Resumo Fundamento A obesidade tem sido associada com ativação crônica do sistema renina-angiotensina-aldosterona e importantes alterações no desempenho cardíaco. Objetivo Avaliar a influência do bloqueio de receptores de angiotensina-II do tipo 1 (AT1) sobre a morfologia e desempenho cardíaco de ratos obesos por dieta Métodos Ratos Wistar (n=48) foram submetidos a dieta controle (2,9 kcal/g) ou hiperlipídica (3,6 kcal/g) durante 20 semanas. Após a 16ª semana, foram distribuídos em quatro grupos: Controle (CO), Obeso (OB), Controle Losartan (CL) e Obeso Losartan (OL). CL e OL receberam losartan (30 mg/kg/dia) na água durante quatro semanas. Posteriormente, foram analisadas composição corporal, pressão arterial sistólica (PAS) e ecocardiograma. A função de músculos papilares foi avaliada em situação basal com concentração de cálcio ([Ca2+]o) de 2,50 mM e após manobras inotrópicas: potencial pós-pausa (PPP), elevação da [Ca2+]o e durante estimulação beta-adrenérgica com isoproterenol. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de comparações apropriado. O nível de significância considerado foi de 5%. Resultados Embora a alteração da PAS não tenha se mantido ao final do experimento, a obesidade se associou com hipertrofia cardíaca e maior velocidade de encurtamento da parede posterior do ventrículo esquerdo.No estudo de músculos papilares em condição basal, CL mostrou menor velocidade máxima de variação negativa da tensão desenvolvida (-dT/dt) do que CO. O PPP de 60s promoveu menor -dT/dt e pico de tensão desenvolvida (TD) em OB e CL, comparados ao CO, e maior variação relativa de TD e velocidade máxima de variação positiva (+dT/dt) no OL em relação a CL e OB. Sob 1,5, 2,0 e 2,5mM de [Ca2+]o, o grupo OL exibiu maior -dT/dt do que CL. Conclusão Losartan melhora a função miocárdica de ratos com obesidade induzida por dieta. (Arq Bras Cardiol. 2020; 115(1):17-28)

Abstract Background Obesity has been associated with chronic activation of the renin-angiotensin-aldosterone system and with significant changes in cardiac performance. Objective To assess the impact of a blockade of angiotensin-II receptor type 1 (AT1receptor) on morphology and on myocardial functional performance in rats with high-fat diet- induced obesity. Methods Wistar rats (n=48) were submitted to control (2.9 kcal/g) or high-fat (3.6 kcal/g) diet for 20 weeks. After the 16thweek they were divided into four groups: Control (CO), Obese (OB), Control Losartan (CL) and Obese Losartan (OL). CL and OL received losartan (30 mg/kg/day) in drinking water for four weeks. Subsequently, body composition, systolic blood pressure (SBP) and echocardiographic variables were analyzed. Papillary muscle function was assessed at baseline with 2.50 mM calcium concentration ([Ca2+]o) and after inotropic maneuvers: post-pause potentiation (PPP), [Ca2+]oelevation, and during beta-adrenergic stimulation with isoproterenol. Analysis of the results was performed by the Two-Way ANOVA and by the appropriate comparison test. The level of significance was set at 5%. Results Although SBP change had been not maintained at the end of the experiment, obesity was associated with cardiac hypertrophy and with increased left ventricle posterior wall shortening velocity. In the study of papillary muscles in basal condition, CL showed lower developed tension maximum negative variation velocity (-dT/dt) than CO. The 60s PPP promoted lower -dT/dt and maximum developed tension (DT) in OB and CL compared with CO, and higher relative DT variation and maximum positive variation velocity (+dT/dt) in OL compared with CL and OB. Under 1.5, 2.0, and 2.5mM [Ca2+]o, the OL group showed higher -dT/dt than CL. Conclusion Losartan improves myocardial function in high-fat diet-induced obesity. (Arq Bras Cardiol. 2020;115(1):17-28)

