Mestrado em Ciências Fisiológicas

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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.
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.
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.
Avaliação cardiovascular e respiratória de ratas ooforectomizadas submetidas a hipertensão arterial pulmonar induzida pela monocrotalina
(Universidade Federal do Espírito Santo, 2010-12-02) Gava, Pablo Lúcio; Mauad, Helder; Moyses, Margareth Ribeiro; Pereira, Fausto Edmundo Lima; Pires, José Guilherme Pinheiro
Pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) constitutes the pathophysiological conditions that involve several cardiovascular, respiratory and autonomic changes. Previous experimental model studies suggest that female sex hormones provide protective effects in the development of PAH. However, effects arising from the deficiency of these hormones on the PAH remain to be elucidated. The aims of the present study were to evaluate the possible hemodynamic, morphological, respiratory and gasometrical changes arising from PAH in female rats submitted to ooforectomy and shamoperated. Wistar female rats were used (200-220 g) and divided into 4 groups: control (CON), MCT, OVX and OVX+MCT. Rats were submitted to OVX or SHAM, and 10 days later, received a single injection of MCT (60 mg/kg, SC), or the same volume of saline (~0.8 mL). After 4 weeks, recordings of cardiovascular, respiratory, gasometric were made and pulmonary histology. The results showed a significant increase of the dry and wet weight of the right ventricle, as well as pulmonary index in MCT groups, compared to respective control groups. We also observed that MCT groups showed values significantly higher of the peak systolic pressure (PSmax) of VD in relation to the respective control group. These findings were also observed in relation to the OVX group and the respective control group. The morphological analysis showed a marked thickening of the media layer of the distal branches of the pulmonary artery in the MTC groups. In relation to autonomic evaluation, we observed a significant increase of a sympathetic component, as well as an attenuation of the parasympathetic component in the MCT, OVX and OVX+MCT groups. For the respiratory parameters, we observed an increase of the alveolar ventilation in the MCT group, while OVX+MCT group showed an attenuation of this parameter. Gasometric evaluation showed that MCT groups present a reduction in the partial pressure of O2 (PaO2) and reduction of the percentage of the hemoglobin saturation (% Sat Hb) when compared to respective control groups, but OVX+MCT group showed an attenuation of the %Sat Hb when compared to MCT. In relation to cardiovascular reflexes, we observed an attenuation of the baroreflex 17 gain in the MCT groups and also a higher reduction in the OVX+MCT group compared to MCT. In the Bezold-Jarisch reflex evaluation, we observed an attenuation of the hypotensive responses in the MCT groups, but only in OVX+MCT group was an attenuation of the bradicardic responses observed. These data suggest that MCT produces important cardiovascular, autonomic, morphological, respiratory and gasometric changes, which are worsened by ooforectomy. Therefore, these results indicate that female sex hormones play an important protective function in this model of PAH.
Avaliação da deposição de placa aterosclerótica e disfunção vascular em aorta de camundongos ApoE-/- após exposição crônica ao cádmio
(Universidade Federal do Espírito Santo, 2018-04-12) Oliveira, Thiago Fernandes de; Batista, Priscila Rossi de; Padilha, Alessandra Simão; Graceli, Jones Bernardes; Pereira, Camila Almenara Cruz; Balarini, Camille de Moura
Introduction: Cadmium exposure is related to cardiovascular diseases, including hypertension and atherosclerosis, which are linked to oxidative stress induced by this metal. Objective: the present study investigated whether the exposure to cadmium promotes the formation of atherosclerotic plaque and promotes endothelial dysfunction in the aorta, in addition to oxidative stress in knockout mice for lipoprotein E (ApoE-/- ). Methods: Experiments were performed on 14 week-old male C57BL / 6 and ApoE-/- mice treated with cadmium chloride (100 mg / L CdCl2 in drinking water for 28 days) or vehicle (distilled water). After exposure to the metal a cholesterol dosage was made and vascular reactivity in response to phenylephrine, acetylcholine or sodium nitroprusside were analysed in the isolated aorta. Bone marrow cells were isolated to evaluate the production of nitric oxide and reactive species of oxygen and nitrogen and the atherosclerotic plaque in the aortic arch was measured. Result: ApoE-/- mice exposed to cadmium showed higher levels of cholesterol than the animals that were not exposed. Cadmium exposure reduced acetylcholine induced relaxation in ApoE-/- , although it did not alter the responses elicited by phenylephrine or sodium nitroprusside. L-NAME incubation reduced the vasodilator response to acetylcholine, but this effect was smaller in cadmium treated ApoE-/- mice, suggesting a reduction in nitric oxide bioavailability. In addition, in cells hematopoietic, cadmium decreased cytoplasmic levels of nitric oxide and increased superoxide anion, hydrogen peroxide and peroxynitrite in ApoE-/- mice exposed to cadmium. Morphological analysis showed that cadmium-treated ApoE-/- mice exhibited increased plaque deposition in the aorta by approximately 3-fold comparing to the non-treated ApoE-/- mice. Conclusion: our results suggest that a cadmium exposure induces endothelial dysfunction in ApoE-/- mice. In addition, cadmium increased cholesterol plasmatic levels, which may promote the development of atherosclerosis in the aorta of ApoE-/- mice. Our findings support a hypothesis that the exposure to cadmium may increase the risk of atherosclerosis development.
