Dexamethasone is the most clinically used glucocorticoid with an established role in the treatment of a wide spectrum of inflammatory-related diseases. While the therapeutic actions are well known, ...dexamethasone treatment causes a number of cardiovascular side effects, which are complex, frequent and, in some cases, clinically unnoticeable. Here, we investigated whether a therapeutic regimen of dexamethasone affects cardiac arrhythmogenesis, focusing on the contribution of Nox-derived reactive oxygen species (ROS). Male Wistar rats were treated with dexamethasone (2 mg/kg, i.p.) for 7 days. Afterward, hemodynamic measurements, autonomic modulation, left ventricular function, cardiac fibrosis, reactive oxygen species (ROS) generation, Nox protein expression, superoxide dismutase (SOD) and catalase activities, and arrhythmias incidence were evaluated. Here, we show that dexamethasone increases blood pressure, associated with enhanced cardiac and vascular sympathetic modulation. Moreover, a marked increase in the cardiac ROS generation was observed, whereas the enhanced SOD activity did not prevent the higher levels of lipid peroxidation in the dexamethasone group. On the other hand, increased cardiac Nox 4 expression and hydrogen peroxide decomposition rate was observed in dexamethasone-treated rats, while Nox 2 remained unchanged. Interestingly, although preserved ventricular contractility and β-adrenergic responsiveness, we found that dexamethasone-treated rats displayed greater interstitial and perivascular fibrosis than control. Surprisingly, despite the absence of arrhythmias at basal condition, we demonstrated, by in vivo and ex vivo approaches, that dexamethasone-treated rats are more susceptible to develop harmful forms of ventricular arrhythmias when challenged with pharmacological drugs or burst pacing-induced arrhythmias. Notably, concomitant treatment with apocynin, an inhibitor of NADPH oxidase, prevented these ectopic ventricular events. Together, our results reveal that hearts become arrhythmogenic during dexamethasone treatment, uncovering the pivotal role of ROS-generating NADPH oxidases for arrhythmias vulnerability.
•Autonomic imbalance underlies hypertension in dexamethasone-treated rats.•Dexamethasone causes cardiac oxidative stress without ventricular dysfunction.•Dexamethasone-treated rats displayed greater cardiac fibrosis.•Dexamethasone-treated rats have higher incidence of arrhythmias.•Inhibition of NADPH oxidase prevents arrhythmias in dexamethasone-treated rats.
Introdução: Os glicocorticoides (GC) são utilizados como antialérgicos e anti-inflamatórios, mas o seu uso prolongado pode causar distúrbios metabólicos, como hiperglicemia, resistência à insulina e ...diminuição da síntese de proteínas. No entanto, o exercício resistido (ER) tem sido uma alternativa importante na prevenção e tratamento desses distúrbios metabólicos. Objetivo: Investigar o efeito de uma única sessão de RE sobre a homeostase da glicose e a proteína mTOR de ratos tratados com glicocorticoide. Materiais e métodos: Ratos Wistar machos foram divididos aleatoriamente nos grupos controle (CO), Dexametasona Sedentário (DEX) e Dexametasona+Exercício resistido (DEX+ER). Os grupos DEX e DEX+RE receberam dexametasona durante 7 dias (2,0mg/kg/dia). O protocolo de ER baseou-se em cinco séries, de 10 repetições, com intensidade de 60% de uma repetição máxima (1RM) realizado no aparelho de agachamento. Foram aferidos o peso corporal, a glicemia, teste de tolerância à insulina (TTI) e expressão proteica da Akt-fosforilada/total, da AMPK-fosforilada/total e da mTOR-fosforilado/total. Resultados: A glicose apresentou-se elevada e o TTI reduzido no grupo DEX, porém uma única sessão de ER reduziu a glicose e melhorou a tolerância à insulina. Já razão da expressão proteica da Akt-fosforilada/total e da AMPK-fosforilada/total não apresentou diferença entre os grupos. No entanto, em relação a razão mTOR-fosforilada/total houve um aumento no DEX+ER comparado apenas ao grupo CO. Conclusão: Uma única sessão de RE, mesmo na presença de altas doses de dexametasona, melhorou a homeostase da glicose e aumentou a razão mTOR-fosforilada/total que está envolvida na síntese de proteínas no músculo esquelético. Palavras-chave: Resistência à Insulina. Glicocorticoide. Exercício resistido. Effects of resistance exercise on glucose homeostasis and mTOR activation in rats treated with dexametasone Introduction: Glucocorticoids (GC) are used as antiallergic and anti-inflammatory drugs, but their prolonged use can cause metabolic disorders, such as hyperglycemia, insulin resistance and decreased protein synthesis. However, resistance exercise (RE) has been an important alternative in the prevention and treatment of these metabolic disorders. Objective: To investigate the effect of a single session of RE on glucose homeostasis and mTOR protein in rats treated with glucocorticoids. Materials and methods: Male Wistar rats were randomly divided into the control (CO), Sedentary Dexamethasone (DEX) and Dexamethasone + Resistance Exercise (DEX + RE) groups. The DEX and DEX+RE groups received dexamethasone for 7 days (2.0mg / kg / day). The RE protocol was based on five sets of 10 repetitions, with an intensity of 60% of a maximum repetition (1RM) performed on the squat machine. Body weight, blood glucose, insulin tolerance test (TTI) and protein expression of Akt-phosphorylated/total, AMPK-phosphorylated/total and mTOR-phosphorylated/total were measured. Results: Glucose was high and TTI reduced in the DEX group, but a single session of RE reduced glucose and improved insulin tolerance. As for the protein expression of Akt-phosphorylated/total and AMPK-phosphorylated/total, there was no difference between groups. However, in relation to the mTOR-phosphorylated/total ratio, there was an increase in DEX+ER compared only to the CO group. Conclusion: A single session of RE, even in the presence of high doses of dexamethasone, improved glucose homeostasis and increased the mTOR-phosphorylated / total ratio that is involved in protein synthesis in skeletal muscle. Key words: Insulin resistance. Glucocorticoid. Resistance exercise.
