Benefits of combined exercise training on arterial stiffness and blood pressure in spontaneously hypertensive rats treated or not with dexamethasone.

Dexamethasone (DEX)-induced arterial stiffness is an important side-effect, associated with hypertension and future cardiovascular events, which can be counteracted by exercise training. The aim of this study was to evaluate the mechanisms induced by combined training to attenuate arterial stiffness and hypertension in spontaneously hypertensive rats treated or not with dexamethasone. Spontaneously hypertensive rats (SHR) underwent combined training for 74 days and were treated with dexamethasone (50 µg/kg s. c.) or saline solution during the last 14 days. Wistar rats were used as controls. Echocardiographic parameters, blood pressure (BP) and pulse wave velocity (PWV), as well as histological analyses of the heart and aorta, carotid and femoral arteries were performed. At the beginning, SHR had higher BP and PWV compared with Wistar rats. After 60 days, while BP increased in sedentary SHR, combined exercise training decreased BP and PWV. After 74d, the higher BP and PWV of sedentary SHR was accompanied by autonomic imbalance to the heart, cardiac remodeling, and higher arterial collagen deposition. DEX treatment did not change these parameters. On the other hand, trained SHR had reduced BP and PWV, which was associated with better autonomic balance to the heart, reduced myocardial collagen deposition, as well as lower arterial collagen deposition. The results of this study suggest that combined training, through the reduction of aortic collagen deposition, is an important strategy to reduce arterial stiffness in spontaneously hypertensive rats, and these lower responses were maintained regardless of dexamethasone treatment.

Differential effects of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.

Dexamethasone (DEX)-induced hypertension is observed in normotensive rats, but little is known about the effects of DEX on spontaneously hypertensive animals (SHR). This study aimed to evaluate the effects of DEX on hemodynamics, cardiac hypertrophy and arterial stiffness in normotensive and hypertensive rats. Wistar rats and SHR were treated with DEX (50 µg/kg s.c., 14 d) or saline. Pulse wave velocity (PWV), echocardiographic parameters, blood pressure (BP), autonomic modulation and histological analyses of heart and thoracic aorta were performed. SHR had higher BP compared with Wistar, associated with autonomic unbalance to the heart. Echocardiographic changes in SHR (vs. Wistar) were suggestive of cardiac remodeling: higher relative wall thickness (RWT, +28%) and left ventricle mass index (LVMI, +26%) and lower left ventricle systolic diameter (LVSD, -19%) and LV diastolic diameter (LVDD, -10%), with slightly systolic dysfunction and preserved diastolic dysfunction. Also, SHR had lower myocardial capillary density and similar collagen deposition area. PWV was higher in SHR due to higher aortic collagen deposition. DEX-treated Wistar rats presented higher BP (~23%) and autonomic unbalance. DEX did not change cardiac structure in Wistar, but PWV (+21%) and aortic collagen deposition area (+21%) were higher compared with control. On the other side, DEX did not change BP or autonomic balance to the heart in SHR, but reduced RWT and LV collagen deposition area (-12% vs. SHRCT ). In conclusion, the results suggest a differential effect of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.

Dexamethasone and Training-Induced Cardiac Remodeling Improve Cardiac Function and Arterial Pressure in Spontaneously Hypertensive Rats.

INTRODUCTION: Dexamethasone (DEX)-induced hypertension and cardiac remodeling are still unclear, especially in spontaneously hypertensive rats (SHR). On the other side, exercise training is a good strategy to control hypertension. Therefore, this study investigated the effects of DEX treatment and physical training on arterial pressure and cardiac remodeling in SHR. MATERIAL AND METHODS: SHR underwent treadmill training (5 days/week, 1h/session, at 50-60% of maximal capacity, 0% degree, 75 days) and received low-dose of DEX (50µg/kg, s.c.) during the last 15 days. Sedentary Wistar rats (W) were used as control. Echocardiography and artery catheterization were performed for cardiac remodeling and function, arterial pressure and autonomic nervous system analyses. In addition, left ventricle (LV) capillary density, myocyte diameter and collagen deposition area were analyzed using specific histological staining. RESULTS: Low-dose of DEX treatment did not exacerbate arterial pressure of SHR and trained groups had lower values, regardless of DEX. DEX and training decreased relative left ventricle wall thickness (RWT) and determined LV angiogenesis (+19%) and lower collagen deposition area (-22%). In addition, it determined increased left ventricular diastolic diameter. These changes were followed by improvements on systolic and diastolic function, since it was observed increased posterior wall shortening velocity (PWSV) and reduced isovolumetric relaxation time (IVRT). CONCLUSION: In conclusion, this study is unique to indicate that low-dose of DEX treatment does not exacerbate arterial pressure in SHR and, when associated with training, it improves LV systolic and diastolic function, which may be due to LV angiogenesis and reduction of wall collagen deposition area.

