scholarly journals Restoration of endothelin-1-induced impairment in endothelium-dependent relaxation by interleukin-10 in murine aortic ringsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (8) ◽  
pp. 557-565 ◽  
Author(s):  
Saiprasad M. Zemse ◽  
Rob H.P. Hilgers ◽  
G. Bryan Simkins ◽  
R. Daniel Rudic ◽  
R. Clinton Webb
Keyword(s):  
Endothelial Dysfunction ◽  
Immunohistochemical Analysis ◽  
Interleukin 10 ◽  
Enos Expression ◽  
Short Term ◽  
Response Curves ◽  
Endothelin 1 ◽  
Short Term Exposure ◽  
Endothelium Dependent Relaxation ◽  
Antiinflammatory Cytokine

Endothelin-1 (ET-1) is implicated in the development of endothelial dysfunction through the generation of reactive oxygen species by NADPH oxidase activation. Interleukin-10 (IL-10) is an antiinflammatory cytokine that stimulates nitric oxide production, decreases superoxide production, and restores endothelial integrity after vascular injury. In this study, we tested whether IL-10 attenuates ET-1-induced endothelial dysfunction by improving acetylcholine (ACh)-induced relaxation of cultured murine aortic rings. Aortic rings (2 mm long) of C57BL/6 mice were incubated in 2 mL DMEM containing 120 U/mL penicillin and 120 μg/mL streptomycin in the presence of one of 4 treatments: vehicle (deionized water), ET-1 (100 nmol/L), recombinant mouse IL-10 (300 ng/mL), or a combination of both ET-1 and IL-10. After incubation at 37 °C for either 1 or 6 h (short-term exposure) or 22 h (overnight exposure), rings were mounted in a wire myograph and stretched to a passive force of 5 mN. Endothelium-dependent vasorelaxation was assessed by constructing cumulative concentration–response curves to ACh (0.001–10 μmol/L) during 10 μmol/L phenylephrine (PE)-induced contraction. Short-term exposure of ET-1 did not result in an impairment of ACh-induced relaxation. Overnight exposure of aortic rings to ET-1 resulted in a statistically significant endothelial dysfunction characterized by a reduced maximal relaxation response to ACh compared with that of untreated rings (Emax 57% ± 3% versus 82% ± 4%). IL-10 treatment restored ACh-induced relaxation (Emax 77% ± 3%). Western blotting showed decreased eNOS expression in response to ET-1, whereas vessels treated with a combination of ET-1 and IL-10 showed increased expression of eNOS. Immunohistochemical analysis showed decreased eNOS expression in ET-1-treated vessels compared with those treated with both ET-1 and IL-10. We conclude that, in murine aorta, the antiinflammatory cytokine IL-10 prevents impairment in endothelium-dependent relaxation induced in response to long-term incubation with ET-1 via normalization of eNOS expression.

scholarly journals Interleukin-10 inhibits the in vivo and in vitro adverse effects of TNF-α on the endothelium of murine aorta

2010 ◽  
Vol 299 (4) ◽  
pp. H1160-H1167 ◽  
Author(s):  
Saiprasad M. Zemse ◽  
Chin Wei Chiao ◽  
Rob H. P. Hilgers ◽  
R. Clinton Webb
Keyword(s):  
Endothelial Dysfunction ◽  
Interleukin 10 ◽  
Enos Expression ◽  
Response Curves ◽  
Female Mice ◽  
In Vivo Experiments ◽  
Tnf Α ◽  
Significant Impairment

TNF-α is a proinflammatory cytokine and is an important mediator of maternal endothelial dysfunction leading to preeclampsia. In this study, we tested whether IL-10 protects against TNF-α-induced endothelial dysfunction in murine aorta. In in vitro experiments, aortic rings of C57BL/6 female mice were incubated in Dulbecco's modified Eagle's medium in the presence of either vehicle (distilled H2O), TNF-α (4 nmol/l), or recombinant mouse IL-10 (300 ng/ml) or in the presence of both TNF-α and IL-10 for 22 h at 37°C. In in vivo experiments C57BL6/IL-10 knockout female mice were treated with saline or TNF-α (220 ng·kg−1·day−1) for 14 days. Aortic rings were isolated from in vitro and in vivo experiments and mounted in a wire myograph (Danish Myotech) and stretched to a tension of 5 mN. Endothelium-dependent relaxation was assessed by constructing cumulative concentration-response curves to acetylcholine (ACh, 0.001–10 μmol/l) during phenylephrine (10 μmol/l)-induced contraction. As a result, overnight exposure of aortic rings to TNF-α resulted in significant blunted maximal relaxing responses ( Emax) to ACh compared with untreated rings (22 ± 4 vs. 82 ± 3%, respectively). IL-10 knockout mice treated with TNF-α showed significant impairment in ACh responses ( Emax) compared with C57BL/6 mice treated with TNF-α (51 ± 3 vs. 72 ± 3%, respectively). Western blot analysis showed that endothelial nitric oxide synthase (eNOS) expression was reduced by TNF-α in in vitro and in vivo experiments, whereas IL-10 restored the eNOS expression. In conclusion, the anti-inflammatory cytokine IL-10 prevents impairment in endothelium-dependent vasorelaxation caused by TNF-α by protecting eNOS expression.

