Aerobic exercise attenuates dysautonomia, cardiac diastolic dysfunctions, and hemodynamic overload in female mice with atherosclerosis.

Cardiovascular risk increases during the aging process in women with atherosclerosis and exercise training is a strategy for management of cardiac risks in at-risk populations. Therefore, the aims of this study were to evaluate: (1) the influence of the aging process on cardiac function, hemodynamics, cardiovascular autonomic modulation, and baroreflex sensitivity in females with atherosclerosis at the onset of reproductive senescence; and (2) the impact of exercise training on age-related dysfunctions in this model. Eighteen Apolipoprotein-E knockout female mice were divided equally into young (Y), middle-aged (MA), and trained middle-aged (MAT). Echocardiographic exams were performed to verify cardiac morphology and function. Cannulation for direct recording of blood pressure and heart rate, and analysis of cardiovascular autonomic modulation, baroreflex sensitivity were performed. The MA had lower cardiac diastolic function (E'/A' ratio), and higher aortic thickness, heart rate and mean arterial pressure, lower heart rate variability and baroreflex sensitivity compared with Y. There were no differences between Y and MAT in these parameters. Positive correlation coefficients were found between aortic wall thickness with hemodynamics data. The aging process causes a series of deleterious effects such as hemodynamic overload and dysautonomia in female with atherosclerosis. Exercise training was effective in mitigating aged-related dysfunctions.

Concurrent exercise training potentiates the effects of angiotensin-converting enzyme inhibitor on regulatory systems of blood pressure control in ovariectomized hypertensive rats.

OBJECTIVE: Enalapril has shown satisfactory potential in controlling increased and sustained blood pressure (BP). However, multiple dysregulated mechanisms that interact with each other and are involved in the pathophysiology of arterial hypertension may not be affected, contributing to the remaining cardiovascular risk. Using an exercise training protocol, we investigated whether adding both approaches to arterial hypertension management could promote higher modulation of regulatory mechanisms of BP in postmenopausal rats. METHODS: Spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with enalapril maleate (OSE) and trained treated with enalapril maleate (OTE). Both the pharmacological and exercise training protocols lasted for 8 weeks. The BP was directly recorded. Inflammation and oxidative stress were evaluated in the cardiac tissue. RESULTS: Although BP reduction was similar between OSE and OTE, trained group showed lower vasopressor systems outflow after sympathetic ganglion blocking by hexamethonium (mean BP) (OTE: -53.7 ±â€Š9.86 vs. OS: -75.7 ±â€Š19.2 mmHg). Bradycardic and tachycardic response were increased in OTE group (-1.4 ±â€Š0.4 and -2.6 ±â€Š0.4 vs. OS: -0.6 ±â€Š0.3 and -1.3 ±â€Š0.4 bpm/mmHg, respectively), as well as BP variability. In addition, the combination of approaches induced an increase in interleukin 10, antioxidant defense (catalase and glutathione peroxidase) and nitrite levels compared with the OS group. CONCLUSION: Despite similar BP, the inclusion of exercise training in antihypertensive drug treatment exacerbates the positive adaptations induced by enalapril alone on autonomic, inflammatory and oxidative stress profiles, probably affecting end-organ damage and remaining risk.

Altered locomotor muscle metaboreflex control of ventilation in patients with COPD.