Dexamethasone Does Not Inhibit Treadmill Training-Induced Angiogenesis in Myocardium: Role of MicroRNA-126 Pathway.

Dexamethasone (DEX) has important anti-inflammatory activities; however, it induces hypertension and skeletal muscle microcirculation rarefaction. Nevertheless, nothing is known about DEX outcomes on cardiac microcirculation. By contrast, exercise training prevents skeletal and cardiac microvessel loss because of microRNA expression and a better balance between their related angiogenic and apoptotic proteins in spontaneously hypertensive rats. The purpose of this study was to investigate whether DEX and/or exercise training could induce microRNA alterations leading to cardiac angiogenesis or microvascular rarefaction. Animals performed 8 weeks of exercise training and were treated with DEX (50 µg/kg per day, subcutaneously) for 14 days. Cardiovascular parameters were measured, and the left ventricle muscle was collected for analyses. DEX treatment increased arterial pressure and did not cause cardiac microcirculation rarefaction. Treadmill training prevented the DEX-induced increase in arterial pressure. In addition, training, regardless of DEX treatment, increased microRNA-126 expression, phospho-protein kinase B/protein kinase B, and endothelial nitric oxide synthase levels associated with cardiac angiogenesis. In conclusion, this study suggests, for the first time, that treadmill training induces myocardial angiogenesis because of angiogenic pathway improvement associated with an increase in microRNA-126. Furthermore, DEX, per se, did not cause capillary density alterations and did not attenuate cardiac angiogenesis induced by training.

MicroRNA-126 upregulation, induced by training, plays a role in controlling microcirculation in dexamethasone treated rats.

Microcirculation maintenance is associated with microRNAs. Nevertheless, the role of microRNAs induced by training in preventing dexamethasone (DEX)-induced microvascular rarefaction remains unknown. The study aim was to investigate if training-induced microRNAs are able to improve microcirculation proteins and prevent DEX-induced microvascular rarefaction. Rats underwent training for 8 weeks and then were treated with DEX (50 µg/kg per day, s.c.) for 14 days. Arterial pressure was measured and tibialis anterior (TA) muscle was collected for analyses. DEX induced hypertension concomitantly with capillary density loss (CD, -23.9%) and decrease of VEGF (-43.0%), p-AKT/AKT (-39.6%) and Bcl-2 (-23.0%) and an increase in caspase-3-cleaved protein level (+34.0%) in TA muscle. Training upregulated microRNA-126 expression (+13.1%), prevented VEGF (+61.4%), p-AKT/AKT (+37.7%), Bcl-2 (+7.7%) decrease and caspase-3-cleaved (-23.1%) increase associated with CD (+54.7%) reduction and hypertension prevention. MiRNA-126 upregulation, induced by training, plays a role in controlling microcirculation, which may be a potential target against DEX-induced microvascular rarefaction.

Training counteracts DEX-induced microvascular rarefaction by improving the balance between apoptotic and angiogenic proteins.

This work investigated the mechanisms induced by exercise training that may contribute to attenuate dexamethasone (DEX)-induced microvascular rarefaction and hypertension. Wistar rats underwent training protocol or were kept sedentary for 8 weeks. Dexamethasone was administered during the following 14-days and hemodynamic parameters were recorded at the end. Capillary density (CD) and capillary-to-fiber ratio (C:F ratio) were obtained in soleus muscle (SOL). Also, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax), p-BAX and caspase-3 cleaved protein levels were analyzed. DEX treatment significantly increased blood pressure (+14%), which was associated with reduced C:F ratio (-41.0%) and CD (-43.1%). Reduction of vessel density was associated with decreased VEGF (-15.6%), VEGFR-2 (-14.6%), Bcl-2 (-18.4%), Bcl-2/Bax ratio (-29.0%) and p-Bax/Bax (-25.4%), and also with increased caspase-3 cleaved protein level (25%). Training, on the other hand, prevented microvessels loss by mitigating all proteins changes induced by DEX. In addition, angiogenic and apoptotic proteins were significantly correlated with CD, which, in turn, was associated with blood pressure. Therefore, we may point out that exercise training is a good strategy to attenuate DEX-induced microvascular rarefaction in soleus muscle and this response involves a better balance between apoptotic and angiogenic proteins, which may contribute for the attenuation of hypertension.