scholarly journals Improvement of Huangqi Decoction on Endothelial Dysfunction in 5/6 Nephrectomized Rats

2016 ◽  
Vol 40 (6) ◽  
pp. 1354-1366 ◽  
Author(s):  
Shuang Chu ◽  
Li Wang ◽  
Xiao-dong Mao ◽  
Wen Peng
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Structural Changes ◽  
Vascular Complications ◽  
Immunohistochemical Analysis ◽  
Isometric Tension ◽  
Ros Generation ◽  
Male Wistar Rats ◽  
No Bioavailability ◽  
Endothelium Dependent Relaxation

Background/Aims: Endothelial dysfunction is a major factor in the progression of chronic kidney disease, which correlates with oxidative stress and NO deficiency. Huangqi decoction (HQD) is a potential anti-oxidant ingredient in renoprotection. However, the underlying mechanisms remained identified. Therefore, we investigated whether HQD exhibit improvement in endothelial dysfunction in the 5/6 nephrectomy (Nx) rat model. Methods: Male Wistar rats (180 - 250 g) were divided into sham, Nx and Nx + HQD (0.05, 0.15 and 0.45 g/kg) group, respectively. Renal function and histology were examined with ELISA and Immunohistochemical analysis. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Oxidative stress and NO bioavailability were detected by ELISA, DHE-staining, DAF-2 staining and western blotting. Results: Compared with Nx rats, HQD treatment reversed the functional and structural changes of kidney significantly. Besides, endothelium-dependent relaxation of rat aortas was also improved by HQD treatment. NADPH oxidase and ROS generation were inhibited while NO bioavailability was enhanced. Conclusion: HQD can act as a potent prescription for the treatment of endothelium related vascular complications.

Interleukin-10 reduces inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats

2010 ◽  
Vol 298 (3) ◽  
pp. R713-R719 ◽  
Author(s):  
John H. Tinsley ◽  
Sanique South ◽  
Valorie L. Chiasson ◽  
Brett M. Mitchell
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Systolic Blood Pressure ◽  
Interleukin 10 ◽  
Urinary Protein Excretion ◽  
Urinary Protein ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelin 1 ◽  
Protein Excretion ◽  
Hypertensive Disorders

Hypertensive disorders of pregnancy are characterized by systemic and placental inflammation; however, treatment for these conditions has remained elusive. We tested whether administration of the anti-inflammatory cytokine interleukin-10 (IL-10) during pregnancy would attenuate the hypertension, endothelial dysfunction, proteinuria, and inflammation seen in pregnant DOCA/saline-treated (PDS) rats. Normal pregnant (NP) rats and PDS were given daily intraperitoneal injections of recombinant IL-10 from gestational day 13 until death on day 20. Systolic blood pressure, aortic endothelium-dependent relaxation responses, and urinary protein excretion were measured on days 13 and 20 of gestation. Fetal number and development, plasma endothelin-1 levels, serum and placental levels of IFNγ and IL-10, and aortic and placental levels of platelet endothelial cell adhesion molecule (PECAM) were assessed on gestational day 20. Systolic blood pressure, aortic endothelial dysfunction, and urinary protein excretion were significantly increased at gestational day 13 in PDS rats. However, all of these were restored to NP levels following IL-10 treatment in PDS rats. IL-10 treatment also significantly increased the number of pups per litter in PDS rats and did not further affect fetal development. The beneficial effects of IL-10 in PDS rats were likely mediated by the decreased plasma levels of endothelin-1, decreased levels of circulating and placental IFNγ, as well as decreased aortic and placental expression of PECAM. These data demonstrate that exogenous IL-10 can normalize blood pressure and endothelial function in pregnancy-induced hypertensive rats and may be beneficial in women with hypertensive disorders of pregnancy.

