Ciências Fisiológicas

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A disfunção ventricular direita pós-infarto do miocárdio está associada com o desenvolvimento da insuficiência cardíaca
(Universidade Federal do Espírito Santo, 2010-05-07) Fernandes, Aurélia Araújo; Zornoff, Leonardo Antônio mamede; Stefanon, Ivanita; Alessandra Simao Padilha; Vassallo, Dalton Valentim; Pereira,Fausto Edmundo Lima
Heart failure (HF) is the major cause of death and morbidity after myocardial infarction (MI) that can result in reduced cardiac output, increased venous pressure and cardiac remodeling. Usually, the left ventricle failing causes right dysfunction being related to greater risk of hospitalization. It has been suggested that assessment of right ventricle (RV) function is of important value to prognostic of HF after MI. Therefore, the aim of this study was to assess right ventricle contractility early (one week) and late phase (eight weeks) after MI. MI with signal of HF (HF group) and without signal of HF (Inf group) were compared to a sham-operated group (sham). Wistar male rats were anaesthetized with Ketamine (50 mg/kg) and Xylazine (5 mg/kg), i.m., and MI was induced through left coronary artery ligation at 3 mm of its origin. After 1 and 8 weeks the rats was anaesthetized with urethane (1.2 g/kg i.p.) and a catheter was inserted into the aorta and left ventricle to pressures measurements using a pressure transducer (TSD 104A) coupled to a Biopac MP100 system. Strips from the right ventricle were removed and attached to an isometric transducer and superfused at 30ºC with Krebs solution, stimulated at 0.5 Hz and 80 mV. The experimental protocols were approved by the local animal ethics committee (CEUA-EMESCAM). Both infarct groups presented same scar size (Inf 1 week= 32.4 ± 3; HF 1 week=33.7 ± 2.2; Inf 8 weeks= 26.5 ± 1.1; HF 8 weeks= 25 ± 0.9). The scar size did not have correlation with HF signals (left ventricle end diastolic pressure (LVEDP), increased lung weight and body weight ratio (LW/BW) and right ventricle to body weight ratio (RV/BW) neither with RV contractility. The LVEDP increased in HF group but not in the Inf group early (1 week: HF=15 ± 1*; Inf=5.2 ± 0.8; Sham=3,7 ± 0,6 mmHg) and late after MI (8 weeks: Hf=16 ± 2.5*, Inf- 7.5 ± 0.7; Sham= 5.2 ± 0.8 mmHg), *P< 0.05 ANOVA one way, post hoc Tukey. In the HF group LW/BW and RV/BW ratio was increased in the late phase, but not in the early phase after MI. The body weight was smaller in the HF group at 1 week, but similar to sham 13 and Inf 8 weeks after MI. Therefore, there was a negative correlation between force development in the RV strips and body weight in both early and late phase after MI. The inotropic responses to Ca2+ and Isoproterenol were preserved in HF group one week after MI and reduced at 8 weeks (8 weeks; CaCl2 2.5 mM: sham= 157 ± 18.4; Inf= 138 ± 17.3; HF= 62 ± 10.3 g/g P<0.05; Isoproterenol 10- 5 M: sham = 149 ± 14; Inf = 137 ± 18.7; HF = 58 ± 8.1 g/g P<0.05). Inversely, in the Inf group, the positive intropic response was reduced in the early phase and reduced in the late phase (1 week; CaCl2 2.5 mM: Sham= 186 ± 8.3; Inf = 135 ± 11.7; HF= 158 ± 13.1 g/g; P<0.05; Isoproterenol 10-5 M: Sham= 145 ± 9.9; Inf= 108 ± 10.8; HF= 166 ± 12 g/g P<0.05). The Ca2+ handling proteins expression (sarcoplasmatic reticulum calcium pump (SERCA-2a), phosfolamban (PLB total), PLB phosphorylated and Na+ /Ca2+ exchange) were not different among the groups in the early phase. But, in the late phase there was a SERCA-2a overexpression and an higher SERCA/PLB ratio just in the Inf group. In conclusion, the scar size did not correlate with HF signals neither with RV contractility. The RV dysfunction was found in the late phase after MI in rats with HF. However, the rats with HF maintain the RV function in early phase after MI. The infarct rats without HF maintained the RV contractility and increase SERCA-2a expression in the late phase after MI. The different inotropic βadrenergic response between the groups with and without HF could be induced by different mechanisms involving upregulation and downregulation of the βreceptors during the early and late phase after MI.
A exposição aguda a alta concentração de cobre prejudica a contratilidade miocárdica: participação das espécies reativas de oxigênio
(Universidade Federal do Espírito Santo, 2018-04-13) Filetti, Filipe Martinuzo; Vassallo, Dalton Valentim; Simões, Maylla Ronacher; Santos, Leonardo dos; Fioresi, Mirian
Copper is an essential metal for homeostasis and the functioning of living organisms, but in overload can lead to systemic harmful effects. Copper toxicity can be related to reactive oxygen species (ROS) production and cardiovascular diseases. We testing the effects of high copper concentration (10 μg/mL) on the myocardial mechanics, investigating the ROS-mediated effects. The developed force of papillary muscles was reduced after acute exposure to high copper and prevented by co-incubation with tempol, DMSO and catalase. The indirect evaluation of sarcoplasmic reticulum activity was reduced by copper and restored by tempol. The contractile response to calcium was reduced by copper and reversed by antioxidants. The response to β-adrenergic agonist decreased after exposure to copper and restored by tempol and catalase. Contractions dependent on the sarcolemmal calcium influx were impaired by copper and restored by antioxidants. In addition, in situ detection in papillary muscles showed increased O2 •- and OH• . The myosin-ATPase activity decreased significantly. In conclusion, high copper concentration can acutely impair myocardial excitationcontraction coupling reducing the capacity to generate force, by reducing calcium inflow and of its reuptake, myosin-ATPase activity, and these effects are mediate by local production of O2 •- , OH• and H2O2. These toxicity effects suggest that exposure to high copper concentration is a risk factor for cardiovascular disease
A exposição crônica ao chumbo diminui a reatividade vascular em aorta de ratos: papel do peróxido de hidrogênio
(Universidade Federal do Espírito Santo, 2014-12-17) Nunes, Karolini Zuqui; Fioresi, Mirian; Vassallo, Dalton Valentim; Gouvea, Sonia Alves; Moyses, Margareth Ribeiro; Peçanha, Giulia Alessandra Wiggers
We investigated whether exposure to small concentrations of lead alters blood pressure and vascular reactivity.Wistar rats were sorted randomly into the following two groups: control (Ct) and treatment with 100 ppm of lead (Pb), which was added to drinking water, for 30 days. Systolic blood pressure (BP) was measured weekly. Following treatment, aortic ring vascular reactivity was assessed. Tissue samples were properly stored for further biochemical investigation. The lead concentration in the blood reached approximately 8 µg/dL. Treatment increased blood pressure and decreased the contractile responses of the aortic rings to phenylephrine. Following LNAME administration, contractile responses increased in both groups but did not differ significantly between them. Lead effects on Rmax were decreased compared to control subjects following superoxide dismutase administration, Catalase, DETCA, and apocynin increased the vasoconstrictor response induced by phenylephrine in the aortas of lead-treated rats but did not increase the vasoconstrictor response in the aortas of untreated rats. TEA potentiated the vasoconstrictor response induced by phenylephrine in aortic segments in both groups, but these effects were greater in lead-treated rats. The co-incubation of TEA and catalase abolished the vasodilatory effect noted in the lead group. The present study is the first to demonstrate that blood lead concentrations well below the values established by international legislation increased blood pressure and decreased phenylephrine-induced vascular reactivity. The latter effect was associated with oxidative stress, specifically oxidative stress induced via increases in hydrogen peroxide levels and the subsequent effects of hydrogen peroxide on potassium channels.