ABSTRACT Objective The current study was aimed at analyzing sarcoplasmic reticulum Ca2+ ATPase (Serca2) and ryanodine receptor type 2 (Ryr2) gene expression in rats subjected to surgery that induced HF and were subsequently treated with T4 using physiological doses. Materials and methods HF was induced in 18 male Wistar rats by clipping the ascending thoracic aorta to generate aortic stenosis (HFS group), while the control group (9-sham) underwent thoracotomy. After 21 weeks, the HFS group was subdivided into two subgroups. One group (9 Wistar rats) with HF received 1.0 µg of T4/100 g of body weight for five consecutive days (HFS/T4); the other group (9 Wistar rats) received isotonic saline solution (HFS/S). The animals were sacrificed after this treatment and examined for signs of HF. Samples from the left ventricles of these animals were analyzed by RT-qPCR for the expression of Serca2 and Ryr2 genes. Results Rats with HF developed euthyroid sick syndrome (ESS) and treatment with T4 restored the T3 values to the Sham level and increased Serca2 and Ryr2 gene expression, thereby demonstrating a possible benefit of T4 treatment for heart function in ESS associated with HF. Conclusion The T4 treatment can potentially normalize the levels of T3 as well elevated Serca2 and Ryr2 gene expression in the myocardium in heart failure rats with euthyroid sick syndrome.

FUNDAMENTO: Vários mecanismos têm sido propostos contribuir para a disfunção cardíaca em modelos de obesidade, tais como alterações nas proteínas do trânsito de cálcio (Ca+2) e nos receptores beta-adrenérgicos. Todavia, o papel desses fatores no desenvolvimento da disfunção miocárdica induzida pela obesidade ainda não está claro. OBJETIVO: Este estudo pretende investigar se a obesidade induzida por um ciclo de dieta hipercalóricas resulta em disfunção cardíaca. Além disso, foi avaliado se essa alteração funcional em ratos obesos está relacionada com o prejuízo do trânsito de Ca+2 e do sistema beta-adrenérgico. MÉTODOS: Ratos Wistar machos, 30 dias de idade, foram alimentados com ração padrão (C) e um ciclo de cinco dietas hipercalóricas (Ob) por 15 semanas. A obesidade foi definida pelo aumento da porcentagem de gordura corporal dos ratos. A função cardíaca foi avaliada mediante análise isolada do músculo papilar do ventrículo esquerdo em condições basais e após manobras inotrópicas e lusitrópicas. RESULTADOS: Em comparação com o grupo controle, os ratos obesos apresentaram aumento da gordura corporal e intolerância a glicose. Os músculos dos ratos obesos desenvolveram valores basais semelhantes; entretanto, as respostas miocárdicas ao potencial pós-pausa e aumento de Ca+2 extracelular foram comprometidas. Não houve alterações na função cardíaca entre os grupos após a estimulação beta-adrenérgica. CONCLUSÃO: A obesidade promove disfunção cardíaca relacionada com alterações no trânsito de Ca+2 intracelular. Esse prejuízo funcional é provavelmente ocasionado pela redução da atividade da bomba de Ca+2 do retículo sarcoplasmático (SERCA2a) via Ca+2 calmodulina-quinase.

BACKGROUND: Several mechanisms have been proposed to contribute to cardiac dysfunction in obesity models, such as alterations in calcium (Ca2+) handling proteins and β-adrenergic receptors. Nevertheless, the role of these factors in the development of myocardial dysfunction induced by obesity is still not clear. OBJECTIVE: The purpose of this study was to investigate whether obesity induced by hypercaloric diets results in cardiac dysfunction. Furthermore, it was evaluated whether this functional abnormality in obese rats is related to abnormal Ca2+ handling and the β-adrenoceptor system. METHODS: Male 30-day-old Wistar rats were fed with standard food (C) and a cycle of five hypercaloric diets (Ob) for 15 weeks. Obesity was defined as increases in body fat percentage in rats. Cardiac function was evaluated by isolated analysis of the left ventricle papillary muscle under basal conditions and after inotropic and lusitropic maneuvers. RESULTS: Compared with the control group, the obese rats had increased body fat and glucose intolerance. The muscles of obese rats developed similar baseline data, but the myocardial responsiveness to post-rest contraction stimulus and increased extracellular Ca2+ were compromised. There were no changes in cardiac function between groups after β-adrenergic stimulation. CONCLUSION: Obesity promotes cardiac dysfunction related to changes in intracellular Ca2+ handling. This functional damage is probably caused by reduced cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activation via Ca2+ calmodulin kinase.

