Bloqueio de Receptores AT1 Melhora o Desempenho Funcional Miocárdico na Obesidade / AT1Receptor Blockade Improves Myocardial Functional Performance in Obesity

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)

Thyroxine increases Serca2 and Ryr2 gene expression in heart failure rats with euthyroid sick syndrome

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.

Thyroxine increases Serca2 and Ryr2 gene expression in heart failure rats with euthyroid sick syndrome.

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.

Saturated high-fat diet-induced obesity increases adenylate cyclase of myocardial ß-adrenergic system and does not compromise cardiac function.

Obesity is a worldwide pandemic associated with high incidence of cardiovascular disease. The mechanisms by which the obesity leads cardiac dysfunction are not fully elucidated and few studies have evaluated the relationship between obesity and proteins involved in myocardial ß-adrenergic (ßA) system. The purpose of this study was to evaluate the cardiac function and ßA pathway components in myocardium of obese rats. Male Wistar rats were distributed into two groups: control (n = 17; standard diet) and obese (n = 17; saturated high-fat diet) fed for 33 weeks. Nutritional profile and comorbidities were assessed. Cardiac structure and function was evaluated by macroscopic postmortem, echocardiographic and isolated papillary muscle analyzes. Myocardial protein expression of ß1- and ß2-adrenergic receptors, Gαs protein, adenylate cyclase (AC) and protein kinase A (PKA) was performed by Western blot. Cardiac cyclic adenosine monophosphate (cAMP) levels and PKA activity were assessed by ELISA Obese rats showed increased adiposity index (P < 0.001) and several comorbidities as hypertension, glucose intolerance, insulin resistance, and dyslipidemia compared with control rats. Echocardiographic assessment revealed increased left atrium diameter (C: 4.98 ± 0.38 vs. Ob: 5.47 ± 0.53, P = 0.024) and posterior wall shortening velocity (C: 37.1 ± 3.6 vs. Ob: 41.8 ± 3.8, P = 0.007) in obese group. Papillary muscle evaluation indicated that baseline data and myocardial responsiveness to isoproterenol stimulation were similar between the groups. Protein expression of myocardial AC was higher in obese group than in the control (C: 1.00 ± 0.21 vs. Ob: 1.25 ± 0.10, P = 0.025), whereas the other components were unchanged. These results suggest that saturated high-fat diet-induced obesity was not effective in triggering cardiac dysfunction and impair the beta-adrenergic signaling.

Regulation of cardiac microRNAs induced by aerobic exercise training during heart failure.

Exercise training (ET) has beneficial effects on the myocardium in heart failure (HF) patients and in animal models of induced cardiac hypertrophy and failure. We hypothesized that if microRNAs (miRNAs) respond to changes following cardiac stress, then myocardial profiling of these miRNAs may reveal cardio-protective mechanisms of aerobic ET in HF. We used ascending aortic stenosis (AS) inducing HF in Wistar rats. Controls were sham-operated animals. At 18 wk after surgery, rats with cardiac dysfunction were randomized to 10 wk of aerobic ET (HF-ET) or to a heart failure sedentary group (HF-S). ET attenuated cardiac remodeling as well as clinical and pathological signs of HF with maintenance of systolic and diastolic function when compared with that of the HF-S. Global miRNA expression profiling of the cardiac tissue revealed 53 miRNAs exclusively dysregulated in animals in the HF-ET, but only 11 miRNAs were exclusively dysregulated in the HF-S. Out of 23 miRNAs that were differentially regulated in both groups, 17 miRNAs exhibited particularly high increases in expression, including miR-598, miR-429, miR-224, miR-425, and miR-221. From the initial set of deregulated miRNAs, 14 miRNAs with validated targets expressed in cardiac tissue that respond robustly to ET in HF were used to construct miRNA-mRNA regulatory networks that revealed a set of 203 miRNA-target genes involved in programmed cell death, TGF-ß signaling, cellular metabolic processes, cytokine signaling, and cell morphogenesis. Our findings reveal that ET attenuates cardiac abnormalities during HF by regulating cardiac miRNAs with a potential role in cardio-protective mechanisms through multiple effects on gene expression.

Aerobic exercise training prevents heart failure-induced skeletal muscle atrophy by anti-catabolic, but not anabolic actions.

BACKGROUND: Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. METHODS AND RESULTS: We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-α serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-α, NFκB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters were decreased. Interestingly, changes in anabolic factor expression (IGF-I, AKT, and mTOR) were not observed. Nevertheless, in the plantaris muscle, ET maintained high PGC1α levels. CONCLUSIONS: Thus, the ET capability to attenuate cardiac function during the transition from cardiac dysfunction to HF was accompanied by a prevention of skeletal muscle atrophy that did not occur via an increase in anabolic factors, but through anti-catabolic activity, presumably caused by PGC1α action. These findings indicate the therapeutic potential of aerobic ET to block HF-induced muscle atrophy by counteracting the increased catabolic state.