A exposição única ao contaminante ambiental tributilestanho induz disfunção endotelial e estresse oxidativo em aorta
(Universidade Federal do Espírito Santo, 2018-09-27) Santos, Gersica de Almeida Correia; Ribeiro Júnior, Rogério Faustino; Stefanon, Ivanita; Andrade, Tadeu Uggere de; Rodrigues, Lívia Carla de Melo
INTRODUCTION: Organotins such as tributyltin (TBT) are environmental contaminants with a cytotoxic effect. Animals chronically exposed to TBT have vascular reactivity dysfunction associated with increased production of reactive oxygen species (ROS). The aim of this study was to investigate the effect of a single exposure to TBT. Vascular reactivity of isolated female rat aorta rings was evaluated 24 hours after exposure to a single dose of TBT (500 ng / kg) per gavage. METHOD: Wistar rats (240-260 g) were divided into control (CT) groups, and exposed to a single dose of TBT. The aorta was isolated and cut into rings, which were immersed in Krebs solution submitted to the concentration response curve of phenylephrine, LNG-nitroarginine methyl ester (L-NAME), Apocynine, Tiron and Losartan. The vasodilatory response was assessed by relaxing the increasing doses of Acetylcholine (ACh). In addition, the presence of ROS was measured by the intensity of the fluorescence produced by the oxidation of the dihydroetide (DHE). Data were expressed as mean ± SEM and analyzed by 2-way ANOVA or unpaired t-test with significance of p <0.05. The protocols were approved by the Ethics Committee on Animal Experimentation UFES (Protocols 27/2016). RESULTS: The aortic rings from the TBT group showed reduction of sensitivity (pD2) and the maximum response (Rmax) to ACh (pD2 TBT: 6.37 ± 0.27 * vs CT: 7.3 ± 0.25; Rmax TBT: 77 ± 5,18 * vs. CT: 92.9 ± 1.88 *, * p <0.05 vs CT), and increased maximal response and phenilefrine sensitivity (Rmax: TBT: 142 ± 7.2 ** vs CT : 110 ± 4% KCl, ** p <0.01; pD2: TBT: 7.68 ± 0.08 * vs. CT: 7.19 ± 0.13% KCl, * p <0.05 vs. CT). A incubation of the aortic rings with L-NAME increased the reactivity to phenilefrine in both groups (Rmax TBT: 142.2 ± 7.2 vs TBT L-NAME: 175 ± 7.8 # and CT: 110 ± 4 vs. CT LNAME: 165 , 7 ± 8.6 **% KCl, # p <0.05 vs TBT, ** p <0.01 vs CT). However, the area under the curve (dAUC %) was lower in the TBT vs CT group (CT: 52.4 ± 4.61 vs TBT: 35.8 ± 4.31 * p <0.05). The maximum response to phenilefrine was reduced in the TBT group after incubation with Apocinin, Tiron, Catalase and Losartan (TBT: 142 ± 7.2 vs TBT APO: 102.9 ± 5.42 # # TBT TIRON: 104.3 ± 9, TBT: 101.8 ± 7.38 % KCl; # # p <0.01 vs TBT). ROS was increased in the aorta of the animals exposed to TBT. CONCLUSION: We conclude that 24 hours after exposure to a single dose of 20 500 ng / kg TBT causes endothelial dysfunction, increase in the vasoconstrictor response to phenylephrine and a reduction in the vasodilatory response to acetylcholine that appears to be mediated by vascular oxidative stress.