Characterization of endothelin receptors mediating contraction and relaxation in rabbit saphenous artery and vein

1993 ◽  
Vol 71 (10-11) ◽  
pp. 818-823 ◽  
Author(s):  
Michel Auguet ◽  
Sylvie Delaflotte ◽  
Pierre-Etienne Chabrier ◽  
Pierre Braquet
Keyword(s):  
Smooth Muscle ◽  
Saphenous Vein ◽  
Rank Order ◽  
Endothelin Receptors ◽  
Response Curves ◽  
Endothelin 1 ◽  
The Right ◽  
Endothelin 3 ◽  
Endothelium Dependent Relaxation ◽  
Saphenous Artery

The endothelin receptors in rabbit isolated rings of saphenous artery and saphenous vein have been characterized using endothelin-1, endothelin-2, endothelin-3, sarafotoxin S6c, and BQ123. Although artery rings were more sensitive than those from vein to the contractile action of phenylephrine, endothelin-1 was about three times more potent as a contractile agonist on vein than on artery. In rings precontracted with phenylephrine, carbachol was 10 times more potent in vein than in artery rings to induce endothelium-dependent relaxation. However, in rings precontracted to a similar tone by endothelin-1, the relaxation elicited by carbachol was reduced in the vein but remained unchanged in the artery. In endothelium-denuded saphenous artery, endothelin-1 and endothelin-2 elicited contraction with equal potency, whereas endothelin-3 and sarafotoxin S6c were weak agonists. In saphenous vein, the rank order of sensitivity was sarafotoxin S6c > endothelin-2 > endothelin-1 = endothelin-3, whereas sarafotoxin S6c and, to a lesser extent, endothelin-3 act as partial agonists. The ETA receptor antagonist BQ123 shifted, to the right, the concentration–response curves of endothelin-1 on endothelium-denuded saphenous artery (pA2 = 7.25). In the endothelium-denuded saphenous vein, 10 μM BQ123 shifted to the right only the response to high concentrations of endothelin-1. In vein but not in artery, endothelin-1 and sarafotoxin S6c induced an endothelium-dependent relaxation, which was increased, in the case of endothelin-1, in the presence of BQ123. These results indicate that the rabbit saphenous vein contains a mixed population of ETA and ETB vasoconstrictor receptors located in the smooth muscle cells and vasorelaxant ETB receptors situated on endothelial cells. In contrast, the saphenous artery only possesses smooth muscle cell ETA receptors responsible for constriction.Key words: endothelium, endothelin, vein, artery, BQ123.

scholarly journals High Glucose-enhanced Acetylcholine Stimulated CGMP Masks Impaired Vascular Reactivity in Tail Arteries from Short-Term Hyperglycemic Rats

2000 ◽  
Vol 1 (1) ◽  
pp. 69-79 ◽  
Author(s):  
Marwan Hamaty ◽  
Cristina B. Guzmán ◽  
Mary F. Walsh ◽  
Ann M. Bode ◽  
Joseph Levy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Vascular Function ◽  
No Production ◽  
Short Term ◽  
Contractile Responses ◽  
Vascular Responses ◽  
Short Term Exposure ◽  
Endothelium Dependent Relaxation

Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several models of long-term hyperglycemia. However, the effects of short-term ambient hyperglycemia are poorly understood. Since oxidative stress has been implicated as a contributor to impaired vascular function, we investigated the following:Aims: (1) the effects of high glucose exposurein vitro(7 – 10 days) on vascular relaxation to acetylcholine (Ach) and contractility to norepinephrine (NE) and KCl; (2) if NO-dependent cGMP generation is affected under these conditions; and (3) aortic redox status.Methods: Non-diabetic rat tail artery rings were incubated in normal (5mM) (control NG) or high (20mM) glucose buffer (control HG). Vascular responses to Ach, NE and KCl were compared to those of streptozotocin (SZ) diabetic animals in the same buffers (diabetic NG, diabetic HG). Ach stimulated cGMP levels were quantitated as an indirect assessment of endothelial nitric oxide (NO) production and oxidative stress evaluated by measuring vascular glutathione and oxidized glutathione.Results: Rings from diabetic rats in NG showed impaired relaxation to Ach (P= 0.002) but relaxed normally, when maintained in HG. Similarly, contractile responses to NE were attenuated in diabetic rings in NG but similar to controls in HG. HG markedly augmented maximal contraction to KCl compared to control and diabetic vessels in NG (P< 0.0001). Diabetic vessels in a hyperosmolar, but normoglycemic, milieu respond like those in HG.in vitro, HG for 2 hours changed neither relaxation nor contractile responses to NE and KCl in control rings. Basal cGMP levels were lower in aortae from diabetic animals pre-incubated in NG than in HG/LG or in control rings in NG (P< 0.05). cGMP responses to Ach were exaggerated in diabetic vessels in HG (P= 0.035vs. control NG,P= 0.043vs. diabetic NG) but not different between control and diabetic rings in NG. Vessels from diabetic animals had lower levels of GISH (P< 0.0001) and higher levels of GSSG (P< 0.0001) indicating oxidative stress.Conclusions: Our data indicate that endothelium dependent relaxation is altered early in the diabetic state and that increased NO responses may compensate for augmented oxidative stress but the lack of effect of short-term exposure of normal vessels to HG suggests that short-term hyperglycemiaper sedoes not cause abnormal vascular responses.