Avaliação da função endotelial de camundongos hipercolesterolêmicos fêmeas
(Universidade Federal do Espírito Santo, 2009-09-11) Cola, Maíne Sousa; Meyrelles, Silvana dos Santos; Gava, Ágata Lages; Vasquez, Elisardo Corral; Pereira, Raquel Binda; Moyses, Margareth Ribeiro
The effects of hypercholesterolemia on vasomotricity in apolipoprotein E-deficient (ApoE) mice, a murine model of spontaneous atherosclerosis, are still controversial. The studies were mostly made on conductance vessels and they indicate that females are more susceptible than males to endothelial dysfunction. In the present study we evaluated the endothelium function of resistance vessels from normal C57BL/6 (C57) and hypercholesterolemic (ApoE) female mice in both normal and ovariectomy conditions. Five month-old C57 and ApoE mice underwent ovariectomy (OVX) or sham surgery and were studied 30 days later. The vascular reactivity to norepinephrine (NE, 10-9 to 2x10-3 mol/L), acetylcholine (ACh, 10-10 to 10-3 mol/L) and sodium nitroprusside (SNP, 10-10 to 10-3 mol/L) was evaluated in the isolated mesenteric arteriolar bed through concentrationeffect curves. ACh-induced relaxation was significantly reduced in ApoE compared to C57 animals, as indicated by both the maximal response (37±4% vs. 72±1%) and the LogEC50 (5.67 ± 0.18 vs. 6.23 ± 0.09 mol/L). Ovariectomy caused a significant impairment in the ACh-induced relaxation in the C57 group (maximal response: 61 ± 4%) but did not worse the deficient state of relaxation of ApoE animals (maximal response: 39 ± 5%). SNP-induced vasorelaxation and NE-induced vasoconstriction were similar in ApoE and C57 female mice. This is the first study to show an impairment of endothelial function in resistance vessels of spontaneously atherosclerotic (ApoE-deficient) female mice compared with normal (C57) female mice. The endothelial dysfunction in hypercholesterolemic animals was so marked that ovariectomy, which impaired the endothelial function in C57, did not cause additional damage in ApoE-deficient mice.
