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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.
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COVID-19 , Força da Mão , Adulto , Humanos , Pessoa de Meia-Idade , Pressão Sanguínea/fisiologia , Hemodinâmica , Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Sistema Nervoso Simpático , Antebraço/irrigação sanguínea , Músculo Esquelético/inervaçãoRESUMO
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.
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Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13-18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.
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Doenças Renais Policísticas , Fumar , Animais , Progressão da Doença , Camundongos , FenótipoRESUMO
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.
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Encefalite/fisiopatologia , Bulbo/fisiopatologia , Estresse Oxidativo , Condicionamento Físico Animal/fisiologia , Núcleo Solitário/fisiopatologia , Animais , Antioxidantes/metabolismo , Encefalite/genética , Expressão Gênica , Masculino , Bulbo/metabolismo , Estresse Oxidativo/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Comportamento Sedentário , Núcleo Solitário/metabolismoRESUMO
Patients undergoing coronary angiography after myocardial infarction (MI) often develop cardiac and renal dysfunction. We hypothesized that the apolipoprotein A-I mimetic peptide 4F (4F) would prevent those complications. Male Wistar rats were fed a high-cholesterol diet for 8 days. The rats were then anesthetized with isoflurane and randomly divided into five groups: a control group (sham-operated rats), and four groups of rats induced to MI by left coronary artery ligation, the rats in three of those groups being injected 6 h later, with the nonionic contrast agent iopamidol, 4F, and iopamidol plus 4F, respectively. At postprocedure hour 24, we performed the following experiments/tests (n = 8 rats/group): metabolic cage studies; creatinine clearance studies; analysis of creatinine, urea, sodium, potassium, triglycerides, total cholesterol, very low-, low- and high-density lipoproteins (VLDL, LDL, and HDL); immunohistochemistry; histomorphometry; Western blot analysis; and transmission electron microscopy. In another set of experiments (n = 8 rats/group), also performed at postprocedure hour 24, we measured mean arterial pressure, heart rate, heart rate variability, echocardiographic parameters, left ventricular systolic pressure, and left ventricular end-diastolic pressure. 4F protected against MI-induced increases in total cholesterol, triglycerides, and LDL; increased HDL levels; reversed autonomic and cardiac dysfunction; decreased the myocardial ischemic area; minimized renal and cardiac apoptosis; protected mitochondria; and strengthened endothelia possibly by minimizing Toll-like receptor 4 upregulation (thus restoring endothelial nitric oxide synthase protein expression) and by upregulating vascular endothelial growth factor protein expression. 4F-treated animals showed signs of cardiac neovascularization. The nitric oxide-dependent cardioprotection and renoprotection provided by 4F could have implications for post-MI treatment.
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Rim/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Triglicerídeos/metabolismo , Animais , Vasos Coronários/metabolismo , Coração/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI.
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BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. METHODS: In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). RESULTS: Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 µg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. CONCLUSION: Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02283242. FUNDING: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.
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Introduction: Recurrent hypoxia (HPX), a hallmark of the obstructive sleep apnea (OSA), impairs autonomic balance, and increases arterial blood pressure (BP). Oxidative stress is one of the mechanisms involved in these alterations. The cumulative effect of acute intermittent HPX and the chronicity may determine whether the response crosses the threshold from having protective value to pathology. However, the impact of acute intermittent HPX-reoxygenation on markers of oxidative stress in healthy individuals remains to be fully understood. Objective: To analyze the effects of the acute intermittent HPX on the generation of neutrophil-derived superoxide, sympathovagal balance, and vascular function in healthy subjects. Methods: We applied six cycles of intermittent HPX (10% O2 and 90% N2) for 5 min followed by 2 min of room-air in 15 healthy volunteers (34 ± 2 years; 22.3 ± 0.46 kg/m2), without OSA (polysomnography), during wakefulness. During the experimental protocol, we recorded O2 saturation, end-tidal CO2, heart rate (HR), systolic, and diastolic BP, cardiac output (CO) and peripheral resistance (PR). Cardiac sympathovagal balance was determined by HR variability analysis (low frequency and high frequency bands, LF/HF). Superoxide generation in polymorphonuclear neutrophil cells were established using relative luminescence units (PMNs RLU) at baseline (pre-HPX) and immediately after hypoxia induction (post-HPX6). Results: The studied subjects had normal levels of BP, plasma glucose, lipid profile, and inflammatory marker (C-reactive protein). Acute intermittent HPX increased HR, systolic BP, CO, and decreased PR. Additionally, acute intermittent HPX increased PMNs RLU, measured post-HPX6 (470 ± 50 vs. 741 ± 135, P < 0.05). We found a similar increase in LF/HF post-HPX6 (0.91 ± 0.11 vs. 2.85 ± 0.40, P < 0.05). PR was diminished from pre-HPX to post-HPX6 (1.0 ± 0.03 vs. 0.85 ± 0.06, P < 0.05). Further analysis showed significant association between O2 saturation and PMNs RLU (R = -0.62, P = 0.02), and with LF/HF (R = -0.79, P = 0.02) post-HPX6. In addition, an association was found between PMNs RLU and PR post-HPX6 (R = 0.58, P = 0.04). Conclusion: Acute exposure to intermittent HPX not only increased superoxide generation in neutrophils, but also impaired cardiac sympathovagal balance in healthy subjects. These data reinforce the role of intermittent HPX in superoxide generation on neutrophils, which may lead to an impairment in peripheral vascular resistance.