O exercício físico intenso e prolongado pode ocasionar estresse oxidativo e danos musculares, gerando prejuízo no desempenho do atleta. O estudo tem como objetivo investigar o efeito agudo do teste ...de 1600m sobre o estresse oxidativo e danos musculares em corredores juvenis. Participaram desse estudo nove adolescentes entre 15 e 18 anos de idade. Foi realizado o teste de 1600m para avaliar a capacidade aeróbia, onde os voluntários realizaram quatro voltas em pista de 400m, perfazendo um total de 1600m. Não houve aumento no marcador de estresse oxidativo tecidual avaliado pelo TBARS no pós-teste. Em relação à enzima antioxidante, o protocolo não promoveu um aumento da atividade da glutationa. Nas concentrações plasmáticas de lactato desidrogenase e da creatina quinase tiveram um aumento significativo depois do teste de 1600m comparado ao pré-teste. Conclui-se que o teste de 1600m promove danos musculares, no entanto não foi gerado estresse oxidativo. ABSTRACT Evaluation of the 1600m test on markers of oxidative stress and muscle damage in young runners The intense and prolonged physical exercise can cause oxidative stress and muscular damages, generating damage in the performance of the athlete. The aim of this study was to investigate the acute effect of the 1600m test on oxidative stress and muscle damage in young runners. Nine adolescents between 15 and 18 years of age participated in this study. The 1600m test was performed to evaluate the aerobic capacity, where the volunteers performed four laps on the 400m lane, making a total of 1600m. There was no increase in the tissue oxidative stress marker evaluated by the TBARS in the post-test. In relation to the antioxidant enzyme, the protocol did not promote an increase of glutathione activity. Plasma concentrations of lactate dehydrogenase and creatine kinase had a significant increase after the 1600m test compared to the pre-test. It was concluded that the 1600m test promotes muscle damage, however no oxidative stress was generated.
O exercício físico intenso e prolongado pode ocasionar estresse oxidativo e danos musculares, gerando prejuízo no desempenho do atleta. O estudo tem como objetivo investigar o efeito agudo do teste ...de 1600m sobre o estresse oxidativo e danos musculares em corredores juvenis. Participaram desse estudo nove adolescentes entre 15 e 18 anos de idade. Foi realizado o teste de 1600m para avaliar a capacidade aeróbia, onde os voluntários realizaram quatro voltas em pista de 400m, perfazendo um total de 1600m. Não houve aumento no marcador de estresse oxidativo tecidual avaliado pelo TBARS no pós-teste. Em relação à enzima antioxidante, o protocolo não promoveu um aumento da atividade da glutationa. Nas concentrações plasmáticas de lactato desidrogenase e da creatina quinase tiveram um aumento significativo depois do teste de 1600m comparado ao pré-teste. Conclui-se que o teste de 1600m promove danos musculares, no entanto não foi gerado estresse oxidativo. Palavras-chave: Exercício Físico. Estresse Oxidativo. Dano Muscular. Corredores. Evaluation of the 1600m test on markers of oxidative stress and muscle damage in young runners The intense and prolonged physical exercise can cause oxidative stress and muscular damages, generating damage in the performance of the athlete. The aim of this study was to investigate the acute effect of the 1600m test on oxidative stress and muscle damage in young runners. Nine adolescents between 15 and 18 years of age participated in this study. The 1600m test was performed to evaluate the aerobic capacity, where the volunteers performed four laps on the 400m lane, making a total of 1600m. There was no increase in the tissue oxidative stress marker evaluated by the TBARS in the post-test. In relation to the antioxidant enzyme, the protocol did not promote an increase of glutathione activity. Plasma concentrations of lactate dehydrogenase and creatine kinase had a significant increase after the 1600m test compared to the pre-test. It was concluded that the 1600m test promotes muscle damage, however no oxidative stress was generated. Key words: Physical exercise. Oxidative stress. Muscle Damage. Runners.