FUNDAMENTO: Embora dietas hiperlipídicas (DH) promovam distúrbios nutricionais e cardíacos, poucos estudos avaliaram sua influência em ratos normotensos Wistar-Kyoto (WKY) e espontaneamente hipertensos (SHR). OBJETIVO: Avaliar e comparar o perfil nutricional e cardiovascular de WKY e SHR tratados com DH. MÉTODOS: 20 WKY e 20 SHR foram distribuídos em quatro grupos: WKY-controle (WKY-C), WKY-DH, SHR-controle (SHR- C) e SHR-DH. Os grupos C e DH receberam, respectivamente, dieta normocalórica e DH durante 20 semanas. Foram avaliados: peso corporal (PC), adiposidade, glicemia, lípides séricos, com dosagens de colesterol total e triacilglicerol, insulina e leptina. O estudo cardiovascular contemplou a pressão arterial sistólica (PAS), avaliação cardiopulmonar anatômica, ecocardiograma e histologia cardíaca. RESULTADOS: Os SHRs apresentaram menor PC, adiposidade, glicose, colesterol, triacilglicerol, leptina e insulina, quando comparados aos WKYs. Nos SHR, a ingestão calórica aumentou com a DH. Já nos WKYs, a DH elevou a eficiência energética, a adiposidade e a leptina e reduziu a glicemia. Na avaliação cardiovascular, os SHR apresentaram maior PAS, umidade pulmonar, hipertrofia e fibrose intersticial miocárdica em relação aos WKYs (p<0,01); mas a função cardíaca foi similar entre as cepas. A DH reduziu o diâmetro sistólico ventricular nos WKY e acentuou a relação E/A mitral, as espessuras diastólicas do septo interventricular e da parede posterior bem como a fibrose intersticial do ventrículo esquerdo. CONCLUSÃO: Embora não tenha afetado significativamente o perfil nutricional dos SHRs, o tratamento acentuou a remodelação cardíaca e precipitou o aparecimento de disfunção diastólica ventricular. Nos WKY, a dieta aumentou a adiposidade e a leptinemia, e promoveu modificações cardiovasculares não significantes.

BACKGROUND: Although a high fat diet (HFD) promotes nutritional and heart disorders, few studies have assessed its influence in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). OBJECTIVE: To evaluate and compare the nutritional and cardiovascular profiles of WKY and SHR on a high fat diet. METHODS: 20 WKY and 20 SHR were divided into four groups: Control-WKY (C-WKY), HFD-WKY, Control-SHR (C-SHR) and HFD-SHR. The C and HFD groups received, respectively, a normocaloric diet and a HFD for 20 weeks. The following features were evaluated: body weight (BW), adiposity, blood glucose, serum lipids, with measurements of total cholesterol and triacylglycerol levels, insulin and leptin. The cardiovascular study included the systolic blood pressure (SBP), a cardiopulmonary anatomical evaluation, an echocardiography and heart histology. RESULTS: The SHR had BW, adiposity, glucose, cholesterol, triacylglycerol, leptin and insulin levels lower than the WKY. In SHR, the caloric intake increased with HFD. In WKY, the HFD increased energy efficiency, adiposity and blood leptin, and reduced glucose. In the cardiovascular assessment, the SHR had SBP, pulmonary moisture, myocardial hypertrophy and interstitial fibrosis higher than the WKY (p <0.01); the cardiac function was similar in both strains. The HFD reduced the ventricular systolic diameter in the WKY and increased the mitral E/A ratio, the diastolic thickness of the interventricular septum and the posterior wall, as well as the interstitial fibrosis of the left ventricle. (Arq Bras Cardiol 2009; 93(5) : 487-494) CONCLUSION: Although it had not significantly affected the nutritional profile of the SHR, the treatment increased cardiac remodeling and precipitated the emergence of ventricular diastolic dysfunction. In WKY, the diet increased adiposity and leptinemia, and promoted non-significant cardiovascular changes.