Short-term exposure to cigarette smoke induces endothelial dysfunction in small intrapulmonary arteries: analysis using guinea pig precision cut lung slices

2008 ◽  
Vol 104 (5) ◽  
pp. 1462-1469 ◽  
Author(s):  
J. L. Wright ◽  
A. Churg
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Cigarette Smoke ◽  
Pulmonary Arteries ◽  
Delayed Response ◽  
No Production ◽  
Short Term ◽  
No Donor ◽  
Short Term Exposure ◽  
Precision Cut Lung Slices

The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We have previously shown that smoke rapidly and persistently, but discoordinately, upregulates gene expression of mediators that control vasoconstriction, vasoproliferation, and vasorelaxation in small intrapulmonary arteries. To investigate the possibility that smoke also induces endothelial dysfunction, a finding common to other forms of pulmonary hypertension, we exposed guinea pigs to smoke or air (control) daily for 2 wk and then prepared precision-cut lung slices. After exposure to endothelin-1, a vasoconstrictor, intra-acinar arteries in lung slices derived from smoke-exposed animals constricted more rapidly (greater constriction at a given concentration of endothelin) than did vessels from air-exposed animals. To examine relaxation responses, arteries were constricted with the vasconstrictor U-46619 and then relaxed with progressively increasing doses of acetylcholine. Vessels from smokers had a delayed response to acetylcholine compared with vessels from controls. The NO synthase inhibitor NG-nitro-l-arginine methyl ester reduced relaxation in both control and smoke-exposed arteries, whereas the NO donor sodium nitroprusside increased relaxation of the smoke-exposed arteries, confirming that endothelial dysfunction with decreased effective NO production is present. These findings show that precision cut lung slices can be used to examine the physiological effects of cigarette smoke on intra-acinar pulmonary arteries and indicate that even relatively short-term exposure to smoke produces endothelial dysfunction with a resulting tendency to earlier constriction and later relaxation in cigarette smokers. These changes may be important in the development of pulmonary hypertension.

scholarly journals Short-Term Esmolol Improves Coronary Artery Remodeling in Spontaneously Hypertensive Rats through Increased Nitric Oxide Bioavailability and Superoxide Dismutase Activity

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ana Arnalich-Montiel ◽  
María Carmen González ◽  
Emilio Delgado-Baeza ◽  
María Jesús Delgado-Martos ◽  
Luis Condezo-Hoyos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery ◽  
Spontaneously Hypertensive Rats ◽  
Histological Study ◽  
Hypertensive Rats ◽  
Short Term ◽  
Response Curves ◽  
Spontaneously Hypertensive ◽  
Artery Remodeling ◽  
Endothelium Dependent Relaxation

The aim of this study was to assess the effects of short-term esmolol therapy on coronary artery structure and function and plasma oxidative stress in spontaneously hypertensive rats (SHR). For this purpose, 14-month-old male SHR were treated for 48 hours with esmolol (SHR-E, 300 μg/kg/min). Age-matched untreated male SHR and Wistar Kyoto rats (WKY) were used as hypertensive and normotensive controls, respectively. At the end of intervention we performed a histological study to analyze coronary artery wall width (WW), wall-to-lumen ratio (W/L), and media cross-sectional area (MCSA). Dose-response curves for acetylcholine (ACh) and sodium nitroprusside were constructed. We also assessed several plasma oxidative stress biomarkers, namely, superoxide scavenging activity (SOSA), nitrites, and total antioxidant capacity (TAC). We observed a significant reduction in WW (P<0.001), W/L (P<0.05), and MCSA (P<0.01) and improved endothelium-dependent relaxation (AUCSHR-E=201.2±33versusAUCSHR=97.5±21,P<0.05) in SHR-E compared with untreated SHR; no differences were observed for WW, MCSA, and endothelium-dependent relaxation by ACh at higher concentrations (10−6to 10−4 mol/l) for SHR-E with respect to WKY. SOSA (P<0.001) and nitrite (P<0.01) values were significantly higher in SHR-E than in untreated SHR; however, TAC did not increase after treatment with esmolol. Esmolol improves early coronary artery remodeling in SHR.