Short-term exposure to dexamethasone promotes autonomic imbalance to the heart before hypertension.

Hypertension is one of the chronic side effects of dexamethasone (DEX) treatment; however, almost nothing is known about its acute effects. Therefore, the aim of this study was to investigate the possible mechanisms involved in blood pressure control after acute or short-term DEX treatment in adult animals. Eighty Wistar rats were divided into four groups: C1 and C5, for rats treated with saline for 1 or 5 days, respectively; D1 and D5, for rats treated with DEX for 1 or 5 days, respectively (decadron, 1 mg/kg, i.p.). Heart rate was increased in DEX treatment, but arterial pressure and cardiac muscle mass were not altered. Only few and isolated changes on gene expression and protein level of renin-angiotensin system components were observed. Five days of DEX treatment, but not one day, determined an increase in sympathetic component of spectral analysis (+75.93%, P < .05) and a significant reduction of parasympathetic component (-18.02%, P < .05), which contributed to the autonomic imbalance to the heart (LF/HF, +863.69%). The results of this present study demonstrated, for the first time, that short-term exposure to DEX treatment impairs the autonomic balance to the heart before hypertension, which was independent of renin-angiotensin system.

Exercise attenuates dexamethasone-induced hypertension through an improvement of baroreflex activity independently of the renin-angiotensin system.

Dexamethasone-induced hypertension may be caused by baroreflex alterations or renin-angiotensin system (RAS) exacerbation. Aerobic training has been recommended for hypertension treatment, but the mechanisms responsible for reduction of arterial pressure (AP) in dexamethasone (DEX) treated rats are still inconclusive.This study evaluated whether mechanisms responsible for training-induced attenuation of hypertension involve changes in autonomic nervous system and in RAS components. Rats underwent aerobic training protocol on treadmill or were kept sedentary for 8 weeks. Additionally, animals were treated with DEX during the last 10 days of exercise. Body weight (BW), AP and baroreflex activity were analyzed. Tibialis anterior (TA), soleus (SOL) and left ventricle (LV) were collected for evaluation of RAS components gene expression and protein levels. Dexamethasone decreased BW (20%), caused TA atrophy (16%) and increased systolic AP (SAP, 16%) as well as decreased baroreflex activity. Training attenuated SAP increase and improved baroreflex activity, although it did not prevent DEX-induced BW reduction and muscle atrophy. Neither DEX nor training caused expressive changes in RAS components. In conclusion, exercise training was effective in attenuating hypertension induced by DEX and this response may be mediated by a better autonomic balance through an improvement of baroreflex activity rather than changes in RAS components.

Exercise Training Prevents Dexamethasone-induced Rarefaction.

Dexamethasone (DEX) causes rarefaction. In contrast, training (T) prevents rarefaction and stimulates angiogenesis. This study investigated the mechanisms responsible for the preventive role of T in DEX-induced rarefaction. Rats underwent T or were kept sedentary (8 weeks) and were treated with DEX or saline during the following 14 days. Tibialis anterior muscle was used for measurements of capillary density (CD), capillary-to-fiber ratio (C:F ratio), superoxide dismutase CuZn (SOD-1), superoxide dismutase MnSOD (SOD-2), catalase (CAT) mRNA as well as SOD-1, SOD-2, CAT, vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGF-R2), cyclooxygenase-2 (COX-2), B-cell lymphoma 2 (Bcl-2), Bd-2-like protein 4 (Bax), p-Bax, and caspase-3 cleaved protein levels. DEX decreased CD (-38.1%), C:F ratio (-30.0%), VEGF (-19.0%), VEGFR-2 (-20.1%), COX-2 (-22.8%), Bcl-2 (-20.5%), Bcl-2/Bax ratio (-13.7%), p-Bax/Bax (-20.0%) and increased SOD-2 (+41.6%) and caspase-3 cleaved (+24.1%). Conversely, T prevented reductions in CD (+54.2%), C:F ratio (+32.9%), VEGF (+25.3%), VEGFR-2 (+22.2%), COX-2 (+31.5%), Bcl-2 (+35.5%), Bcl-2/Bax ratio (+19.9%), p-Bax/Bax (+32.1%), and caspase-3 cleaved increase (-7.8%). T increased CAT mRNA (+21.5%) in the DEX-treated group. In conclusion, T prevented the DEX-induced rarefaction by increasing antioxidant enzymes resulting in a better balance between apoptotic and anti-apoptotic protein levels.