We investigated the locomotor muscle metaboreflex control of ventilation, circulation, and dyspnea in patients with chronic obstructive pulmonary disease (COPD). Ten patients [forced expiratory volume in 1 second (FEV1; means ± SD) = 43 ± 17% predicted] and nine age- and sex-matched controls underwent 1) cycling exercise followed by postexercise circulatory occlusion (PECO) to activate the metaboreflex or free circulatory flow to inactivate it, 2) cold pressor test to interpret whether any altered reflex response was specific to the metaboreflex arc, and 3) muscle biopsy to explore the metaboreflex arc afferent side. We measured airflow, dyspnea, heart rate, arterial pressure, muscle blood flow, and vascular conductance during reflexes activation. In addition, we measured fiber types, glutathione redox balance, and metaboreceptor-related mRNAs in the vastus lateralis. Metaboreflex activation increased ventilation versus free flow in patients (∼15%, P < 0.020) but not in controls (P > 0.450). In contrast, metaboreflex activation did not change dyspnea in patients (P = 1.000) but increased it in controls (∼100%, P < 0.001). Other metaboreflex-induced responses were similar between groups. Cold receptor activation increased ventilation similarly in both groups (P = 0.46). Patients had greater type II skeletal myocyte percentage (14%, P = 0.010), lower glutathione ratio (-34%, P = 0.015), and lower nerve growth factor (NGF) mRNA expression (-60%, P = 0.031) than controls. Therefore, COPD altered the locomotor muscle metaboreflex control of ventilation. It increased type II myocyte percentage and elicited redox imbalance, potentially producing more muscle metaboreceptor stimuli. Moreover, it decreased NGF expression, suggesting a downregulation of metabolically sensitive muscle afferents.NEW & NOTEWORTHY This study's integrative physiology approach provides evidence for a specific alteration in locomotor muscle metaboreflex control of ventilation in patients with COPD. Furthermore, molecular analyses of a skeletal muscle biopsy suggest that the amount of muscle metaboreceptor stimuli derived from type II skeletal myocytes and redox imbalance overcame a downregulation of metabolically sensitive muscle afferents.

Impact of exercise training associated with enalapril treatment on blood pressure variability and renal dysfunctions in an experimental model of arterial hypertension and postmenopause.

OBJECTIVE: In this study, we aimed to investigate the effects of the concurrent exercise training (CET) associated with the enalapril maleate on blood pressure variability (BPV) and renal profile in an experimental model of arterial hypertension (AH) and postmenopause. METHODS: Female ovariectomized spontaneously hypertensive rats (SHR) were distributed into 4 groups (n = 8/group): sedentary (SO), sedentary + enalapril (SOE), trained (TO) and trained + enalapril (TOE). Both enalapril (3mg/kg) and CET (3 days/week) were conducted during 8 weeks. Blood pressure (BP) was directly recorded for BPV analyses. Renal function, morphology, inflammation and oxidative stress were assessed. RESULTS: The SOE, TO e TOE groups presented decreased systolic BP compared with SO. Both trained groups (TO and TOE) presented lower BPV and increased baroreflex sensitivity (TO: 0.76 ± 0.20 and TOE: 1.02 ± 0.40 vs. SO: 0.40 ± 0.07 ms/mmHg) compared with SO group, with additional improvements in TOE group. Creatinine and IL-6 levels were reduced in SOE, TO and TOE compared with SO group, while IL-10 was increased only in TOE group (vs. SO). Enalapril combined with CET promote reduction in lipoperoxidation (TOE: 1.37 ± 0.26 vs. SO: 2.08 ± 0.48 and SOE: 1.84 ± 0.35 µmol/mg protein) and hydrogen peroxide (TOE: 1.89 ± 0.40 vs. SO: 3.70 ± 0.19 and SOE: 2.73 ± 0.70 µM), as well as increase in catalase activity (vs. sedentary groups). The tubulointerstitial injury was lower in interventions groups (SOE, TO and TOE vs. SO), with potentialized benefits in the trained groups. CONCLUSIONS: Enalapril combined with CET attenuated BPV and baroreflex dysfunctions, probably impacting on end-organ damage, as demonstrated by attenuation in the AH-induced renal inflammations, oxidative stress and morphofunctional impairments in postmenopausal rats.

Impact of an active lifestyle on cardiovascular autonomic modulation and oxidative stress in males with overweight and parental history of hypertension.