scholarly journals Mixture toxicity analysis in zebrafish embryo: a time and concentration resolved study on mixture effect predictivity

2020 ◽  
Vol 32 (1) ◽  
Author(s):  
Gianina Jakobs ◽  
Janet Krüger ◽  
Andreas Schüttler ◽  
Rolf Altenburger ◽  
Wibke Busch
Keyword(s):  
Exposure Duration ◽  
Prediction Accuracy ◽  
Mixture Toxicity ◽  
Concentration Addition ◽  
Short Term ◽  
Response Curves ◽  
Low Concentrations ◽  
Short Term Exposure ◽  
Deviation Factor ◽  
Ca Model

Abstract Background Humans and wildlife are continuously exposed to chemical mixtures. These mixtures vary in composition but typically contain hundreds of micropollutants at low concentrations. As it is not feasible to measure the toxicity of all possibly occurring mixtures, there is a need to predict mixture toxicity. Two models, Concentration Addition (CA) and Independent Action (IA), have been applied to estimate mixture toxicity. Here, we compared measured with predicted toxicity of nine mixtures designed from 15 environmentally relevant substances in zebrafish embryos to investigate the usability of these models for predicting phenotypic effects in a whole organism short term acute assay. Results In total, we compared 177 toxicity values derived from 31 exposure scenarios with their predicted counterparts. Our results show that mixture toxicity was either correctly estimated (86%) by the prediction window, the concentration-effect space that is spanned between both models, or was underestimated with both models (14%). The CA model correctly predicted the measured mixture toxicity in 100% of cases when a prediction deviation factor of 2.5 was allowed. However, prediction accuracy of mixture toxicity prediction was dependent on exposure duration and mixture potency. The CA model showed highest prediction quality for long-term exposure with highly potent mixtures, respectively, whereas IA proved to be more accurate for short-term exposure with less potent mixtures. Obtained mixture concentration–response curves were steep and indicated the occurrence of remarkable combined effects as mixture constituents were applied at concentrations below their respective individual effect threshold in 90% of all investigated cases. Conclusions Experimental factors, such as exposure duration or mixture potency, influence the prediction accuracy of both inspected models. The CA model showed highest prediction accuracy even for a set of diverse mixtures and various exposure conditions. However, the prediction window served as the most robust predicator to estimate mixture toxicity. Overall, our results demonstrate the importance of considering mixture toxicity in risk assessment schemes and give guidance for future experiment design regarding mixture toxicity investigations.

scholarly journals Short term associations of ambient nitrogen dioxide with daily total, cardiovascular, and respiratory mortality: multilocation analysis in 398 cities

BMJ ◽  
2021 ◽  
pp. n534
Author(s):  
Xia Meng ◽  
Cong Liu ◽  
Renjie Chen ◽  
Francesco Sera ◽  
Ana Maria Vicedo-Cabrera ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Nitrogen Dioxide ◽  
Linear Models ◽  
Meta Analysis ◽  
Short Term ◽  
Response Curves ◽  
Respiratory Mortality ◽  
Short Term Exposure ◽  
Increased Risk ◽  
Time Series Approach

Abstract Objective To evaluate the short term associations between nitrogen dioxide (NO 2 ) and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide, using a uniform analytical protocol. Design Two stage, time series approach, with overdispersed generalised linear models and multilevel meta-analysis. Setting 398 cities in 22 low to high income countries/regions. Main outcome measures Daily deaths from total (62.8 million), cardiovascular (19.7 million), and respiratory (5.5 million) causes between 1973 and 2018. Results On average, a 10 μg/m 3 increase in NO 2 concentration on lag 1 day (previous day) was associated with 0.46% (95% confidence interval 0.36% to 0.57%), 0.37% (0.22% to 0.51%), and 0.47% (0.21% to 0.72%) increases in total, cardiovascular, and respiratory mortality, respectively. These associations remained robust after adjusting for co-pollutants (particulate matter with aerodynamic diameter ≤10 μm or ≤2.5 μm (PM 10 and PM 2.5 , respectively), ozone, sulfur dioxide, and carbon monoxide). The pooled concentration-response curves for all three causes were almost linear without discernible thresholds. The proportion of deaths attributable to NO 2 concentration above the counterfactual zero level was 1.23% (95% confidence interval 0.96% to 1.51%) across the 398 cities. Conclusions This multilocation study provides key evidence on the independent and linear associations between short term exposure to NO 2 and increased risk of total, cardiovascular, and respiratory mortality, suggesting that health benefits would be achieved by tightening the guidelines and regulatory limits of NO 2 .

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