A Influência dos hormônios sexuais no balanço entre as citocinas pró-inflamatórias e anti-inflamatórias em machos e fêmeas SHR, após o tratamento com enalapril
(Universidade Federal do Espírito Santo, 2011-12-16) Dalpiaz, Polyana Lima Meireles; Moyses, Margareth Ribeiro; Bissoli, Nazaré Souza; Gouvea, Sonia Alves; Garcia, Ana Raquel Santos de Medeiros
Introduction: Angiotensin II, a peptide formed from the action of angiotensin converting enzyme (ACE) on angiotensin I, is a primary mediator of the reninangiotensin system (RAS) and in addition to hemodynamic effects, is involved in key events the inflammatory process. The use of ACE inhibitors, apart from hemodynamic benefits, is associated with anti-inflammatory effects, however, still unclear whether ACE inhibitors have beneficial effects on the balance between pro-and anti-inflammatory cytokines and hormones can interfere with this relationship. Thus, this study was designed to investigate in SHR rats, males and females, castrated and intact, the potential benefit of ACE inhibitors on serum levels of inflammatory biomarkers, IL-10, IL-6 and TNF-α, since that these cytokines play important roles in the pathogenesis of inflammatory diseases. Objective: To evaluate the influence of gender on the effect of enalapril on serum levels of proinflammatory cytokines (IL-6 and TNF-α) and antiinflammatory (IL-10) in SHR rats. Methods: SHR, adults, both sexes, with 12 weeks, weight 150 ± 8 g (females) and 230 ± 10 g (males), were separated into eight experimental groups (n = 7) are: Males and Females 1) SHAM + Treatment with vehicle, 2) SHAM + treatment with enalapril, 3) castration + treatment with enalapril, 4) castration + treatment with vehicle. Treatment by gavage with enalapril (10mg/kg/day) was started after 21 days of castration and lasted 4 weeks. Sham group animals underwent sham surgery group and the castrated animals, underwent bilateral ovariectomy and orchidectomy, males and females respectively. We analyzed the plasma ACE activity of the cytokines IL-10, IL-6 and TNF-α. Level of significance: p <0.05. Results: Enalapril reduced SBP and ACE activity in all treated groups, we observed sexual dimorphism in plasma levels of IL-10, TNF-α and IL-6 in the sham groups, with higher values in females. The withdrawal of sex hormones made disappear the difference between males and females in relation to inflammatory cytokines and reversed the pattern of response. Enalapril treatment increased IL-10 in all treated groups, thus improving the balance proand anti-inflammatory, regardless of gender. Conclusion: The neutralization of the actions of angiotensin II by ACE inhibitors in SHR may exert anti-inflammatory and anti-hypertensives, regardless of sex, but dependent on sex hormones to reduce pro-inflammatory cytokines.
A ingestão elevada de frutose altera a reatividade vascular mesentérica em ratos normotensos
(Universidade Federal do Espírito Santo, 2017-02-17) Sousa, Glauciene Januário de; Bissoli, Nazaré Souza; Baldo, Marcelo Perim; Gouvêa, Sônia Alves; Nogueira, Breno Valentim
Chronic metabolic diseases are a common outcome of modern western lifestyle, as shown by the current prevalence of as obesity, insulin resistance and metabolic syndrome (MS), which correlates with increased fructose consumption and can leads to cardiovascular diseases. We hypothesize that high intake of chronic fructose mimics the early stages of cardiometabolic disease like to the MS, leading to initial vascular alterations. Methods: Wistar rats was separated in tow groups: (FRU) fructose 10% in drink water for 6 weeks and (CON) without fructose. Blood pressure was evaluated by tail plethysmography. Fasting glucose, insulin and glucose tolerance test was made using a strip-based glucometer. Mesenteric vascular beds reactivity was tested in a perfused system. Western blot analysis of iNOS, eNOS, Nox2 and COX-2 was performed. DHE stain was used to vascular O2 - detection. Scanning electron microscopy provided ultrastructural vessel observation. Results: Blood pressure was no altered. FRU shown increased visceral fat deposition and liver weight as well as increased fasting glucose and impaired insulin and glucose tolerance. Fructose increased NEinduced vasoconstriction which was abolished by both indomethacin and endothelium removal. ACh-induced relaxation was preserved, and L-NAME promoted a significant reduction in response in the FRU group. The SNP-induced relaxation was not altered. Protein expression of iNOS was increased, however, there was no changes in the eNOS, Nox2 and COX-2. DHE shown no differences. Additionally, the scanning electron microscopy images showed a slight disarray in the endothelium layer surface that are suggestive of derangement of the intima layer with a change in the shape and arrangement of the endothelial cells. Conclusions: High fructose intake for 6 weeks leads to metabolic disturbance and promotes increased NOR-induced vasoconstriction through endothelial prostaglandins pathway as well as increased the NO-mediated relaxation associated with iNOS increase.
A inibição da DPP-4 previne a disfunção vascular induzida pela hiperatividade β-adrenérgica
(Universidade Federal do Espírito Santo, 2018-08-10) Oliveira, Bruna Coelho de; Santos, Leonardo dos; Barauna, Valério Garrone; Santos, Roger Lyrio dos; Campos, Luciene Cristina Gastalho; Caceres, Viviane de Menezes
The increase in sympathetic activity is involved with the genesis and maintenance of disease states that affect the cardiovascular system. Β-adrenergic hyperactivity induces the formation of local inflammatory factors in vascular tissue, leading to vascular dysfunction. A possible pharmacological strategy of controlling vascular injury by the inflammatory process is to inhibit the enzyme dipeptidyl peptidase-4. DPP-4 inhibitors are of the class of drugs used to treat type 2 diabetes mellitus by increasing the half-life of GLP- 1 and improve glycemic control. We aimed to test the hypothesis that the DPP-4 inhibitor reverses vascular dysfunction and attenuates the inflammatory process caused by β-adrenergic hyperactivity. Male Wistar rats (Rattus norvegicus) weighing between 300 and 350g were used. The animals were randomly divided into three groups: vehicle group (VHC), isoproterenol (non-selective βadrenergic agonist) (ISO) and isoproterenol group plus sitagliptin (DPP-4 inhibitor) (ISO + SITA). A human umbilical vein endothelial cell line (EAhy.926) and primary vascular smooth muscle cells (VSMC), obtained by the explant method of the thoracic aorta of wistar rats, were used. We have shown in our results that isoproterenol caused cardiac hypertrophy of 28% and sitagliptin was not able to prevent this response. There was no change in cardiorespiratory function. Inhibition of DPP-4 was able to prevent the increase in the contractile response to phenylephrine, in addition, it prevented the endothelial dysfunction caused by isoproterenol in vascular reactivity, observed by the mechanical removal of the endothelium. Chronic treatment with isoproterenol did not alter DPP-4 activity, but increased mRNA expression of the proinflammatory cytokines IL-1β (86%), IL-6 (45%) and MCP-1 (84%) in the aorta , while sitagliptin reduced to baseline. In vitro, isoproterenol did not alter the activity of DPP-4 and the expression of inflammatory cytokines in VSCV, but increased the activity of DPP-4 and inflammatory cytokines in endothelial cells (IL-1β, 49%, IL-6, 39%; MCP-1, 43%) and sitagliptin reduced to baseline. In conclusion, our study demonstrated that inhibition of DPP-4 by sitagliptin improves vascular dysfunction and significantly attenuates endothelial inflammation in an experimental model of β-adrenergic hyperactivity.