Family history of hypertension is associated with early autonomic dysfunction and increased oxidative stress. These alterations have been found to be reinforced by the overweight factor. Conversely, an active lifestyle is effective in improving the mechanisms regulating blood pressure control. Hence, we ought to investigate the effects of an active lifestyle on the hemodynamic, autonomic and oxidative stress parameters in individuals carrying both family history of hypertension and overweight risk factors. Fifty-six normotensive males were divided into four groups: eutrophic offspring of normotensive parents (EN, n = 12), eutrophic and inactive with hypertensive parents (EH, n = 14), overweight and inactive with hypertensive parents (OH, n = 13), and overweight and physically active with hypertensive parents (OAH, n = 17). Cardiovascular autonomic modulation was assessed by heart rate (HRV) and blood pressure (BPV) variability indexes. Oxidative stress included pro/antioxidant markers and nitrite concentration. Inactive offspring of hypertensive parents (EH and OH) showed higher LFSBP (vs EN), an indicator of sympathetic outflow to the vasculature and reduced anti-oxidant activity (vs EN), while higher pro-oxidant markers were found exclusively in OH (vs EN and EH). Conversely, the OAH group showed bradycardia, higher vagally-mediated HFabs index (vs OH and EN), lower sympathovagal balance (vs OH) and preserved LFSBP. Yet, the OAH showed preserved pro/antioxidant markers and nitrite levels. Our findings indicates that overweight offspring of hypertensive parents with an active lifestyle have improved hemodynamic, cardiac autonomic modulation and oxidative stress parameters compared to their inactive peers.

Parental fructose consumption induces early baroreflex dysfunction in offspring: impact on arterial pressure and on insulin resistance.

Fructose overconsumption is a worldwide trend, and it has been found to cause metabolic disorders in parents and their offspring. Additionally, metabolic syndrome has been closely associated with increased cardiovascular risk. In this study, we hypothesized that the chronic fructose consumption by parents could trigger autonomic dysfunction and cardiometabolic disorders in their offspring. Wistar rats undergo an intake of 10% of fructose in drinking water or regular water for 60 days before mating. Their offspring, control (C) and fructose (F) groups, were evaluated 30 days after weaning. Lower birth weight, increased levels of blood triglycerides and insulin resistance were observed in F compared to C group. The offspring of the fructose parents showed increased mean arterial pressure (C: 104 ± 1 vs. F: 111 ± 2 mmHg) and baroreflex sensitivity impairment, characterized by reduced bradycardic (C: -1.6 ± 0.06 vs. F: -1.3 ± 0.06 bpm/mmHg) and tachycardic responses (C: -4.0 ± 0.1 vs. F: -3.1 ± 0.2 bpm/mmHg). Finally, a higher baroreflex-induced tachycardia was associated with lower insulin tolerance (r = -0.55, P < 0.03) and higher systolic arterial pressure (r = 0.54, P < 0.02). In conclusion, our findings indicate that the excessive consumption of fructose by parents is associated with early autonomic, cardiovascular, and metabolic derangement in the offspring, favoring an increased cardiometabolic risk when they reach adulthood.

Concurrent exercise training induces additional benefits to hydrochlorothiazide: Evidence for an improvement of autonomic control and oxidative stress in a model of hypertension and postmenopause.