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BACKGROUND: Physical activity has been considered an effective method to treat and prevent cardiovascular and metabolic disease. An important mechanism benefited by exercise training is the cardiovascular autonomic control, often impaired in cardiometabolic disease. Cycling used as a daily means of transport can be considered an interesting alternative to regular physical exercise practice. Therefore, this study intent to compare metabolic, hemodynamic and cardiovascular autonomic profiles of young adult men who were used to cycle for transportation (CT) with those considered insufficiently actives (IA). METHODS: Body composition, blood pressure, glucose, total cholesterol and triglycerides were evaluated at rest. Heart rate variability was analyzed in time and frequency domains. RESULTS: No differences were observed for body composition, blood pressure, glycemia nor lipids between groups. CT group presented resting bradycardia. Heart rate variability was increased in cyclists, as well as the parameters of parasympathetic modulation. Sympathetic modulation was reduced in CT group when compared to IA group. Additionally, positive correlations were observed between resting heart rate and RMSSD and heart rate variability, while heart rate variability was correlated with sympathovagal balance. CONCLUSIONS: Our results demonstrated that bicycling regularly used as a means of transport is able to improve cardiovascular autonomic modulation, thus reducing the risk of cardiovascular disease.
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Ciclismo/fisiologia , Frequência Cardíaca/fisiologia , Aptidão Física/fisiologia , Descanso/fisiologia , Meios de Transporte/métodos , Adulto , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Composição Corporal/fisiologia , Estudos Transversais , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: To investigate the effects of acute and chronic exercise in female patients with remissive Takayasu arteritis (TAK). METHODS: This was a 2-part prospective study. In study 1, cytokines and soluble tumor necrosis factor (TNF) receptors were assessed at rest and every 60 minutes during a 3-hour recovery period following an acute exercise session in TAK (n = 11) and heathy control (n = 10) groups. In study 2, a subsample from the TAK group (n = 6) underwent a 12-week exercise training program. Before and after training, the acute session of aerobic exercise was performed and cytokines and soluble TNF receptors were assessed at the same time points described above. Muscle function, strength, aerobic capacity, endothelial function, quality of life, and walking impairment scores were evaluated. RESULTS: In study 1, the acute session of aerobic exercise led to overall similar responses on cytokine kinetics in the TAK and heathy control groups. In study 2, the exercise training program did not exacerbate inflammatory cytokines in TAK patients, while the proinflammatory cytokine TNF was diminished both at rest and following the acute session of aerobic exercise. In addition, the exercise training program increased the pro-angiogenic factors vascular endothelial growth factor (at rest) and platelet-derived growth factor AA (at rest and in response to the acute session of aerobic exercise). The exercise training program improved muscle strength and function, whereas aerobic capacity, quality of life, and endothelial function parameters remained unchanged. CONCLUSION: Exercise could be a well-tolerated, safe, and effective intervention able to induce immunomodulatory and pro-angiogenic effects and to increase strength and function in patients with TAK.