A terapia com células mononucleares atenua a aterosclerose em camundongos ApoE Knockout
(Universidade Federal do Espírito Santo, 2011-12-12) Porto, Marcella Leite; Meyrelles, Silvana dos Santos; Vasquez, Elisardo Corral; Baldo, Marcelo Perim; Errera, Flávia Imbroisi Valle
Cardiovascular diseases are leading causes of morbidity and mortality worldwide. Among these, there is atherosclerosis, a chronic inflammatory disease of the arterial wall. Despite conventional therapies (pharmacological or surgical interventions) are of great value, cell therapy emerges as a new therapeutic strategy for treating and preventing atherosclerosis. Thus, the aim of this study was to evaluate the effects of mononuclear cell (MNC) therapy on the development of atherosclerotic lesions in the apolipoprotein E knockout (apoE KO) mouse. ApoE KO female mice (24-week-old) were randomly divided into two groups: 1) an apoE KO control group (n = 8) and 2) an apoE KO group that received MNC therapy (apoE KO-MNC, n = 8). β-galactosidase (β-gal) (encoded by the lacZ gene) transgenic mice (12-week-old) were used as MNC donors. Six-month-old apoE KO mice were fed a cholesterol-rich diet (1.25% cholesterol) for 4 to accelerate the process of atherogenesis. ApoE KO-MNC received mononuclear cells isolated from the spleen of lacZ mice (106 cells / week) for 8 weeks. After euthanasia, a blood sample was collected and the plasma total cholesterol was measured. The aorta was removed for immunohistochemical analysis. We investigated vascular lipid deposition, vascular remodeling, oxidative stress, endothelial nitric oxide synthase (eNOS) expression and the presence of endothelial progenitor cells. in apoE KO mice treated with spleen MNCs isolated from lacZ transgenic mice (apoE KO-MNC) compared to untreated control mice (apoE KO). Data are presented as the mean ± SEM. Statistical analysis was performed with Student’s t-test for independent samples or one-way analysis of variance (ANOVA). Statistical significance was set at p < 0.05. Histological analysis of aortas showed a significant reduction in the lipid deposition area in apoE KO-MNC mice compared to apoE KO mice (0.051 ± 0.004 vs 0.117 ± 0.016 mm2, respectively, p < 0.01). In addition, vessel morphometry revealed that MNC therapy prevented the outward (positive) remodeling in apoE KO mice that is normally observed (apoE KO-MNC: 0.98 ± 0.07 vs apoE KO: 1.37 ± 0.09), using wildtype mice (C57BL/6J) as a reference. ApoE KO-MNC mice also have reduced 15 production of superoxide anions and increased eNOS expression compared to apoE KO mice. Finally, immunohistochemistry analysis revealed a homing of endothelial progenitor cells (EPCs) in the aortas of apoE KO-MNC mice. We concluded that MNC therapy attenuates the progression of atherosclerosis in the aortas of apoE KO mice. Our data provide evidence that the mechanism by which this attenuation occurs includes the homing of EPCs, a decrease in oxidative stress and an upregulation of eNOS expression.
Ação moduladora da tibolona no sistema de peptídeos natriuréticos: Implicações cardiovasculares e imunológicas
(Universidade Federal do Espírito Santo, 2010-11-24) Garcia, Ana Raquel Santos de Medeiros; Andrade, Tadeu Uggere de; Bissoli, Nazaré Souza; Reis, Adelina Martha dos; Boechät, Giovanna Assis Pereira; Padilha, Alessandra Simão
Cardiovascular and immune system abnormalities have been reported in females with estrogen deficiency. Nevertheless, the capacity of the exogenous estrogen therapy to manage these hazard effects in postmenopausal women is still to be better investigated. Objective: this study is addressed to determine the abnormalities on the natriuretic peptide system in ovariectomized rats with and without tibolone reposition therapy, and if these changes are or not related with cardiovascular and immunological parameters. Materials and Methods: female rats with the average weight of 160-180 g were used and divided into four groups (n = 7 per group): SHAM, ovariectomized (OVX), OVX treated with 17β-estradiol (EST) and OVX treated with tibolone (TIB). The treatment period was 14 days with TIB (1.5 mg / kg / day) and EST (0.5 mg / kg / day), after 21 days of the ovariectomy procedure. At the end of treatment, the animals were euthanized, the thoracic aorta was isolated, and rings of 4-5 mm were removed. Rings with endothelium, were placed in an isolated organ tank with Krebs solution. Dose-response curves to phenylephrine (PHE) and acetylcholine (ACH) were obtained for assessment of vascular reactivity. Upper segment of the thoracic aorta was used for analysis of protein expression of eNOS by Western Blotting. The kidneys, the atria and blood were collected for further analysis. Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay (RIA) and serum cytokines (IL-6 and TNF-α) by ELISA. Atria were removed for analysis by RIA of ANP and atrial ANP mRNA by RT-PCR. The kidneys were used for analysis of mRNA of type A receptor (NPR-A) and C (NPR-C) by RT-PCR. Data were presented as mean ± standard error of mean. Statistical analysis of the reactivity of aortic rings was performed by analysis of variance (ANOVA), and one or two way, followed by post-hoc test of Tukey. For the peptides system data it was performed one-way analysis of variance (ANOVA) followed by post hoc Newman-Keuls, and for eNOS it was used one-way analysis of variance (ANOVA) followed by Fisher's post hoc test. Significance levels were p<0,05. Results: the OVX group showed increase of contractile response to PHE compared to the SHAM group, and the TIB and EST groups were able to normalize this response (Emax - SHAM: 91,0 ± 3,9; OVX: 140,0 ± 5,5; EST: 115,4 ± 3,7; TIB: 113,2 ± 5,1 - % Tension). The endothelium-dependent relaxation (dose-response curves to ACH) was similar for all groups. The OVX, EST and TIB groups showed no difference in the eNOS protein expression compared with the SHAM group, however, serum levels of IL-6 and TNF-α were increased in ovariectomized females. However, the treatments with EST and TIB were able to decrease these levels compared to the SHAM group, except the levels of IL-6 which remained high in the TIB group (TNF-α: SHAM 20.3 ± 2.0, OVX 31.0 ± 5.0, 17.6 ± EST 2.0; TIB: 20.5 ± 3.1 / IL-6: SHAM 19.3 ± 6.0, 32.8 ± 5.0 OVX, EST 20.0 ± 3.0; TIB: 34.4 ± 2.8 pg / ml). The plasmatic and left atrial levels of ANP (ANP plasma: 263.3 ± 53.3 SHAM, OVX 92.5 ± 19.5, 247.3 ± 29.9 EST; TIB: 285.7 ± 60.4 pg / ml / left atrial ANP: SHAM 5.68 ± 0.35; OVX 3.48 ± 0.40, 0.97 ± 6:48 EST; TIB: 3.59 ± 0.25 mg / mg protein), the mRNA expression of ANP left atrial (SHAM 91.3 ± 4.4, OVX 40.0 ± 10.1; 122.3 ± 12.0 EST; TIB: 167.9 ± 25.7 AU) and NPR-A (SHAM 5.20 ± 12:00; OVX 0.68 ± 0.11; EST 0.92 ± 0.28; TIB: 2.04 ± 1.4 AU) were depressed after ovariectomy, and NPRC did not change. The treatment normalized these parameters, except that the TIB group did not normalize the levels of atrial ANP. Conclusion: data from this study show, for the first time, that tibolone treatment after ovariectomy influence the natriuretic peptide system and the inflammatory cytokines. Tibolone was able to normalize the levels of ANP and its atrial expression as well as reduce levels of TNF-α. Additionally, the results show that Hormonal Therapy used in this study partially normalized the changes in vascular reactivity, possibly through regulation of the peptide system and inflammatory cytokines.