OBJECTIVE: This study aimed to evaluate whether exercise training could contribute to a better modulation of the neurohumoral mechanisms linked to the pathophysiology of arterial hypertension (AH) in postmenopausal hypertensive rats treated with hydrochlorothiazide (HCTZ). METHODS: Female spontaneously hypertensive rats (SHR) (150-200g, 90 days old) were distributed into 5 hypertensive groups (n = 7-8 rats/group): control (C), ovariectomized (O), ovariectomized treated with HCTZ (OH), ovariectomized submitted to exercise training (OT) and ovariectomized submitted to exercise training and treated with HCTZ (OTH). Ovarian hormone deprivation was performed through bilateral ovariectomy. HCTZ (30mg/kg/day) and concurrent exercise training (3d/wk) were conducted lasted 8 weeks. Arterial pressure (AP) was directly recorded. Cardiac effort was evaluated using the rate-pressure product (RPP = systolic AP x heart rate). Vasopressin V1 receptor antagonist, losartan and hexamethonium were sequentially injected to evaluate the vasopressor systems. Inflammation and oxidative stress were evaluated in cardiac tissue. RESULTS: In addition to the reduction in AP, trained groups improved RPP, AP variability, bradycardic (OT: -1.3 ± 0.4 and OTH: -1.6 ± 0.3 vs. O: -0.6 ± 0.3 bpm/mmHg) and tachycardic responses of baroreflex sensitivity (OT: -2.4 ± 0.8 and OTH: -2.4 ± 0.8 vs. O: -1.3 ± 0.5 bpm/mmHg), NADPH oxidase and IL-10/TNF-α ratio. Hexamethonium injection revealed reduced sympathetic contribution on basal AP in OTH group (OTH: -49.8 ± 12.4 vs. O: -74.6 ± 18.1 mmHg). Furthermore, cardiac sympathovagal balance (LF/HF ratio), IL-10 and antioxidant enzymes were enhanced in OTH group. AP variability and baroreflex sensitivity were correlated with systolic AP, RPP, LF/HF ratio and inflammatory and oxidative stress parameters. CONCLUSION: The combination of HCTZ plus concurrent exercise training induced additional positive adaptations in cardiovascular autonomic control, inflammation and redox balance in ovariectomized SHR. Therefore, combining exercise and medication may represent a promising strategy for managing classic and remaining cardiovascular risks in AH.

Combined Exercise Training Promotes More Benefits on Cardiovascular Autonomic Modulation in Ovariectomized Rats Than Isolated Aerobic or Resistance Training.

Introduction: Cardiovascular risk increase after ovarian deprivation has been extensively demonstrated by our research group through cardiovascular autonomic analysis. Interventions involving different types of exercises, such as resistance exercises or combined exercises (aerobic and resistance) have been widely recommended to prevent or minimize neuromuscular decline in postmenopausal women, which is aggravated by a sedentary lifestyle. Experimentally, the cardiovascular effects of resistance or combined training, as well as comparison between aerobic, resistance, and combined training, in ovariectomized animals are scarce. Purpose: In this study, we hypothesized that the combination of aerobic and resistance training may be more effective in preventing muscle mass loss, as well as improving cardiovascular autonomic modulation and baroreflex sensitivity, than aerobic or resistance training individually in ovariectomized rats. Animals and Methods: Female rats were divided into 5 groups: sedentary (C); ovariectomized (Ovx); trained ovariectomized submitted to aerobic training (OvxAT); resistance training (OvxRT); combined training (OvxCT). Exercise training lasted 8 weeks, with the combined group alternating between aerobic training and resistance training every other day. At the end of the study, glycemia and insulin tolerance were evaluated. Arterial pressure (AP) was directly recorded. Baroreflex sensitivity was assessed by heart rate response to changes in arterial pressure. Cardiovascular autonomic modulation was evaluated by spectral analysis. Results: Combined training was the only training regime that increased baroreflex sensitivity for tachycardic response and reduced all systolic blood pressure variability parameters. Furthermore, all animals submitted to exercise training on a treadmill (OvxAT and OvxCT) presented lower systolic, diastolic, and mean pressure, as well as improvements in the autonomic modulation for the heart. Conclusion: Combined training showed to be more effective than isolated aerobic and resistance training, mixing the isolated benefits of each modality. It was the only modality able to increase baroreflex sensitivity to tachycardic responses, reduce arterial pressure and all parameters of vascular sympathetic modulation.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Effects of Exercise Intensity on Cardiometabolic Parameters of Ovariectomized Obese Mice.