FUNDAMENTO: Embora dietas hiperlipídicas (DH) promovam distúrbios nutricionais e cardíacos, poucos estudos avaliaram sua influência em ratos normotensos Wistar-Kyoto (WKY) e espontaneamente hipertensos (SHR). OBJETIVO: Evaluar y comparar el perfil nutricional y cardiovascular de WKY y SHR tratadas con DH. MÉTODOS: Un total de 20 WKY y 20 SHR se distribuyó en cuatro grupos: WKY-control (WKY-C), WKY-DH, SHR-control (SHR-C) y SHR-DH. Los grupos C y DH recibieron, respectivamente, dieta normocalórica y DH durante 20 semanas. Se evaluaron: peso corporal (PC), adiposidad, glucemia, lípidos séricos, con dosificaciones de colesterol total y triacilglicerol, insulina y leptina. El estudio cardiovascular contempló la presión arterial sistólica (PAS), evaluación cardiopulmonar anatómica, ecocardiograma e histología cardiaca. RESULTADOS: Las SHRs presentaron menor PC, adiposidad, glucosa, colesterol, triacilglicerol, leptina e insulina, cuando comparadas a las WKYs. En las SHR, la ingestión calórica aumentó con la DH. Sin embargo en las WKYs, la DH elevó la eficiencia energética, la adiposidad y la leptina y reduzco la glucemia. En la evaluación cardiovascular, las SHR presentaron mayor PAS, humedad pulmonar, hipertrofia y fibrosis intersticial miocárdica en cuanto a las WKYs (p<0,01); sin embargo la función cardiaca se halló similar entre las cepas. La DH reduzco el diámetro sistólico ventricular en los WKY y acentuó la relación E/A mitral, los espesores diastólicos del septo interventricular y de la pared posterior así como la fibrosis intersticial del ventrículo izquierdo. CONCLUSIÓN: Aunque no afectó significativamente el perfil nutricional de las SHRs, el tratamiento acentuó la remodelación cardiaca y precipitó el aparecimiento de disfunción diastólica ventricular. En los WKY, la dieta aumentó la adiposidad y la leptinemia, y promovió modificaciones cardiovasculares no significantes.

O objetivo do estudo foi desenvolver um ciclo de dietas hipercalóricas para promover obesidade em ratos. Ratos Wistar foram distribuídos em dois grupos: dieta normal (ND = 32; 3,5 kcal/g) e dietas hipercalóricas (HD; n = 32; 4,6 kcal/g). O grupo ND recebeu ração comercial e os animais HD um ciclo de diferentes dietas hipercalóricas, por 14 semanas. As variáveis analisadas foram peso corporal, parâmetros metabólicos e hormonais, pressão arterial sistólica e teste oral de tolerância à glicose. O nível de significância foi de 5%. O ciclo de dietas hipercalóricas promoveu aumento de peso e gordura corporal, pressão arterial sistólica e níveis séricos de glicose, triacilglicerol, insulina e leptina no grupo HD. Além disso, o grupo HD apresentou tolerância à glicose diminuída. Em conclusão, os resultados deste estudo mostram que o ciclo de dietas hipercalóricas promove obesidade e exibe várias características comumente associadas com a obesidade humana, como aumento da pressão arterial, resistência à insulina, hiperglicemia, hiperinsulinemia, hiperleptinemia e dislipidemia.

The present study was carried to develop and analyze the consequences of hypercaloric pellet-diet cycle that promotes obesity in rats. Male Wistar rats were randomly distributed into two groups that received either normal diet (ND; n =32; 3,5 Kcal/g) or a hypercaloric diet (HD; n =32; 4,6 Kcal/g). The ND group received commercial Labina rat feeding while the HD animals received a cycle of five hypercaloric diets over a 14-week period. The effects of the diets were analyzed in terms of body weight, body composition, hormone-metabolite levels, systolic arterial pressure and glucose tolerance at the 5% significance level. The hypercaloric pellet diet cycle promoted an increase in body weight and fat, systolic arterial pressure and a high serum level of glucose, triacylglycerol, insulin and leptin. The HD group also presented an impaired glucose tolerance. In conclusion, the results of this study show that the hypercaloric pellet-diet cycle promoted obesity in Wistar rats and displayed several characteristics that are commonly associated with human obesity, such as high arterial pressure, insulin resistance, hyperglycaemia, hyperinsulinaemia, hyperleptinaemia and dyslipidaemia.