ABSTRACT The aim of the study was to evaluate the acute resistance exercise on glucose metabolism in animals with insulin resistance. 30 Wistar rats were divided into three groups: control (CON), ...Dexamethasone Sedentary (DS) and dexamethasone + exercise (DE). Resistance exercise was conducted in the squat machine consisting of five sets, 10 repetitions, with intensity of 70% of 1RM. Concurrently, the DS and DE groups received daily intraperitoneal dexamethasone (4.0mg / kg). The body weight, glycemia and insulin sensitivity test were measured in all groups. One single resistance exercise session reduced blood glucose levels and improved insulin sensitivity. The DT group showed a lower area under the curve when compared to the DS group. The high intensity acute resistance exercise promoted a reduction of blood glucose levels and improved insulin sensitivity in rats with insulin resistance dexamethasone- induced.
O objetivo do estudo foi avaliar o efeito o exercício resistido agudo sobre o metabolismo glicêmico em animais com resistência à insulina induzidos com dexametasona. Foram utilizados 30 ratos Wistar ...divididos em três grupos: Controle (CON), Dexametasona Sedentário (DS) e Dexametasona + Exercício (DE). O exercício resistido foi realizado no aparelho de agachamento composto por cinco séries, 10 repetições, com intensidade de 70% de 1RM. Concomitantemente, os grupos DS e DE recebiam diariamente dexametasona intraperitoneal (4,0mg/kg). Foram aferidos o peso corporal, a glicemia e o teste de sensibilidade à insulina de todos os grupos. Única sessão de exercício resistido reduziu a glicemia e melhorou a sensibilidade à insulina, o grupo DT apresentou menor área sob a curva em relação ao grupo DS. O exercício resistido agudo de alta intensidade promoveu redução da glicemia e melhorou a sensibilidade da insulina em ratos com resistência a insulina induzidos com dexametasona.Palavras-chaves: Resistência à Insulina, glicemia, exercício resistido
Hypertension is a public health problem and increases the incidence of cardiovascular diseases.
To evaluate the effects of a resistance exercise session on the contractile and relaxing mechanisms of ...vascular smooth muscle in mesenteric arteries of NG-nitro L-arginine methyl ester (L-NAME)-induced hypertensive rats.
Wistar rats were divided into three groups: control (C), hypertensive (H), and exercised hypertensive (EH). Hypertension was induced by administration of 20 mg/kg of L-NAME for 7 days prior to experimental protocols. The resistance exercise protocol consisted of 10 sets of 10 repetitions and intensity of 40% of one repetition maximum. The reactivity of vascular smooth muscle was evaluated by concentration‑response curves to phenylephrine (PHEN), potassium chloride (KCl) and sodium nitroprusside (SNP).
Rats treated with L-NAME showed an increase (p < 0.001) in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) compared to the initial period of induction. No difference in PHEN sensitivity was observed between groups H and EH. Acute resistance exercise reduced (p < 0.001) the contractile response induced by KCl at concentrations of 40 and 60 mM in group EH. Greater (p < 0.01) smooth muscle sensitivity to NPS was observed in group EH as compared to group H.
One resistance exercise session reduces the contractile response induced by KCl in addition to increasing the sensitivity of smooth muscle to NO in mesenteric arteries of hypertensive rats.
Resistance exercise effects on cardiovascular parameters are not consistent.
The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in ...diabetic rats.
Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings.
A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2%) and an increase in the trained diabetic group (95 ± 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg) as compared to the sedentary diabetic group.
Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats.
Several pathological conditions predict the use of glucocorticoids for the management of the inflammatory response; however, chronic or high dose glucocorticoid treatment is associated with ...hyperglycemia, hyperlipidemia, and insulin resistance and can be considered a risk factor for cardiovascular disease. Therefore, we investigated the mechanisms involved in the vascular responsiveness and inflammatory profile of mesenteric arteries of rats treated with high doses of glucocorticoids. Wistar rats were divided into a control (CO) group and a dexamethasone (DEX) group, that received dexamethasone for 7 days (2mg/kg/day, i.p.). Blood samples were used to assess the lipid profile and insulin tolerance. Vascular reactivity to Phenylephrine (Phe) and insulin, and O2•-production were evaluated. The intracellular insulin signaling pathway PI3K/AKT/eNOS and MAPK/ET-1 were investigated. Regarding the vascular inflammatory profile, TNF-α, IL-6, IL-1β and IL-18 were assessed. Dexamethasone-treated rats had decreased insulin tolerance test and endothelium-dependent vasodilation induced by insulin. eNOS inhibition caused vasoconstriction in the DEX group, which was abolished by the ET-A antagonist. Insulin-mediated relaxation in the DEX group was restored in the presence of the O2.- scavenger TIRON. Nevertheless, in the DEX group there was an increase in Phe-induced vasoconstriction. In addition, the intracellular insulin signaling pathway PI3K/AKT/eNOS was impaired, decreasing NO bioavailability. Regarding superoxide anion generation, there was an increase in the DEX group, and all measured proinflammatory cytokines were also augmented in the DEX group. In addition, the DEX-group presented an increase in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-c) levels. In summary, treatment with high doses of dexamethasone promoted changes in insulin-induced vasodilation, through the reduction of NO bioavailability and an increase in vasoconstriction via ET-1 associated with generation of O2•- and proinflammatory cytokines.
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