The aim of this study was to compare the effects of continuous-moderate vs. high-intensity interval aerobic training on cardiovascular and metabolic parameters in ovariectomized high-fat-fed mice. C57BL/6 female ovariectomized were divided into four groups (n=8): low-fat-fed sedentary (SLF); high-fat-fed sedentary (SHF); high-fat-fed moderate-intensity continuous trained (MICT-HF); and high-fat-fed high-intensity interval aerobic trained (HIIT-HF). The high-fat diet lasted 10 weeks. Ovariectomy was performed in the fourth week. The exercise training was carried out in the last four weeks of protocol. Fasting glycemia, oral glucose tolerance, arterial pressure, baroreflex sensitivity, and cardiovascular autonomic modulation were evaluated. Moderate-intensity continuous training prevented the increase in arterial pressure and promoted a reduction in HR at rest, associated with an improvement in the sympathovagal balance in MICT-HF vs. SHF. The high-intensity interval training reduced blood glucose and glucose intolerance in HIIT-HF vs. SHF and MICT-HF. In addition, it improved sympathovagal balance in HIIT-HF vs. SHF. Moderate-intensity continuous training was more effective in promoting cardiovascular benefits, while high-intensity interval training was more effective in promoting metabolic benefits.

Food readjustment plus exercise training improves cardiovascular autonomic control and baroreflex sensitivity in high-fat diet-fed ovariectomized mice.

Despite consensus on the benefits of food readjustment and/or moderate-intensity continuous exercise in the treatment of cardiometabolic risk factors, there is little evidence of the association between these two cardiovascular risk management strategies after menopause. Thus, the objective of this study was to evaluate the effects of food readjustment and/or exercise training on metabolic, hemodynamic, autonomic, and inflammatory parameters in a model of loss of ovarian function with diet-induced obesity. Forty C57BL/6J ovariectomized mice were divided into the following groups: high-fat diet-fed - 60% lipids throughout the protocol (HF), food readjustment - 60% lipids for 5 weeks, readjusted to 10% for the next 5 weeks (FR), high-fat diet-fed undergoing moderate-intensity exercise training (HFT), and food readjustment associated with moderate-intensity exercise training (FRT). Blood glucose evaluations and oral glucose tolerance tests were performed. Blood pressure was assessed by direct intra-arterial measurement. Baroreflex sensitivity was tested using heart rate phenylephrine and sodium nitroprusside induced blood pressure changes. Cardiovascular autonomic modulation was evaluated in time and frequency domains. Inflammatory profile was evaluated by IL-6, IL-10 cytokines, and TNF-alpha measurements. Only the exercise training associated with food readjustment strategy induced improved functional capacity, body composition, metabolic parameters, inflammatory profile, and resting bradycardia, while positively changing cardiovascular autonomic modulation and increasing baroreflex sensitivity. Our findings demonstrate that the association of these strategies seems to be effective in the management of cardiometabolic risk in a model of loss of ovarian function with diet-induced obesity.