AT1 receptor blockade attenuates insulin resistance and myocardial remodeling in rats with diet-induced obesity.

BACKGROUND: Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. MATERIAL AND METHODS: Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit ß (ßIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot. RESULTS: Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated ßIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-ßRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. CONCLUSION: Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.

Disfunção miocárdica e alterações no trânsito de cálcio intracelular em ratos obesos / Myocardial dysfunction and abnormalities in intracellular calcium handling in obese rats

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.

Diet-induced obesity in rats leads to a decrease in sperm motility.

BACKGROUND: Obesity is rapidly becoming a worldwide epidemic that affects children and adults. Some studies have shown a relationship between obesity and infertility, but until now it remains controversial. Thus, the aim of the present study was to investigate the effect of high-fat diet-induced obesity on male reproductive parameters. METHODS: In a first experiment, male Wistar rats were fed a high-fat diet (HFD) or standard chow (SD) for 15, 30 or 45 weeks, after which they were evaluated by adiposity index, serum leptin levels, reproductive organ weights and sperm counts. In a second experiment, rats received HFD or SD only for 15 weeks, long enough to cause obesity. Sexual hormones and sexual behavior were evaluated in these animals, as well as fertility after natural mating. Another group of rats was submitted to motility analysis and fertility evaluation after in utero insemination. RESULTS: After 15, 30 or 45 weeks, HFD-fed animals presented significant increases in obesity index and serum leptin levels. Reproductive organ weights and sperm counts in the testis and epididymis were similar between the two groups at all timepoints studied. Sexual behavior was not altered by the diet regimen, and HFD fertility after natural mating was also similar to SD-fed animals. Intergroup testosterone levels were also comparable, but estradiol levels were increased in HFD rats. Furthermore, sperm quality was reduced in HFD animals as evidenced by their decreased percentage of sperm with progressive movement. This altered motility parameter was followed by a trend toward reduction in fertility potential after artificial in utero insemination. CONCLUSIONS: The results reported herein showed that obesity can affect sperm quality, by reducing sperm motility, without affecting other sperm parameters. The low sperm quality caused a slight reduction in fertility potential, showing that obesity may lead to impairment in male fertility.

Perfil nutricional e cardiovascular de ratos normotensos e hipertensos sob dieta hiperlipídica / Nutritional and cardiovascular profiles of normotensive and hypertensive rats kept on a high fat diet / Perfil nutricional y cardiovascular de ratas normotensas e hipertensos bajo dieta hiperlipídica

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.

A Hypercaloric pellet-diet cycle induces obesity and co-morbidities in wistar rats / Ciclo de dietas hipercalóricas induz obesidade e comorbidades em ratos wistar

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 percent 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.

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 por cento. 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.

Misclassification probability as obese or lean in hypercaloric and normocaloric diet

The aim of the present study was to determine the classification error probabilities, as lean or obese, inhypercaloric diet-induced obesity, which depends on the variable used to characterize animal obesity. Inaddition, the misclassification probabilities in animals 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 HDanimals 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 index, body mass index 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 index. The total misclassification probabilities ranged from 19.21% to 40.91%. In conclusion, the results of this experiment show that misclassification probabilities occur when dietary manipulation is used to promote obesity in animals. This misjudgement ranges from 19.49% to 40.52% in hypercaloric diet and 18.94% to 41.30% in normocaloric diet.

Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats.

This study examined whether sucrose-rich diet (SRD)-induced hyperglycaemia, dyslipidemia and oxidative stress may be inhibited by N-acetylcysteine (C(5)H(9)-NO(3)S), an organosulfur from Allium plants. Male Wistar 40 rats were divided into four groups (n=10): (C) given standard chow and water; (N) receiving standard chow and 2 mg/l N-acetylcysteine in its drinking water; (SRD) given standard chow and 30% sucrose in its drinking water; and (SRD-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of treatment, SRD rats had obesity with increased abdominal circumference, hyperglycaemia, dyslipidemia and hepatic triacylglycerol accumulation. These adverse effects were associated with oxidative stress and depressed lipid degradation in hepatic tissue. The SRD adverse effects were not observed in SDR-N rats. N-Acetylcysteine reduced the oxidative stress, enhancing glutathione-peroxidase activity, and normalizing lipid hydroperoxyde, reduced glutathione and superoxide dismutase in hepatic tissue of SRD-N rats. The beta-hydroxyacyl coenzyme-A dehydrogenase and citrate-synthase activities were increased in SRD-N rats, indicating enhanced lipid degradation in hepatic tissue as compared to SRD. SRD-N rats had reduced serum oxidative stress and diminished glucose, triacylglycerol, very-low-density lipoprotein (VLDL), oxidized low-density lipoprotein (ox-LDL) and cholesterol/high-density lipoprotein (HDL) ratio in relation to SRD. In conclusion, NAC offers promising therapeutic values in prevention of dyslipidemic profile and alleviation of hyperglycaemia in high-sucrose intake condition by improving antioxidant defences. N-Acetylcysteine had also effects preventing metabolic shifting in hepatic tissue, thus enhancing fat degradation and reducing body weight gain in conditions of excess sucrose intake. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection.