Avaliação da toxicidade do tributilestanho sobre a contratilidade miocárdica
(Universidade Federal do Espírito Santo, 2017-08-24) Pereira, Cleydianne Luisa Vieira; Graceli, Jones Bernardes; Stefanon, Ivanita; Fernandes, Aurélia Araújo; Mill, José Geraldo
Tributyltin (TBT) is an organotin environmental contaminant used in farming and antifouling paints. Its release directly into the water, from ships, shipyards and ports, was the cause of environmental impacts on aquatic ecosystems. Numerous studies indicate that organotin compounds produce neuro, cito and genotoxic effects in various systems. However, its toxic effect on the cardiovascular system has not yet been fully elucidated. The aim of this study was to analyze the acute effect of TBT on myocardial contractility Wistar rats weighing 200 - 250 g were anesthetized with intraperitoneal injection of ketamine (40 mg / kg) and Xilazine (8 mg / kg). The heart was isolated and perfused by the Langendorff Technique in Krebs solution, pH 7.4, 37° C. The left ventricular isovolumetric systolic pressure (LVISP) was assessed by insertion of a latex balloon in the LV which was stretched to measure left ventricular diastolic pressure (DP). Experimental animals were randomly grouped into: Control group (N = 7) and group perfused for 5 minutes with TBT solution (50 μM) (TBT group N = 8). To evaluate the participation of reactive oxygen species (ROS) on the effects of TBT, hearts were perfused with anti-oxidants: Tiron (500 μM, N = 5), Tempol (100 μM, N = 5), Apocynin 100 μM, N = 4) and angiotensin receptor blocker, Losartan (10 μM, N = 5). Myocardial contractility was evaluated by homeometric stimulus: calcium and β-adrenergic agonist isoproterenol (injection in bolus, 100 μL, 10-4 M). The heterometric response was assessed using the Frank Starling mechanism by increasing the DP from 0 to 30 mmHg in 5 mmHg intervals. The acute effect of TBT on ROS was evaluated by dihydroethidium technique (Arbitrary Units, AU). In another group of rats, cardiomyocytes were isolated using collagenase in order to measure Ca2+ sparks frequency and amplitude during rest condition and Ca2+ transient in cells stimulated at 0.5 Hz. The Ca2+ content of the sarcoplasmic reticulum (SR) was evaluated using caffeine (10 mM) in intact cardiomyocytes. The results were presented as mean ± SEM. The statistical analysis used was ANOVA 1 or 2 ways with Tukey post hoc, p <0.05. All protocols were approved by CEUA/UFES (27/2016). Perfusion with TBT induced a negative inotropic effect evidenced by the lower contractile response to calcium increase (Control = 115 ± 9 vs TBT = 66 ± 4 mmHg, 1.25 mM CaCl2, p <0.05). Acute exposure to TBT resulted in a reduction in the pressure developed in the Frank Starling curve, in 1.25 mM calcium in all DP (Control= 88 ± 6 vs TBT = 45 ± 2 mmHg, DP = 10 mmHg, p <0.05) and only the antioxidant tiron reversed this reduction in lower DP (TBT = 45 ± 2 vs TBT + tiron = 79 ± 6 mmHg, p <0.05). TBT significantly reduced the response to 19 isoproterenol (Control = 132.78 ± 22 vs TBT = 24,14 ± 13.08 mmHg, p <0.05). Total exposure to TBT increased in situ production of O2• ‾ (Control group = 0.065 ± 0.002 vs TBT group 0.094 ± 0.004 AU p <0.05) and only Tempol and Losartan were able to reverse (TBT + Tempol 0.074 ± 0.003 and TBT+Losartan 0.071 ± 0.004 AU, p <0.05). TBT increased the sparks frequency (Control= 9 ± 1 vs TBT 10 -7 M = 16 ± 1.1 µm/s), decreased its amplitude (Control = 0.582 ± 0.08 vs TBT 10-7 M = 0.342 ± 0.05, p <0, 05), decreased the Ca2+ transient and the SR Ca2+ content. The results demonstrate that TBT induced an important negative inotropic effect that may depend on the Ca2+ regulatory proteins destabilizing the RyR2 receptor and reducing the activity of the SR Ca2+ pump, SERCA2a, which appear to be modulated, at least in part, by ROS.
Avaliação de biomarcadores inflamatórios, dor e qualidade de vida em pacientes com câncer de cabeça e pescoço antes da terapia antineoplásica
(Universidade Federal do Espírito Santo, 2013-04-17) Oliveira, Karine Gadioli de; Gouvea, Sônia Alves; Bissoli, Nazare Souza; Endringer, Denise Coutinho; Von Zeidler, Sandra Lúcia Ventorin
The pain is a common symptom in patients with cancer, including those with head and neck cancer (HNC). This pain can affect physical functions, emotional states, and patients‟ quality of life (QoL). The HNC is the 6th most common cancer worldwide, accounting for approximately 6% of cancer cases. Therefore, the purpose of this study was to assess the pain and its impact on the QoL of HNC patients and the relationship among pain, proinflammatory cytokine tumor necrosis factor alpha (TNFα) and C - reactive protein (CRP). We interviewed 127 untreated patients with primary head and neck squamous cell carcinoma, and clinical data such as gender, age, tobacco and alcohol consumption, tumor location and tumor stage were obtained from medical records. The pain was measured using the item of “average pain” during the last 24 hours in the Brief Pain Inventory (BPI) questionnaire, and the QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and the head and neck module (QLQ-H&N35). The EORTC QLQ-C30 scales revealed that the patients with a tumor in the early stages scored significantly higher in functioning scales. Conversely, the patients with advanced stage cancer scored significantly higher on the symptom scales. On the QLQ-H&N35 scales, the patients with advanced stage tumors had significantly higher scores on the symptom scales. The group of patients with moderate-severe pain indicated a greater impairment on the symptom scales. The TNFα serum (pg/mL) in patients with pain (12,85 ± 1,7) was higher when compared to the no pain group (11,53 ± 2,3) (p < 0,05) and the controls (11,1 ± 1,4) (p < 0,05). The RCP serum (mg/L) in patients with pain (11,25 ± 8,3) was also higher when compared to the no pain group (6,93 ± 3,6) (p < 0,01) and the controls (4,77 ± 2,2) (p < 0,05). These biomarkers may be of great importance in HNC pain and may be future targets for new drugs and result in a better pain management and QoL of these patients.