Enhanced Respiratory Frequency Response to Lower Limb Mechanoreceptors Activation in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: To investigate the mechanoreflex control of respiration and circulation in patients with chronic obstructive pulmonary disease (COPD). METHODS: Twenty-eight patients with moderate-to-severe COPD (mean ± SD: 67.0 ± 7.9 yr, 10 women) and 14 age- and sex-matched controls (67.9 ± 2.6 yr, 7 women) participated in the study. Their dominant knee was passively moved to stimulate mechanoreceptors, whereas vastus lateralis surface electrical activity checked active contractions. A differential pressure flowmeter, an electrocardiogram, and a servo-controlled finger photoplethysmograph acquired cardiorespiratory data. To gain insight into the mechanoreflex arc, we further analyzed reduced/oxidized glutathione ratio and mechanoreceptor-related gene expression in a vastus lateralis biopsy of additional nine patients (63.9 ± 8.1 yr, 33% women) and eight controls (62.9 ± 9.1 yr, 38% women). RESULTS: Patients with COPD had a greater peak respiratory frequency response (COPD: Δ = 3.2 ± 2.3 vs Controls: 1.8 ± 1.2 cycles per minute, P = 0.036) and a smaller peak tidal volume response to passive knee movement than controls. Ventilation, heart rate, stroke volume, and cardiac output peak responses, and total peripheral resistance nadir response, were unaltered by COPD. In addition, patients had a diminished glutathione ratio (COPD: 13.3 ± 3.8 vs controls: 20.0 ± 5.5 a.u., P = 0.015) and an augmented brain-derived neurotrophic factor expression (COPD: 2.0 ± 0.7 vs controls: 1.1 ± 0.4 a.u., P = 0.002) than controls. Prostaglandin E receptor 4, cyclooxygenase 2, and Piezo1 expression were similar between groups. CONCLUSIONS: Respiratory frequency response to mechanoreceptors activation is increased in patients with COPD. This abnormality is possibly linked to glutathione redox imbalance and augmented brain-derived neurotrophic factor expression within locomotor muscles, which could increase mechanically sensitive afferents' stimulation and sensitivity.

Sympathetic Neural Overdrive, Aortic Stiffening, Endothelial Dysfunction, and Impaired Exercise Capacity in Severe COVID-19 Survivors: A Mid-Term Study of Cardiovascular Sequelae.

BACKGROUND: COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress. METHODS: Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects. RESULTS: Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors. CONCLUSIONS: Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.

Comprehensive Time-Course Effects of Combined Training on Hypertensive Older Adults: A Randomized Control Trial.

The aim was to identify whether 16 weeks of combined training (Training) reduces blood pressure of hypertensive older adults and what the key fitness, hemodynamic, autonomic, inflammatory, oxidative, glucose and/or lipid mediators of this intervention would be. Fifty-two individuals were randomized to either 16 weeks of Training or control group who remained physically inactive (Control). Training included walking/running at 63% of V˙O2max, three times per week, and strength training, consisting of one set of fifteen repetitions (seven exercises) at moderate intensity, twice per week. Both groups underwent a comprehensive health assessment at baseline (W0) and every four weeks, for 16 weeks total. p-value ≤ 0.05 was set as significant. Training did not reduce blood pressure. It increased V˙O2max after eight weeks and again after 16 weeks (~18%), differently from the Control group. At 16 weeks, Training increased strength (~8%), slightly reduced body mass (~1%), and reduced the number of individuals with metabolic syndrome (~7%). No other changes were observed (heart rate, carotid compliance, body composition, glycemic and lipid profile, inflammatory markers and oxidative profile, vasoactive substances, heart rate variability indices). Although Training increased cardiorespiratory fitness and strength, Training was able to reduce neither blood pressure nor a wide range of mediators in hypertensive older adults, suggesting other exercise interventions might be necessary to improve overall health in this population. The novelty of this study was the time-course characterization of Training effects, surprisingly demonstrating stability among a comprehensive number of health outcomes in hypertensive older adults, including blood pressure.

Saccharomyces boulardii exerts renoprotection by modulating oxidative stress, renin angiotensin system and uropathogenic microbiota in a murine model of diabetes.

AIMS: We aimed to investigate whether Saccharomyces boulardii strain might exert renoprotective effects by modulating renal renin angiotensin system, oxidative stress and intestinal microbiota in streptozotocin-diabetic mice. MAIN METHODS: Thirty-six C57BL/6 male mice were divided into four groups: control (C), control + probiotic (CP), diabetes (D), diabetes + probiotic (DP). Diabetes was induced by one intraperitoneal injection of streptozotocin and Saccharomyces boulardii was administered by oral gavage for 8 weeks. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7) and the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined, besides that, renal morphology, serotonin and dopamine levels and also microbiota composition were analyzed. KEY FINDINGS: Probiotics significantly increased C-peptide secretion and reduced blood glucose of diabetic animals. Saccharomyces boulardii also improved renal antioxidant defense, restored serotonin and dopamine concentration, and activated the renin-angiotensin system (RAS) vasodilator and antifibrotic axis. The modulation of these markers was associated with a beneficial impact on glomerular structure and renal function of diabetic treated animals. The phenotypic changes induced by Saccharomyces boulardii were also related to modulation of intestinal microbiota, evidenced by the decreased abundance of Proteus and Escherichia-Shigella, considered diabetic nephropathy biomarkers. SIGNIFICANCE: Therefore, probiotic administration to streptozotocin-induced diabetic mice improves kidney structure and function in a murine model and might represent a reasonable strategy to counteract nephropathy-associated maladaptive responses in diabetes.