Interaction of hypercaloric diet and physical exercise on lipid profile, oxidative stress and antioxidant defenses.

The present study examined the interaction of hypercaloric diet (HD) and physical exercise on lipid profile and oxidative stress in serum and liver of rats. Male Wistar rats (60-days-old) were fed with a control (C) and hypercaloric diet (H). Each of the two dietary groups (C and H) was divided into three subgroups (n=8), sedentary (CS and HS), exercised 2days a week (CE2 and HE2) and exercised 5days a week (CE5 and HE5). The swimming was selected as a model for exercise performance. After 8-weeks exercised rats showed decreased lactate dehydrogenase serum activities, demonstrating the effectiveness of the swimming as an aerobic-training protocol. Exercise 5-days a week reduced the body weight gain. Triacylglycerol (TG) and very low-density lipoprotein (VLDL-C) were increased in HD-fed rats. HE5 and CE5 rats had decreased TG, VLDL-C and cholesterol. HE2 rats had enhanced high-density lipoprotein (HDL-C) in serum. No alterations were observed in lipid hydroperoxide (LH), while total antioxidant substances (TAS) were increased in serum of exercised rats. HD-fed rats had hepatic TG accumulation. Superoxide dismutase activities were increased and catalase was decreased in liver of exercised rats. The interaction of HD and physical exercise reduced TAS and enhanced LH levels in hepatic tissue. In conclusion, this study confirmed the beneficial effect of physical exercise as a dyslipidemic-lowering component. Interaction of HD and physical exercise had discrepant effects on serum and liver oxidative stress. The interaction of HD and physical exercise reduced the oxidative stress in serum. HD and physical exercise interaction had pro-oxidant effect on hepatic tissue, suggesting that more studies should be done before using physical exercise as an adjunct therapy to reduce the adverse effects of HD.

Beta-carotene supplementation attenuates cardiac remodeling induced by one-month tobacco-smoke exposure in rats.

OBJECTIVE: The objectives were to analyze the cardiac effects of exposure to tobacco smoke (ETS), for a period of 30 days, alone and in combination with beta-carotene supplementation (BC). RESEARCH METHODS AND PROCEDURES: Rats were allocated into: Air (control, n = 13); Air + BC (n = 11); ETS (n = 11); and BC + ETS (n = 9). In Air + BC and BC + ETS, 500 mg of BC were added to the diet. After three months of randomization, cardiac structure and function were assessed by echocardiogram. After that, animals were euthanized and morphological data were analyzed post-mortem. One-way and two-way ANOVA were used to assess the effects of ETS, BC and the interaction between ETS and BC on the variables. RESULTS: ETS presented smaller cardiac output (0.087 +/- 0.001 vs. 0.105 +/- 0.004 l/min; p = 0.007), higher left ventricular diastolic diameter (19.6 +/- 0.5 vs. 18.0 +/- 0.5 mm/kg; p = 0.024), higher left ventricular (2.02 +/- 0.05 vs. 1.70 +/- 0.03 g/kg; p < 0.001) and atrium (0.24 +/- 0.01 vs. 0.19 +/- 0.01 g/kg; p = 0.003) weight, adjusted to body weight of animals, and higher values of hepatic lipid hydroperoxide (5.32 +/- 0.1 vs. 4.84 +/- 0.1 nmol/g tissue; p = 0.031) than Air. However, considering those variables, there were no differences between Air and BC + ETS (0.099 +/- 0.004 l/min; 19.0 +/- 0.5 mm/kg; 1.83 +/- 0.04 g/kg; 0.19 +/- 0.01 g/kg; 4.88 +/- 0.1 nmol/g tissue, respectively; p > 0.05). Ultrastructural alterations were found in ETS: disorganization or loss of myofilaments, plasmatic membrane infolding, sarcoplasm reticulum dilatation, polymorphic mitochondria with swelling and decreased cristae. In BC + ETS, most fibers showed normal morphological aspects. CONCLUSION: One-month tobacco-smoke exposure induces functional and morphological cardiac alterations and BC supplementation attenuates this ventricular remodeling process.