The aim of the present study was to determine the classification error probabilities, as lean or obese, in hypercaloric diet-induced obesity, which depends on the variable used to characterize animal obesity. In addition, the misclassification probabilities in animáis submitted to normocaloric diet were also evaluated. Male Wistar rats were randomly distributed into two groups: normal diet (ND; n=31; 3,5 Kcal/g) and hypercaloric diet (HD; n=31; 4,6 Kcal/g). The ND group received commercial Labina rat feed and HD animáis a cycle of five hypercaloric diets for a 14-week period. The variables analysed were body weight, body composition, body weight to length ratio, Lee Índex, body mass Índex and misclassification probability. A 5% significance level was used. The hypercaloric pellet-diet cycle promoted increase of body weight, carcass fat, body weight to length ratio and Lee Índex. The total misclassification probabilities ranged from 19.21% to 40.91%. In conclusión, the results of this experiment show that misclassification probabilities occur when dietary manipulation is used to promote obesity in animáis. This misjudgement ranges from 19.49% to 40.52% in hypercaloric diet and 18.94% to 41.30% in normocaloric diet.

OBJETIVO: Avaliar o papel do bloqueador dos receptores AT1 e do inibidor da enzima conversora da angiotensina na remodelação cardíaca induzida por estenose aórtica em ratos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos: controle (C, n=13), estenose aórtica (EAo, n=11), EAo com lisinopril, 20 mg/kg/dia (LIS, n=11) e EAo com losartan, 40 mg/kg/dia (LOS, n=9). Os tratamentos foram iniciados 3 dias antes da cirurgia. Após 6 semanas, os animais foram submetidos ao estudo ecocardiográfico, quantificação da concentração de hidroxiprolina e da área seccional (CSA) miocitária do ventrículo esquerdo (VE). RESULTADOS: A EAo induziu aumento da espessura da parede do VE. Os animais LIS e LOS não apresentaram diferença em relação aos animais controles. Os ratos EAo e LIS apresentaram maiores diâmetros do átrio esquerdo que os ratos controles, enquanto nos animais LOS não houve diferença. Os animais com EAo apresentaram maiores valores da porcentagem de encurtamento que os controle. Esse fato não foi modificado com LIS ou LOS. A CSA dos animais do grupo EAo foi maior que a dos controle. Entretanto, o tratamento com LOS e com LIS atenuou o aumento da área induzida pela EAo. A EAo resultou em aumento na concentração de HOP, enquanto o grupo LOS não apresentou diferença em relação ao grupo controle. CONCLUSÃO: O bloqueio do sistema renina-angiotensina, com bloqueador AT1 e com IECA, pode atenuar o desenvolvimento de hipertrofia cardíaca, porém só o bloqueio dos receptores AT1 atenua a fibrose intersticial do VE.

OBJECTIVE: To assess the role of the AT1 receptor blocker and the angiotensin-converting enzyme inhibitor in cardiac remodeling induced by aortic stenosis in rats. METHODS: Wistar rats were divided into the following 4 groups: 1) C - control (n=13); 2) AoS - aortic stenosis (n=11); 3) LIS - AoS treated with lisinopril, 20 mg/kg/day (n=11); and 4) LOS - AoS treated with losartan, 40 mg/kg/day (n=9). The treatments were initiated 3 days before surgery. After 6 weeks, the animals underwent echocardiographic study, and quantification of the hydroxyproline (HOP) concentration and the left ventricular (LV) myocyte cross-sectional area (CSA). RESULTS: Aortic stenosis induced an increase in left ventricular wall thickness. The LIS and LOS groups showed no difference as compared with the control group. The AoS and LIS rats had greater left atrial diameters than the control rats did, while no difference was observed in the LOS animals. The AoS animals had greater values of shortening percentage than control animals did. This fact was modified with neither LIS nor LOS. The cross-sectional area of the animals in the AoS group was greater than that in the control group. However, treatment with LOS and LIS attenuated the AoS-induced increase in area. Aortic stenosis caused an increase in HOP concentration, while the LOS group showed no difference as compared with the control group. CONCLUSION: Blockade of the renin-angiotensin system with AT1 blocker and ACEI may attenuate the development of heart hypertrophy, but only the blockade of AT1 receptors attenuates left ventricular interstitial fibrosis.