Effects of Postprandial Lipemia Combined With Disturbed Blood Flow on the Flow-Mediated Dilation, Oxidative Stress, and Endothelial Microvesicles in Healthy Subjects.

Aims: Both postprandial lipemia (PPL) and disturbed blood flow (DBF) induce endothelial dysfunction. However, the interactive effect of these stimuli on endothelial function is currently unknown. In the present study, we tested whether PPL plus DBF causes a greater reduction in flow-mediated dilation (FMD) than PPL and if this response is associated with elevations in oxidative stress and endothelial microvesicles (EMVs). Methods: Eighteen individuals (aged 28 ± 1yrs, 3 females, and BMI 24.43 ± 0.8kg/m2) randomly underwent two experimental sessions: PPL and PPL plus DBF. FMD and venous blood samples were obtained at baseline and 30, 70, and 110 min after stimulation. PPL was induced by fat overload via mozzarella pizza ingestion and DBF by forearm cuff inflation to 75 mm Hg per 30 min. Lipidic profile, oxidative stress (thiobarbituric acid reactive substances, TBARS; ferric reducing/antioxidant power, FRAP; hydrogen peroxide, H2O2) and EMVs were measured in blood samples. Results: Hypertriglyceridemia was observed in both sessions. Retrograde shear rate and oscillatory index responses were significantly higher in the PPL plus DBF compared with PPL. PPL plus DBF evoked a greater reduction in FMD than did PPL and EMVs, NADPH oxidase, and H2O2 similarly increased in both sessions, but TBARS and FRAP did not change. Conclusion: These data indicate that the association of PPL plus DBF additively impairs endothelium-dependent function in 110 min after stimulus in healthy individuals, despite a similar increase in oxidative stress and EMVs. Further studies are needed to understand the mechanisms associated with the induced-endothelial dysfunction by association of PPL and DBF.

Reduction of oxidative stress and inflammatory signaling in the commissural nucleus of the solitary tract (commNTS) and rostral ventrolateral medulla (RVLM) in treadmill trained rats.

Inflammation has been associated with cardiovascular diseases and the key point is the generation of reactive oxygen species (ROS). Exercise modulates medullary neurons involved in cardiovascular control. We investigated the effect of chronic exercise training (Tr) in treadmill running on gene expression (GE) of ROS and inflammation in commNTS and RVLM neurons. Male Wistar rats (N = 7/group) were submitted to training in a treadmill running (1 h/day, 5 days/wk/10 wks) or maintained sedentary (Sed). Superoxide dismutase (SOD), catalase (CAT), neuroglobin (Ngb), Cytoglobin (Ctb), NADPH oxidase (Nox), cicloxigenase-2 (Cox-2), and neuronal nitric oxide synthase (NOS1) gene expression were evaluated in commNTS and RVLM neurons by qPCR. In RVLM, Tr rats increased Ngb (1.285 ± 0.03 vs. 0.995 ± 0.06), Cygb (1.18 ± 0.02 vs.0.99 ± 0.06), SOD (1.426 ± 0.108 vs. 1.00 ± 0.08), CAT (1.34 ± 0.09 vs. 1.00 ± 0.08); and decreased Nox (0.55 ± 0.146 vs. 1.001 ± 0.08), Cox-2 (0.335 ± 0.05 vs. 1.245 ± 0.02), NOS1 (0.51 ± 0.08 vs. 1.08 ± 0.209) GE compared to Sed. In commNTS, Tr rats increased SOD (1.384 ± 0.13 vs. 0.897 ± 0.101), CAT GE (1.312 ± 0.126 vs. 0.891 ± 0.106) and decreased Cox-2 (0.052 ± 0.011 vs. 1.06 ± 0.207) and NOS1 (0.1550 ± 0.03559 vs. 1.122 ± 0.26) GE compared to Sed. Therefore, GE of proteins of the inflammatory process reduced while GE of antioxidant proteins increased in the commNTS and RVLM after training, suggesting a decrease in oxidative stress of downstream pathways mediated by nitric oxide.