Ácido Linoleico Reduz a Reatividade Vascular e Melhora a Disfunção Vascular de Artérias Mesentéricas de Ratos Hipertensos
(Universidade Federal do Espírito Santo, 2018-10-04) Nunes, Dieli Oliveira; Ribeiro Junior, Rogerio Faustino; Padilha, Alessandra Simao; Pereira, Fausto Eduardo Lima; Mill, José Geraldo; Stefanon, Ivanita
Omega-6 polyunsaturated fatty acids are well known for their important role in many physiological functions and in reducing the risks of cardiovascular diseases, especially linoleic acid (LA). Therefore, we aimed to investigate the effect of linoleic acid (LA) treatment on the blood pressure and function of mesenteric resistance arteries (MRA) in spontaneous hypertensive rats (SHR). Male SHR were treated daily with LA (15 mg/kg) or vehicle (control) for 15 days. Compared with controls, LA treatment decreased blood pressure (SBP (mmHg) - Control: 139 ± 1,8 vs LA: 128,4 ± 1,7; DBP (mmHg) - Controle: 78,6 ± 1,1 vs AL: 70,1 ± 3,7 and showed the following in MRA: (1) increased lumen and external diameter, (2) decreased wall:lumen ratio and wall thickness, (3) decreased stiffness and (4) less collagen deposition. LA treatment reduced the contractile response to phenylephrine, although there were no changes observed in MRA in regard to the acetylcholine or sodium nitroprusside responses. Incubation with L-NAME leftshifted the reactivity to phenylephrine only in the MRA treated group, suggesting that LA treatment can improve NO bioavailability, which was confirmed by NO “in situ” quantification analyses. Incubation with tiron decreased vascular reactivity to phenylephrine in MRA in LA rats, which was accompanied by decreased superoxide anion production. Moreover, incubation with indomethacin (nonselective COX inhibitor), NS 398 (COX-2 specific inhibitor), furegrelate (TXA2 synthase inhibitor), SQ 29.548 (TP receptor antagonist) and SC 19220 (EP1 receptor antagonist) reduced the vasoconstrictor responses to phenylephrine in MRA in the treated group. These results were accompanied by a reduction in COX-2 protein expression. In conclusion, these findings show that LA treatment decreases blood pressure, accompanied by structural and functional changes in resistance arteries of SHR rats. These functional changes involve NO bioavailability and reduction in superoxide anion production. At last, the improvement of endothelial dysfunction and structural changes in this hypertension model may be responsible for the reduction in blood pressure.
Alterações cardiovasculares induzidas pela peçonha da serpente Bothrops leucurus
(Universidade Federal do Espírito Santo, 2018-04-05) Naumann, Gustavo Baptista; Sanchez, Eládio Flores; Figueiredo, Suely Gomes de; Borges, Márcia Helena; Pires, Rita Gomes Wanderley; Gouvêa, Sonia Alves; Bissoli, Nazaré Souza
Bothrops leucurus (white tail jararaca) is the main responsible for ophidian accidents in the northeastern region of Brazil and northern Espírito Santo. Several studies have evaluated the biochemical features of this snake’s venom, as well as its local effects. However, systemic effects – in particular cardiovascular effects – remain rather poorly explored. In the present study, we sought to investigate the acute cardiovascular activities induced by B. leucurus venom (VB) in vivo and in vitro. In anaesthetized rats it was demonstrated that BlV (10-100µg/kg) induces immediate and transient hypotension, while maximum response was observed in 5 min and a return to baseline was observed in ≈ 20 minutes. No change in the heart rate of the animals was observed. In vitro effects were evaluated on pre-contracted mesenteric artery rings with phenylephrine, employing a resistance myograph.