Avaliação do desempenho cardíaco de ratos infartados e tratados com óleo de soja por via intramuscular
(Universidade Federal do Espírito Santo, 2012-11-28) Lisbôa Júnior, Sérgio; Ribeiro Junior, Rogerio Faustino; Stefanon, Ivanita; Pereira, Fausto Edmundo Lima
After myocardial infarction, compensatory remodeling of cardiac chambers occurs secondary to left ventricular overload with reduction of myocardial contractility (Stefanon et al. 1994; Mill et al 2011). In a previous study we demonstrated that the treatment with soybean oil, 100 µl intramuscular for 15 days, increased cardiac performance without change blood pressure and it was associated with increased Na+ /K+ ATPase activity and SERCA2a protein expression (Ribeiro Junior et a., 2010). Since the decrease in myocardial contractility after myocardial infarction is associated with changes in expression of these enzymes, the purpose of this study was to evaluate whether treatment with soybean oil, intramuscularly for 15 days, can improve cardiac performance in rats subjected to acute myocardial infarction. Methods: Male Wistar rats (230–250 g) were used for this study. All rats had free access to water and were fed with rat chow ad libitum. The animals were divided into four groups: Sham Soybean group: animals underwent sham operation and were treated with soybean oil 0.1 mL for fifteen days. Sham group: animals underwent sham operation and were treated with 0.1 mL of 0.9% NaCl solution for fifteen days. Myocardial Infarction (MI) Soybean group: the left coronary artery was permanently occluded and the animals were treated with 0.1 mL intramuscular soybean oil for fifteen days; Myocardial Infarction group (MI): the left coronary artery was permanently occluded and the animals were treated with 0.1 mL of 0.9% NaCl solution for fifteen days. After 15 days of treatment animals were anesthetized and sacrificed to evaluate the ventricular pressure and myocardial mechanics. Values were analyzed using the t-test or ANOVA (one- or two-way). When ANOVA revealed a significant difference (p < 0.05), the Tukey or Bonferroni test was applied. Results: The myocardial infarction scar was not different between groups (MI Soybean: 34.13 9 ± 5 % N = 8; MI: 34.75 ± 6 % N = 8). The treatment with soybean oil did not change the left ventricular weigh. However, the infarcted group treated with soybean oil showed better cardiac performance compared to infarcted group treated with placebo, and this increase was accompanied by an increase in SBP (MI: 89.11 + 6.4 mmHg x MI Soybean: 108.6 + 9,5 mm Hg) and decreased LVEDP (MI: 6.37 ± 0.9 mmHgx MI Soybean: 4.72 ± 0.4 mm Hg). In addition, the inotropic response to extracellular Ca+ 2 was also significantly increased in the treated groups compared to non-treated. Conclusion: This study demonstrated that treatment with soybean oil intramuscular for 15 days prevented the decrease in cardiac performance in rats that suffered myocardial infarction without modifying the area of the scar.