Cholinergic stimulation with pyridostigmine modulates a heart-spleen axis after acute myocardial infarction in spontaneous hypertensive rats.

The mechanisms regulating immune cells recruitment into the heart during healing after an acute myocardial infarction (AMI) have major clinical implications. We investigated whether cholinergic stimulation with pyridostigmine, a cholinesterase inhibitor, modulates heart and spleen immune responses and cardiac remodeling after AMI in spontaneous hypertensive rats (SHRs). Male adult SHRs underwent sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated or to pyridostigmine treatment (40 mg/kg once a day by gavage). Blood pressure and heart rate variability were determined, and echocardiography was performed at day six after MI. The heart and spleen were processed for immunohistochemistry cellular analyses (CD3+ and CD4+ lymphocytes, and CD68+ and CD206+ macrophages), and TNF levels were determined at day seven after MI. Pyridostigmine treatment increased the parasympathetic tone and T CD4+ lymphocytes in the myocardium, but lowered M1/M2 macrophage ratio towards an anti-inflammatory profile that was associated with decreased TNF levels in the heart and spleen. Treatment with this cholinergic agent improved heart remodeling manifested by lower ventricular diameters and better functional parameters. In summary, cholinergic stimulation by pyridostigmine enhances the parasympathetic tone and induces anti-inflammatory responses in the heart and spleen fostering cardiac recovery after AMI in SHRs.

The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1ß, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.

Study of ER stress and apoptotic proteins in the heart and tumor exposed to doxorubicin.

Although a high cumulative dose of Doxorubicin (Dox) is known to cause cardiotoxicity, there is still a lack of understanding of the subcellular basis of this drug-induced cardiomyopathy. Differential effects of Dox on mitochondria and endoplasmic reticulum (ER) were examined in cardiomyocytes, tumor cells, implanted tumors and hearts of normal as well as tumor-bearing animals. Dox increased mitochondrial (Mito) Bax activation at 3 h in the cardiomyocyte without change in the DNA damage inducible transcriptor-3 (DDIT3) expression in the ER. Increased DDIT3 in these Dox-treated cardiomyocytes at 24 h suggested that increased MitoBax may have promoted ER stress related changes in DDIT3. Dissociation of immunoglobulin-binding protein (Bip) from activating transcription factor 6 (ATF6)-Bip complex in the ER was observed as an adaptive response to Dox. In contrast, breast cancer MCF7 cells showed an ER stress response to Dox with increased DDIT3 as early as 3 h which may have triggered a positive feedback activation of ATF6 at 12 and 24 h and promoted Calnexin. At these later time points, increased Bax activation in cancer cells suggested that MitoBax may be controlled by DDIT3 or by Calnexin. DDIT3 response in tumors was evoked by Dox, however this response was inversely correlated with increased Bip and Bax expression in hearts from tumor bearing animals. It is suggested that in Dox-induced cardiotoxicity both mitochondrial and ER stresses play an integral role through a mutual interaction where an inhibition of DDIT3 or Calnexin may also be crucial to achieve Dox resistance in cardiomyocytes.