Análise da precisão e da aplicabilidade do consumo de oxigênio de reserva durante o exercício aeróbio contínuo nas intensidades de 50% a 80% do consumo máximo de oxigênio
(Universidade Federal do Espírito Santo, 2007-03-27) Santos, Miguel Angelo Alves dos; Orientador1; https://orcid.org/; http://lattes.cnpq.br/; 1º membro da banca
The main objective of this study was to evaluate the accuracy and the applicability of oxygen consumption reserve (VO2R) in the prescription of continuous aerobic exercise for the maximal oxygen consumption (VO2max) intensities of 50%, 60%, 70%, and 80%. Following ergoespirometry, the physical training speeds corresponding to 50%, 60%, 70%, and 80% VO2R were calculated using the equation proposed by ACSM for running and walking in 60 volunteers – 30 males and 30 females – aged 23 ± 3.4 and 21.7 ± 4.1 respectively. After the calculations were done, the volunteers performed continuous aerobic exercise (running or walking) for 30 minutes in a random sequence of the said intensities with intervals of 48 hours between them. During the exercise performance, oxygen consumption was collected. The VO2 consumption collected during the aerobic exercise was called measured oxygen consumption reserve (VO2Rm) for the purpose of comparing VO2R calculations with VO2 consumption at the same exercise intensity. The criteria used for determining the equation accuracy were the following: a) Student’s t test; b) evaluation of the correlation coefficient; c) analysis of estimate standard error of the inclination of the straight line of linear regression. The level of significance used was p< 0.05. Data demonstrated that VO2R and VO2Rm were similar in all intensities. However, the VO2R median values were always higher at each intensity studied than those of VO2Rm (3.4%, 4.2%, 9.2%, and 2.2% in the male group and 9.9%, 3.3%, 7.7%, and 9.7 % in the female group). There was no significant difference between the heart rate measured in the blood lactate (BL) and the heart rate at 70% of HRmaxE and 70% of HRmaxM. The heart rate values prescribed indirectly 85% of HRmaxE and 85% of HRmaxM underestimate the heart rate in the RCP by approximately 6.5% (male group) and 9.1% (female group). The VO2 values prescribed indirectly overestimate by approximately 36.7% (male group) and 66.3% (female group) when VO2 at 60% of the estimated oxygen maximal consumption (VO2maxE) is used and by 18% when VO2 at 60% of VO2maxM is used compared to VO2 values in BL, both groups. There was no significant difference between VO2 in RCP and VO2 at 80% of VO2maxM; however, VO2 in RCP was approximately 9.2% higher in the male group and 6.5% lower in the female group. We came to the conclusion that the oxygen consumption reserve equation demonstrates a good correlation with the VO2 consumed during continuous aerobic exercise; however, the said equation tends to overestimate the aerobic exercise intensity mainly in individuals with poor physical condition. Moreover, the use of both VO2maxE and HRmaxE overestimates the values found, which may predispose to a premature metabolic acidosis, and, as a result of that, cause an overload to the cardio-vascular system. The results suggest that adequate prescriptions of intensities for aerobic exercising are more efficient and safer when determined by ergoespirometry.
Análise do efeito do Sildenafil sobre células-tronco hematopoiéticas em camundongos ateroscleróticos
(Universidade Federal do Espírito Santo, 2017-12-21) Rodrigues, Bianca de Paula e; Vasquez, Elisardo Corral; Padilha, Alessandra Simão; Amorim, Fernanda Gobbi; Campagnaro, Bianca Prandi
A decline in the functionality of stem cells may be a key component in the pathogenesis of cardiovascular diseases. In atherosclerosis, there is an increase in endogenous genotoxic agents, such as reactive oxygen species (ROS), which can cause oxidative damage in DNA. Considering previous report that sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), have antioxidant effects, in the present study we evaluated the effect of this drug on ROS levels, on pro-oxidant and antioxidant systems, on genotoxicity, on DNA repair kinetics and on apoptosis in hematopoietic stem cells (HSC) of atherosclerotic apoE knockout mice (apoE-/-). For this study were used male 20-week old apoE-/- mice. Animals were distributed into three different groups: apoE−/− mice administered with the PDE5 inhibitor sildenafil (apoE−/− sildenafil, Viagra® , 40 mg/kg/day, for 3 weeks, by oral gavage, n=25), apoE-/- mice administered with vehicle (apoE-/- vehicle, n=25) and Wild-type C57Black/6 mice (C57 vehicle, n=25). Then, animals were euthanized, blood collected for analysis of the lipid profile. The HSC were isolated by cell culture for assessed of ROS production, DNA damage, DNA repair kinetics and apoptosis by flow cytometry. Statistical comparisons were done by ANOVA, followed by Bonferroni’s post hoc test.
Análise do proteoma mitocondrial de células do fígado de camundongos apoE knockout tratados com sildenafil
(Universidade Federal do Espírito Santo, 2017-05-19) Menezes, Thiago Nunes de; Orientador1; https://orcid.org/; http://lattes.cnpq.br/; Borges, Márcia Helena; Vasquez, Elisardo Corral; Fronza, Marcio; Bissoli, Nazare Souza
The role of plasmatic lipids in the chronic disease may be associated with oxidative stress, which is characterized by redox imbalance. Proteins are molecules involved in almost all biological phenomena and the understanding of the protein regulation may be a source of new therapeutic strategies. Thus, the aim of the present work was analyse the mitochondrial protein expression in 18-weeks old sildenafil-treated apoE-/- mice as compared to non-treated animals. Previously, the apoE-/- mice presented a plasma lipid profile characteristic of dyslipidemia, and the triacylglycerol, total cholesterol, LDL and VLDL levels were 5, 14, 6 and 36 times higher than observed from control group (C57), which was not reverted by treatment with sildenafil. Flow cytometry showed in liver cells increased levels of intracellular reactive oxygen species of superoxide anion (~82%), hydrogen peroxide (~60%), peroxinitrite (~53%) as well as increased apoptotic cells (from ~2% to ~19%). The treatment was able to prevent the production of analysed ROS and reduced the apoptotic cells, restoring the pattern observed in C57 group. It suggests that sildenafil presents an antioxidant action. Differential two-dimensional electrophoresis coupled with mass spectrometry was applied to study the changes in mitochondrial protein profile in both conditions.