Avaliação do efeito do agonista do receptor de estrogênio acoplado a proteína g (g1) sobre o tônus e reatividade vascular coronariana em ratos normotensos de ambos os sexos
(Universidade Federal do Espírito Santo, 2015-07-24) Debortoli, Angelina Rafaela; Moyses, Margareth Ribeiro; Santos, Roger Lyrio dos; Bendhack, Lusiane Maria; Bissoli, Nazaré Souza
Cardiovascular diseases represent the main cause of death in developed countries. Moreover, the incidence of cardiovascular diseases increases significantly in postmenopausal women, possibly because of a reduction of estrogen levels. Estrogens exert their genomic effects by activating their nuclear receptors α e β, besides no genomic effects via activation of a third estrogen receptor, recently released, named estrogen receptor coupled to protein G (GPER), also known as GPR30. The GPER function were described mainly in the cardiovascular system. Some studies in isolated coronary vessels, demonstrate that the GPER activation, promotes dependently or independently, the vasodilatationin the endothelium. However, in the coronary bed, this receptor role was not described. The aim of our work was to analyze the action of G1, the specific agonist of GPER in both sexes of normotensive rats‟ coronary vascular bed. 10-month-old Wistar Rats, were divided into two groups: males and females. The animals were anesthetized, their chests were opened, their hearts were removed, and rapidly perfused with nourishing solution at 37º C with constant flow of 10 mL/min, according to Langendorff‟s technique. After a period of 40 min of stabilization, the pressure of coronary perfusion was determined. Dose response curve G1 (600 a 10.000 nM) was performed before and after the follow protocols: inhibition of the nitric oxide synthase enzyme (NOS) with L NAME, inhibition of cyclooxygenase enzyme (COX), inhibition of cytochrome enzyme P450 (CYP), associated inhibition of NOS and COX, associates inhibition of NOS and CYP, triple inhibition of NOS, COX and CYP, blockade of potassium channels with tetraethylammonium (TEA) and blockade with GPER specific antagonist (G36). Besides these protocols, the animals‟ systolic blood pressure was measured through tail plethysmography. We also dissected their anterior and septal descending coronaries to perform Western Blotting in order to evaluate the GPER expression, antioxidant enzymes (SOD e catalase) and subunit of NADPH oxidase. Oxidative stress in coronary arteries was evaluated through fluorescence to the DHE. Our results show the existence of a difference in PAS and PPC between males and females. PAS was higher in males while PPC was higher in females. G1 promoted vasodilatation in rats‟ coronary bed in both sexes, being this response more pronounced in females. GPER, SOD and catalase expression was similar in both groups. Whereas gp91phox expression and oxidative stress were larger in males. The dilatation to G1 in females was reduced after individual inhibition of NOS, COX and CYP, after combined inhibition of NOS + CYP and after triple inhibition of NOS + COX + CYP. Using G36 in experimental preparation, the vasodilatation in this group was reverted into vasoconstriction. After using TEA, dilatation in males and females was larger. Relaxation was reduced in males after individual inhibition of COX and CYP and after combined inhibition of NOS + COX. The use of G36 abolished relaxation in this group. Based on the results, we concluded that G1 expanded the Wistar rats coronary vascular bed in both sexes and this response is less pronounced in males, probably because in this group the production of reactive species of oxygen is larger. Furthermore, NO does not participate in the response of relaxation induced by G1 in males. The three endothelial autacoids (NO, PGI2 e EDHF) seem to mediate the relaxation induced by GPER agonist in females. These findings can contribute to a better understanding of G1 action on cardiovascular system, in order to make it a potential drug therapy to be used in postmenopausal period, based on the presented effects on coronary bed.
