatory Responses ◽  
Peritoneal Macrophages ◽  
Significant Inhibition ◽  
Immunomodulatory Effects ◽  
Attachment Mechanism ◽  
Significant Production ◽  
Recombinant Bcg

Introduction: An earlier constructed recombinant BCG expressing the MSP-1C of Plasmodium falciparum, induced inflammatory responses leading to significant production of nitric oxide (NO) alongside higher expression of the enzyme inducible nitric oxide synthase (iNOS) and significant production of the regulatory cytokine, IL-10, indicating significant immunomodulatory effects of the construct. The mechanism of these responses had not been established but is thought to involve toll-like receptor 4 (TLR-4). Methodology: The present study was carried out to determine the role of TLR-4 on eliciting the immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum leading to the production of NO and IL-10, as well as the expression of iNOS. Six groups of mice (n = 6 per group) were immunised thrice, three weeks apart with intraperitoneal phosphate buffered saline T80 (PBS-T80), BCG or rBCG in the presence or absence of a TLR-4 inhibitor; TAK-242, given one hour prior to each immunisation. Peritoneal macrophages were harvested from the mice and cultured for the determination of NO, iNOS and IL-10 via Griess assay, ELISA and Western blot respectively. Results: The results showed significant inhibition of the production of NO and IL-10 and the expression of iNOS in all groups of mice in the presence of TAK-242. Conclusions: These results presented evidence of the role of TLR-4/rBCG attachment mechanism in modulating the production of NO and IL-10 and the expression of iNOS in response to our rBCG-based malaria vaccine candidate expressing MSP-1C of P. falciparum.

scholarly journals Role of nitric oxide-containing factors in the ventilatory and cardiovascular responses elicited by hypoxic challenge in isoflurane-anesthetized rats

2014 ◽  
Vol 116 (11) ◽  
pp. 1371-1381 ◽  
Author(s):  
James P. Mendoza ◽  
Rachael J. Passafaro ◽  
Santhosh M. Baby ◽  
Alex P. Young ◽  
James N. Bates ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Cardiovascular Responses ◽  
Vital Role ◽  
Initial Increase ◽  
Ventilatory Responses ◽  
Arterial Blood ◽  
Anesthetized Rats ◽  
Before And After

Exposure to hypoxia elicits changes in mean arterial blood pressure (MAP), heart rate, and frequency of breathing (fr). The objective of this study was to determine the role of nitric oxide (NO) in the cardiovascular and ventilatory responses elicited by brief exposures to hypoxia in isoflurane-anesthetized rats. The rats were instrumented to record MAP, heart rate, and fr and then exposed to 90 s episodes of hypoxia (10% O2, 90% N2) before and after injection of vehicle, the NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME), or the inactive enantiomer d-NAME (both at 50 μmol/kg iv). Each episode of hypoxia elicited a decrease in MAP, bidirectional changes in heart rate (initial increase and then a decrease), and an increase in fr. These responses were similar before and after injection of vehicle or d-NAME. In contrast, the hypoxia-induced decreases in MAP were attenuated after administration of l-NAME. The initial increases in heart rate during hypoxia were amplified whereas the subsequent decreases in heart rate were attenuated in l-NAME-treated rats. Finally, the hypoxia-induced increases in fr were virtually identical before and after administration of l-NAME. These findings suggest that NO factors play a vital role in the expression of the cardiovascular but not the ventilatory responses elicited by brief episodes of hypoxia in isoflurane-anesthetized rats. Based on existing evidence that NO factors play a vital role in carotid body and central responses to hypoxia in conscious rats, our findings raise the novel possibility that isoflurane blunts this NO-dependent signaling.

Nitric oxide modulates epicardial coronary basal vasomotor tone in awake dogs

1990 ◽  
Vol 258 (4) ◽  
pp. H1250-H1254 ◽  
Author(s):  
A. Chu ◽  
D. E. Chambers ◽  
C. C. Lin ◽  
W. D. Kuehl ◽  
F. R. Cobb
Keyword(s):  
Nitric Oxide ◽  
Coronary Flow ◽  
Diastolic Pressure ◽  
Coronary Vessels ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Vasomotor Tone ◽  
Coronary Vasomotor Tone ◽  
Endogenous Nitric Oxide

This study evaluates the role of endogenous nitric oxide in the modulation of basal coronary vasomotor tone by studying the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation from L-arginine, on resting epicardial coronary diameter and coronary flow. L-NMMA (5 mg/kg) was infused in seven awake dogs chronically instrumented with coronary dimension crystals for measurement of epicardial coronary diameter, and Doppler flow probes for quantitation of phasic coronary flow (vasomotion of distal regulatory resistance coronary vessels). Epicardial coronary diameter decreased 5.5% from 3.47 +/- 0.17 to 3.28 +/- 0.15 mm (mean +/- SE). The diameter change was gradual, reaching a maximum at 13 +/- 2 min after infusion, and persistent, lasting greater than 90 min. Phasic coronary flow did not change. Mean aortic pressure significantly increased from 99 +/- 3 to 111 +/- 3 mmHg and heart rate decreased from 56 +/- 4 to 46 +/- 3 beats/min. Left ventricular end-diastolic pressure and contractility were not significantly altered. L-Arginine (66 mg/kg) but not D-arginine reversed all hemodynamic parameters. These data support an important role of nitric oxide in modulating basal epicardial coronary vasomotor tone and systemic vascular resistance.

Tetrahydrobiopterin Slows the Progression of Atherosclerosis

Pteridines ◽  
2007 ◽  
Vol 18 (1) ◽  
pp. 115-121
Author(s):  
Suzuki Kunihiro ◽  
Yoshiyuki Hattori ◽  
Teruo Jojima ◽  
Atsuko Tomizawa ◽  
Toshie Okayasu ◽  
...  
Keyword(s):  
Drinking Water ◽  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Oral Administration ◽  
Mrna Expression ◽  
Inflammatory Factors ◽  
Apoe Ko Mice ◽  
Progression Of Atherosclerosis ◽  
Apoe Ko

Abstract We investigated whether oral tetrahydrobiopterin (BH4) treatment might slow the progression of atherosclerosis using hypercholesterolemic ApoE-knockout (KO) mice. We report that ingesting BH4 in drinking water is effective to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of ApoE-KO mice. Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring NO-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

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