Angiotensina II intra-renal modula a expressão da óxido nítrico sintase neuronal na hipertensão renovascular 2R1C
(Universidade Federal do Espírito Santo, 2005-12-20) Pereira, Thiago de Melo Costa; Silva, Ian Victor; Meyrelles, Silvana dos Santos; Cabral, Antonio de Melo; Gouvêa, Sônia Alves; Soares, Luciana Saloto
In physiological conditions, nitric oxide (NO) exerts a modulatory influence on renal blood flow mainly due the neuronal nitric oxide synthase (nNOS) enzyme isoform. Although some studies have demonstrated that the renal nNOS mRNA expression is modified in arterial hypertension (HÁ), it has not yet been shown how nNOS protein expression is modulated by endogenous angiotensin II (Ang II), a vasoconstrictor and a NO function inhibitor. Through the western blotting technique have been evaluate the relative role of HA and Ang II on the nNOS protein expression in the kidneys of renovascular hypertensive rats two-kidneys one clip (2K1C). The specific aim was to investigate the role of AT1 receptors and oxidative stress in modulating nNOS expression and the NO bioavaiability by GMPc quantification for enzymeimmunoassay. Then, the animals were divided in 4 groups: 2K1C (n=9), 2K1C+subpressor dose of losartan (10 mg/Kg/day in drinking water; n=4), 2K1C+subpressor dose of tempol (0.2 mmol/Kg/day in drinking water; n=6), and Sham (n=16), presenting values of MAP 179 ± 5 mmHg, 140 ± 7 mmHg, 181 ± 10 mmHg and 99 ± 3 mmHg, respectively. The nNOS expression was increased in the contralateral and clipped kidneys of the animals 2R1C when compared to SHAM group (0,43±0,03 vs. 0,14 ± 0,02 u.d.o. e 0,27±0,03 vs. 0,16±0,03 u.d.o. respectively), normalized in both kidneys in 2R1C + losartan when compared to SHAM group (0,24 ± 0,01 vs 0,27 ± 0,01 u.d.o e 0,21 ± 0,03 vs.0,29 ± 0,02 u.d.o., respectively). In 2R1C + tempol group, the nNOS expression was decreased in the contralateral kidney (0,27 ± 0,06 vs. 0,19 ± 0,06 u.d.o., respectively) but still increased in the clipped kidney when compared to SHAM group (0,35 ± 0,08 vs. 0,17 ± 0,03 u.d.o., respectively). The present results demonstrate that: 1) In the 2K1C renovascular hypertension model, the AT1 receptors and oxidative stress seem to be primary stimuli for increasing nNOS expression but not the HA per se; 2) The increase in nNOS expression does not reflects directly on the more NO bioavaiability in both kidneys (contralaetral or clipped); 3) The increase in nNOS expression induces a compensatory mechanism in order to maintain the renal homeostasis in this model of hypertension.
Antagonista do receptor tipo AMPA reverte a modulação pré-frontal induzida pela estimulação epidural por corrente contínua na memória operacional espacial
(Universidade Federal do Espírito Santo, 2016-08-25) Martins, Cleciane Waldetário; Palacios, Ester Miyuki Nakamura; Rodrigues, Lívia Carla de Melo; Barauna, Valério Garrone; Valle, Ângela Cristina do
The modulation of the prefrontal cortex (PFC) excitability by direct current stimulation improves cognitive function. However, the underlying mechanisms remains unknown. Here we investigated the involvement of glutamate α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acidreceptors (AMPARs) on the effects of repetitive epidural direct current stimulation (eDCS) on long-termed spatial working memory. Methods: Well-trained rats in 8-arm radial maze (8-RM) procedures received acute intraperitoneal (IP) administration of the AMPAR antagonist, perampanel (PRP, 1 mg/kg) or its vehicle (VEH) before performing 4-h delayed tasks in 8-RM. This drug intervention was performed before or after repetitive (once daily, five consecutive days) anodal eDCS (400 µA, 13 minutes) over the left medial PFC or sham procedure. Results: Animals treated with PRP (n = 27) showed larger number of errors (p < 0.01) in the 4-h post-delayed performance compared to those treated with VEH (n = 26). After the repetitive eDCS, animals treated with VEH (n = 13) presented smaller number of errors in the 4-h post-delay performance compared to animals receiving VEH after sham (p = 0.05, n = 12) and those receiving PRP after eDCS (p= 0.001, n = 13). These animals receiving PRP after eDCS showed larger (p = 0.025) number of errors when compared to those treated with PRP after sham (n = 12). Conclusions: AMPARs antagonism disrupted the spatial working memory and reversed the facilitating effects of the eDCS applied over the medial PFC. Thus, the spatial working memory and the prefrontal cognitive modulation by the direct current stimulation are highly dependent on AMPARs activity.
Associação do alisquireno e L-arginina melhora a atividade simpática e função renal na hipertensão renovascular
(Universidade Federal do Espírito Santo, 2015-02-27) Tiradentes, Renata Viana; Abreu, Glaucia Rodrigue; Mauad, Hélder; Neto, Henrique de Azevedo Futuro; Bissoli, Nazare Souza
Renovascular hypertension is characterized by increased renal sympathetic activity, angiotensin II, and by endothelial dysfunction. The purpose of this study was to determine the role of renal sympathetic nerve activity (RSNA) in mediating the anti-hypertensive effects of aliskiren (ALSK) and L-arginine (L-ARG) in a rat renovascular hypertension model. Hypertension was induced by clipping the right renal artery, and the following 5 groups were divided: Sham operated; 2-kidney, 1-clip (2K1C); 2K1C plus ALSK; 2K1C plus L-ARG; and 2K1C plus ALSK+ L-ARG. The systolic blood pressure (SBP) of 2K1C rats increased from 114.4±5.2 to 204±12.7 mmHg, (P< 0.05) and was only reduced by ALSK+L-ARG treatment (138.4±4.37 mmHg). The 2K1C hypertension increased the baseline RSNA (SHAM: 62.4±6.39 vs 2K1C: 97.4±8.43%). L-ARG or ALSK+L-ARG treatment significantly decreased baseline RSNA (2K1C L-ARG:70.7±2.39; 2K1C ALSK+L-ARG: 69.3±4.23%), but ALSK treatment alone did not (2K1C ALSK: 84.2±2.5%). Urinary water, Na+ , Cl- and urea excretion were similar in the 2K1C L-ARG, 2K1C ALSK+L-ARG and SHAM groups. The combination of ALSK+L-ARG restored urine flow and increased the glomerular filtration rate. The nNOS expression in the non clipped kidney was significantly increased in 2K1C ALSK+L-ARG rats. In conclusion, combined ALSK+L-ARG treatment normalizes SBP and prevents renal dysfunction in 2K1C hypertensive rats, an effect that can be partially attributed to reduced RSNA.