Avaliação do potencial neuroprotetor da N-Acetilcisteína sobre parâmetros comportamentais e de estresse oxidativo no modelo experimental de cocaína subaguda em ratos
(Universidade Federal do Espírito Santo, 2018-12-13) Rebelo, Jamille Caneva Oliveira; Rodrigues, Lívia Carla de Melo; Figueiredo, Suely Gomes de; Simões, Maylla Ronacher; Campos, Fabiana Vasconcelos
The use of drugs of abuse is considered a serious social-economic problem around the world. Among these drugs, cocaine stands out since recent researches has pointed out an increase in consumption, mainly due to the increase of users in South America. Consumption of this kind of drug has been associated with cognitive impairment. Because of this, studies have sought medicaments in order to reduce /prevent damage to memory, presenting N-acetylcysteine (NAC) as one of than. So, the present work had the objective of investigating the possible effects of pre-treatment with NAC followed by cocaine consumption, on memory and oxidative stress brain protein. Therefore, male Wistar rats were submitted to the object recognition test (ORT) protocol for short-term memory evaluation 1h 30 min after the training session and long-term memory 24h after the training session. At the end of the behavioral protocol the animals were euthanized and the cerebral regions of the prefrontal cortex (CPF) and hippocampus (HPC) were collected for biochemical analysis, such as: reduced glutathione (GSH), reduced glutathione ratio and oxidized glutathione / GSSG), advanced protein oxidation products (AOPP) and protein carbonylation index by densitometry (Oxyblot). Results showed that animals receiving cocaine (10mg / kg) presented short term memory impairment when compared to control animals (p = 0.005). On other hand, animals that received cocaine but were previously treated with NAC showed improvement in long-term memory when compared to animals that were not previously treated with NAC (p = 0.001). The group submitted to pre-treatment with NAC followed by cocaine treatment did not present a significant difference in protein oxidative damage in the prefrontal cortex (CPF) and hippocampus (HPC) when compared to the group previously treated with saline.The main conclusions of the present work point out NAC was able to protect memory recognition
Avaliação dos efeitos do fator estimulante de colônias de granulócitos (g-csf) sobre os parâmetros estruturais e funcionais do ventrículo esquerdo de ratos submetidos à cardiomiopatia induzida pelo isoproterenol
(Universidade Federal do Espírito Santo, 2011-01-27) Forechi, Ludimila; Mill, Jose Geraldo; Stefanon, Ivanita; Macambira, Simone Garcia
Background: The massive sympathetic discharge occurring in situations of severe stress or use of high doses of stimulants of the central adrenergic system has acute and chronic deleterious effects to the heart because multiple points of focal necrosis may occur on the endocardium with the consequent ventricular remodeling. Injections of high isoproterenol (ISO) doses have been used as an experimental model of this cardiomyopathy. Aim: To evaluate the effects of the Granulocytecolony stimulating factor (G-CSF) in this experimental model in rats. Methods: Male Wistar rats (N=155; 260-300g) were divided into three groups and used in different protocols: Controls (n=41), without any intervention, ISO (n=65) receiving ISO (150mg/kg/day, sc) for two consecutive days, and ISO+G-CSF (n=49) receiving the same dose of ISO and being treated with G-CSF (50µg/kg/day sc) for 7 days, beginning 24 hours after the last dose of ISO. Blood samples were taken from the saphenous vein to check leukocyte mobilization during the protocol. Echocardiography (7.5 MHz) was performed at the beginning and at the end of the protocol. At the 30th day after ISO, the animals were anesthetized (ketamine - 90mg/kg + xylazine -10mg/kg, ip) for arterial and left ventricle hemodynamic records. The heart was then arrested (KCl 3M) and a double lumen catheter was inserted into the LV cavity to obtain the left ventricular pressure x volume curve in the heart in situ. Fragments of left ventricle were prepared to histological analysis (Syrius red) to determine the fractional volumetric density of collagen. Data were analyzed by one and two-way ANOVA as appropriate, and the results expressed as mean ± standard error of mean. The statistical significance was set at p<0,05. Results: Mortality determined by ISO treatment of was 18.4%. The leukocyte count at the 3th day was higher in the ISO (20,393±1,534 céls./mm3 ) and in the ISO+G-CSF (18,987±1,541) groups than in the Control group (14,572±0,888). This difference was undetected at the 30th day of the protocol. There was no significant difference in the functional analysis of the heart in hemodynamic and echocardiograph measurements, as well as in relation to the body weight and viscera weights (heart, lungs and liver). ISO shifted to the right the pressure-volume curve (CT K1=2,70±0,32; ISO K1=2,37±0,24; ISO+G-CSF K1=2,69±0,36) and increased the diameter of the left ventricle at the end-diastole in the echocardiogram (CT 7,7±0,14; ISO 8,7±0,16; ISO+G-CSF 7,8±0,09 mm) characterizing the ventricular dilation in the ISO group, which was 7 prevented by G-CSF treatment. The left ventricular endocardial fractional collagen volume increased markedly in the ISO groups and it was partially reduced (p<0.05) by G-CSF (CT 2,0±0,18; ISO 9,1±0,81; ISO+G-CSF 5,9±0,58%). Conclusion: Treatment with G-CSF for 7 days was effective to prevent the onset of dilated cardiomyopathy produced by ISO in rats, with decreased collagen deposition in the extracellular matrix. This finding may be due to attenuation of lesions or to the reduction of the local inflammatory reaction produced by ISO treatment

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