Exercise training attenuates dexamethasone-induced hypertension by improving autonomic balance to the heart, sympathetic vascular modulation and skeletal muscle microcirculation.

OBJECTIVE: Although aerobic exercise training has been recommended as nonpharmacological treatment of high blood pressure, the mechanisms of training-induced blood pressure lowering effects in dexamethasone (DEX)-induced hypertension remain unclear. Therefore, the aim of this study was to investigate the preventive role of exercise training in counteracting DEX-induced hypertension. METHODS: Rats were submitted to aerobic exercise training for 8 weeks or kept sedentary and then treated with DEX (50 µg/kg/day, s.c.) or saline injections for 14 days. Thereafter, all rats underwent carotid artery catheterization, and cardiovascular autonomic modulation was evaluated by spectral analysis. In addition, soleus muscle was collected for morphometric and protein level analysis. RESULTS: DEX treatment increased arterial pressure concomitantly with an increase in low-frequency spectral power of systolic arterial pressure and low frequency in pulse interval (94.11 and 58.58%, respectively), and a decrease in high-frequency spectral power of pulse interval (-12.05%). Capillary density (-25.87%), capillary-to-fibers ratio (-21.22%), vascular endothelial growth factor level (-15.10%), B-cell lymphoma 2 (Bcl-2) level (-16.40%) and Bcl-2/Bcl-2 associated X protein ratio (-27.14%) were all decreased after DEX treatment. Exercise training attenuated DEX-induced increase in arterial pressure accompanied by an attenuation of low-frequency spectral power of systolic arterial pressure, low frequency in pulse interval increases and high-frequency spectral power of pulse interval decrease. Training also prevented the decrease in capillary density (+44.43%), capillary-to-fibers ratio (+36.97%), vascular endothelial growth factor (+16.46%), Bcl-2 (+15.21%) protein level and Bcl-2/Bcl-2-associated X protein ratio (+30.93%). CONCLUSION: These results demonstrate that exercise training improves cardiovascular autonomic balance to the heart associated with an improvement in sympathetic modulation of vascular tone and microcirculatory function in the skeletal muscle of DEX-induced hypertensive rats.

Low-intensity resistance training attenuates dexamethasone-induced atrophy in the flexor hallucis longus muscle.

This study investigated the potential protective effect of low-intensity resistance training (RT) against dexamethasone (DEX) treatment induced muscle atrophy. Rats underwent either an 8 week period of ladder climbing RT or remained sedentary. During the last 10 days of the exercise protocol, animals were submitted to a DEX treatment or a control saline injection. Muscle weights were assessed and levels of AKT, mTOR, FOXO3a, Atrogin-1 and MuRF-1 proteins were analyzed in flexor hallucis longus (FHL), tibialis anterior (TA), and soleus muscles. DEX induced blood glucose increase (+46%), body weight reduction (-19%) and atrophy in FHL (-28%) and TA (-21%) muscles, which was associated with a decrease in AKT and an increase in MuRF-1 proteins levels. Low-intensity RT prevented the blood glucose increase, attenuated the FHL atrophy effects of DEX, and was associated with increased mTOR and reductions in Atrogin-1 and MuRF-1 in FHL. In contrast, TA muscle atrophy and signaling proteins were not affected by RT. These are the first data to demonstrate that low-intensity ladder-climbing RT specifically mitigates the FHL atrophy, which is the main muscle recruited during the training activity, while not preventing atrophy in other limb muscle not as heavily recruited. The recruitment-dependent prevention of atrophy by low intensity RT likely occurs by a combination of attenuated muscle protein degradation signals and enhanced muscle protein synthesis signals including mTOR, Atrogin-1 and MuRF-1.