Atenuação do reflexo Bezold-Jarisch após tratamento crônico com doses suprafisiológicas de decanoato de nandrolona em ratos sedentários
(Universidade Federal do Espírito Santo, 2007-09-27) Medeiros, Ana Raquel Santos de; Bissoli, Nazaré Souza; Stefanon, Ivanita; Andrade, Tadeu Uggere
While there clinical applications of anabolic-androgenic steroids (AAS), the misuse of AAS is widespread and is not limited to competitive athletes but the majority of AAS abusers are noncompetitive recreational bodybuilders and even nonathletes. Objective: we investigated the influence of treatment with an AAS on the BezoldJarisch reflex (BJR) control of heart rate (HR) and whether this treatment induced cardiac hypertrophy and anabolic effects in rats. Methods: male rats were treated with nandrolone decanoate (ND; 10 mg.Kg-1 body weight/8 wks; DECA) or vehicle control (CON). After 8 wks, the BJR was evaluated by bradicardia responses elicited by serotonin administration (2-32 µg.Kg-1). Mean arterial pressure (MAP) was assessed and cardiac hypertrophy was determined by the left or right ventricle weight/body weight (LVW/BW; RVW/BW; respectively). The measurement of the total body protein content of the animals was performed. Results: ND treatment determined an elevation of the MAP of DECA animals compared with CON group (CON = 99 ± 1; DECA = 109 ± 2 mmHg; p<0.01). There was no change in the mean basal HR of DECA animals (CON = 356 ± 13; DECA = 367 ± 11 bpm). The LVW/BW and RVW/BW ratios indicated significant hypertrophy of the LV and RV in DECA animals (CON = 1.86 ± 0.04, DECA = 2.17 ± 0.04, p<0.01; CON = 0.42 ± 0.02, DECA = 0.53 ± 0.03 mg.g-1, p<0.05; respectively). Total body protein content was enhanced in DECA group compared with CON rats (CON=18.2 ± 1%, DECA = 28.0 ± 1%; p<0.01). In the last two doses of serotonin the BJR control of HR was significantly blunted in DECA rats compared with CON group (CON = -61 ± 4% and -76 ± 3%; DECA = -47 ± 4% and -66 ± 3%; p<0.01 and p<0.05, respectively). Conclusions: We conclude that 8-wks ND treatment induces an anabolic effect, cardiac hypertrophy and an elevation of the MAP in DECA rats. The treatment 15 reduces the sensitivity of the BJR control of bradicardia, what could be explained by the presence of a cardiac hypertrophy and/or an elevated MAP in DECA animals.
Atividade funcional da Na+K+-ATPase sensível à ouabaína em aorta de ratas com e sem sinais de insuficiência cardíaca após infarto do miorcárdio
(Universidade Federal do Espírito Santo, 2007-06-22) Dias, Fernanda Moura Vargas; Rossoni, Luciana Venturini; Stefanon, Ivanita; Vassallo, Dalton Valentim
The identification of two distinct experimental groups (Icc – with, and Inf - without signals of heart failure (HF) folowing myocardial infarction in rats, presenting the same infarct area (IA), could explain, at least in part, the contradictory cardiovascular results in experimental models of HF. Recent research demonstrates the function of the Na+K + -ATPase in the vascular homostasis in the control of tonus. The activity of the Na+K + -ATPase is influenced by vasoativos factors endothelium-derivatives, cardiac glycosides, hormones, ionic concentration and shear stress, frequently altered after INF and HF. The objective of this research was to study the ouabain-sensitive Na+K + -ATPase functional activity in aortic rings of INF rats, with same IA, presenting or not signals of ICC. Female Wistar rats (220 ± 8 g), were distributed in: Sham (n= 13), Infarct without signals of ICC (Inf N = 11) and Infarct with signals of HF (Icc n= 7). MI was surgically induced by occluding left coronary artery. After 30 days the rats were anaesthetized, and the aortic rings was superfused with Krebs solution gasified with 95% O2 - 5% CO2 mixture to study rings with intact endothelium (E+), denuded endothelium (E -) and with L-NAME. The ouabain-sensitive Na+K + -ATPase functional activity was analized using the potassium relaxation technique. No differences was observed in IA (Inf: 30,2 ± 1,6; Icc: 35,6 ± 2,8), body weight (Sham: 236 ± 4 g; Inf: 236 ± 5 g; Icc: 235 ± 5 g) and VE/PC (Sham: 2,12 ± 0,05; Inf: 2,24 ± 0,06; Icc: 2,21 ± 0,07). However, the signals of HF appeared only in the Icc groups VD/PC (Sham: 0,6 ± 0,02; Inf: 0,6 ± 0,03; Icc: 1,4 ± 0,1* P<0.05) and PP/PC (Sham: 5,7 ± 0,3; Inf: 6,1 ± 0,3; Icc: 13,6 ± 1,0* P<0.05). The main results of this study are that in the Inf animals the KCl-induced relaxation was diminished and the endotelial modulation of this relaxation, for nitric oxide, was present. However, the capacity of the OUA to inhibit the Na+K + -ATPase was increased in these animals and it did not present endotelial modulation as seen in the groups Sham and Icc. These results demonstrate that OUA-dependent NO release is absent in the Inf group, but preserved in the Icc. Therefore, the results demonstrate for the first time in literature the participation of the Na+K + -ATPase in the changes of vascular reactivity following myocardial infarction in female rats. Moreover there are differences in the mechanisms involved in the aortic reactivity following myocardial infarction in female rats with same IA, presenting or not signals of HF.
Aumento da Expressão do receptor tipo Toll 4 pela angiotensina II contribui para a hipertensão e disfunção vascular através da produção de espécies reativas de oxigênio.
(Universidade Federal do Espírito Santo, 2014-09-22) Batista, Priscila Rossi de; Vassalo, Dalton Valentin; Barauna, Valerio Garrone; dos Santos, Leonardo; Fausto, Edmundo Lima Pereira; Davel, Ana Paula Couto
Hypertension is considered as a chronic inflammatory disease, with adaptive immunity being an important mediator of this process. Toll like receptor 4 (TLR4) - that triggers the innate immunity - may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to the increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated vascular damage. For this, we used the following groups: Wistar and SHR controls; SHR losartan (losartan 15 mg/kg•day); Wistar and SHR IgG (non-specific IgG 2a, 1 μg/day); SHR anti-TLR4 (antibody anti-TLR4, 1 μg/day). We also used aortic segments and vascular smooth muscle cels (VSMCs) from Wistar and SHRs controls. TLR4 mRNA levels were greater in aortic segments and VSMCs from SHRs compared with Wistar rats; losartan treatment reduced those levels in SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1) reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation in aortic rings; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI095, a TLR4 inhibitor, mitigated the increases in NOX-4, NADPH oxidase activity, superoxide anion production, COX-2 gene and protein expression, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension and by inducing oxidative stress contributes to the endothelial dysfunction associated to this pathologic process. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

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