[Blockade of renin-angiotensin system attenuates cardiac remodeling in rats undergoing aortic stenosis]. / O bloqueio do sistema renina-angiotensina atenua a remodelação cardíaca de ratos submetidos a estenose aórtica.

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.

O bloqueio do sistema renina-angiotensina atenua a remodelação cardíaca de ratos submetidos a estenose aórtica / Blockade of renin-angiotensin system attenuates cardiac remodeling in rats undergoing aortic stenosis

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.

A administração precoce de hormônio de crescimento resulta em efeitos deletérios na remodelação ventricular após o infarto agudo do miocárdio / The early administration of growth hormone results in deleterious effects on ventricular remodeling after acute myocardial infarction

OBJETIVO: Verificar a ação do hormônio de crescimento (GH) sobre a remodelação miocárdica em ratos infartados. MÉTODOS: Ratos Wistar foram submetidos ao infarto e tratados com GH (IAM-GH; n=8), ou com o veículo (IAM; n=8). Ratos controles foram submetidos ao infarto simulado (C; n=8). Após 30 dias, os animais foram submetidos ao estudo funcional por meio de ecocardiograma e as alterações da contratilidade miocárdica estudadas no músculo papilar isolado do ventrículo esquerdo (VE). RESULTADOS: O ecocardiograma identificou aumento nos diâmetros (mm) diastólico (C=7,32±0,49; IAM=8,50±0,73; IAM-GH= 9,34± 0,73; P<0,05) e sistólico (C=3,38±0,47, IAM= 5,16±1,24; IAM-GH=5,96±1,54; P<0,05) no VE dos animais com infarto. Os animais do grupo IAM-GH apresentaram menor fração ( por cento) de ejeção (C=0,9±0,03; IAM=0,76±0,12; IAM-GH=0,72±0,14; P<0,05 para C vs IAM-GH) em relação aos controles. O estudo do músculo papilar isolado do ventrículo esquerdo mostrou que o grupo IAM-GH apresentou alterações (C=1,50±0,59; IAM= 1,28±0,38; IAM-GH=1,98±0,41; P<0,05 para C vs IAM-GH) somente na tensão de repouso (TR - g/mm²) e no delta do tempo para a tensão desenvolvida decrescer 50 por cento (TR50, ms) após estimulação com cálcio (C=23,75±9,16; IAM=-16,56±14,82; IAM-GH=-4,69±8,39; P<0,05 para C vs IAM-GH) e no delta da tensão desenvolvida (TD, g/mm²) após estimulação com isoproterenol (C=0,99±0,17; IAM=0,54±0,62; IAM-GH= 0,08±0,75; P<0,05 para C vs IAM-GH), em relação aos animais controle. CONCLUSÃO: A administração precoce do GH no modelo de infarto experimental em ratos pode resultar em efeitos adversos no processo de remodelação ventricular.

Synergistic action of olive oil supplementation and dietary restriction on serum lipids and cardiac antioxidant defences.

Caloric intake is higher than recommended in many populations. Therefore, enhancing olive oil intake alone may not be the most effective way to prevent cardiovascular diseases. The purpose of the present study was to analyse the association of olive oil and dietary restriction on lipid profile and myocardial antioxidant defences. Male Wistar rats (180-200 g, n = 6) were divided into 4 groups: control ad libitum diet (C), 50% restricted diet (DR), fed ad libitum and supplemented with olive oil (3 mL/(kg x day)) (OO), and 50% restricted diet and supplemented with olive oil (DROO). After 30 days of treatments, OO, DR, and DROO groups had increased total cholesterol and high-density lipoprotein cholesterol concentrations. DR and DROO animals showed decreased low-density lipoprotein cholesterol. DROO had the lowest low-density lipoprotein cholesterol concentration. Total lipids and triacylglycerols were raised by dietary restriction and diminished by olive oil. OO rats had higher myocardial superoxide dismutase and lower catalase and glutathione peroxidase activities than C rats. DR and DROO showed enhanced cardiac superoxide dismutase, catalase, and glutathione peroxidase activities from the control. Olive oil supplementation alone improved the lipid profile but was more effective when coupled with dietary restriction. There was a synergistic beneficial action of dietary restriction and olive oil on serum lipids and myocardial antioxidant defences.