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Exercício Físico/fisiologia , Mediadores da Inflamação/sangue , Arterite de Takayasu/sangue , Arterite de Takayasu/terapia , Adulto , Teste de Esforço/métodos , Feminino , Humanos , Neovascularização Patológica/sangue , Neovascularização Patológica/fisiopatologia , Neovascularização Patológica/terapia , Estudos Prospectivos , Arterite de Takayasu/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
Alterations in myocardial wall texture stand out among ADPKD cardiovascular manifestations in hypertensive and normotensive patients. To elucidate their pathogenesis, we analyzed the cardiac phenotype in Pkd1(cond/cond)Nestin(cre) (CYG+) cystic mice exposed to increased blood pressure, at 5 to 6 and 20 to 24 weeks of age, and Pkd1(+/-) (HTG+) noncystic mice at 5-6 and 10-13 weeks. Echocardiographic analyses revealed decreased myocardial deformation and systolic function in CYG+ and HTG+ mice, as well as diastolic dysfunction in older CYG+ mice, compared to their Pkd1(cond/cond) and Pkd1(+/+) controls. Hearts from CYG+ and HTG+ mice presented reduced polycystin-1 expression, increased apoptosis, and mild fibrosis. Since galectin-3 has been associated with heart dysfunction, we studied it as a potential modifier of the ADPKD cardiac phenotype. Double-mutant Pkd1(cond/cond):Nestin(cre);Lgals3(-/-) (CYG-) and Pkd1(+/-);Lgals3(-/-) (HTG-) mice displayed improved cardiac deformability and systolic parameters compared to single-mutants, not differing from the controls. CYG- and HTG- showed decreased apoptosis and fibrosis. Analysis of a severe cystic model (Pkd1(V/V); VVG+) showed that Pkd1(V/V);Lgals3(-/-) (VVG-) mice have longer survival, decreased cardiac apoptosis and improved heart function compared to VVG+. CYG- and VVG- animals showed no difference in renal cystic burden compared to CYG+ and VVG+ mice. Thus, myocardial dysfunction occurs in different Pkd1-deficient models and suppression of galectin-3 expression rescues this phenotype.
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Doenças Cardiovasculares/genética , Galectina 3/genética , Miocárdio/patologia , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Animais , Apoptose/genética , Doenças Cardiovasculares/complicações , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Humanos , Hipertensão/etiologia , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Fenótipo , Rim Policístico Autossômico Dominante/complicações , Canais de Cátion TRPP/metabolismoRESUMO
INTRODUCTION: Tonin is an enzyme that is able to generate angiotensin II (Ang II) from angiotensin I (Ang I) or directly from angiotensinogen. Our goal was to characterize the renal renin-angiotensin system in transgenic mice that express rat tonin (TGM`(rTon)). MATERIALS AND METHODS: Mice were euthanized and the kidneys removed for analysis. Tonin activity was evaluated by radioimmunoassay and angiotensin I-converting enzyme (ACE) activity by HPLC. Tonin, ACE and angiotensin II-converting enzyme (ACE2) expression was analyzed by Western blotting. RESULTS: Tonin activity was significantly increased in TGM`(rTon) compared to their respective wild-type (WT) littermates (1.7 ± 0.21 vs 0.11 ± 0.02 nmol of Ang II/min/mg of protein). Tonin activity had a strong positive correlation with tonin expression in both TGM`(rTon) and their respective wild-type littermates. The ACE activity and expression levels of 65-kDa N-domain angiotensin I-converting enzyme isoform were significantly increased in the TGM`(rTon) when compared with WT. ACE2 expression levels were statistically significantly higher in the TGM`(rTon) when compared with WT. Angiotensin 1-7 (Ang(1-7)) and Ang I levels were significantly lower in the TGM`(rTon). CONCLUSIONS: We suggest that the environment of tonin abundance may increase N-domain ACE activity liberated by a secretase able to cleave somatic ACE.
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Sistema Renina-Angiotensina/genética , Calicreínas Teciduais/metabolismo , Angiotensinas/metabolismo , Animais , Western Blotting , Isoenzimas/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peptidil Dipeptidase A/metabolismo , Ratos Sprague-Dawley , Renina/metabolismo , Coloração e RotulagemRESUMO
BACKGROUND: Sympathetic hyperactivity may be related to left ventricular (LV) dysfunction and baro- and chemoreflex impairment in hypertension. However, cardiac function, regarding the association of hypertension and baroreflex dysfunction, has not been previously evaluated by transesophageal echocardiography (TEE) using intracardiac echocardiographic catheter. METHODS AND RESULTS: We evaluated exercise tests, baroreflex sensitivity and cardiovascular autonomic control, cardiac function, and biventricular invasive pressures in rats 10 weeks after sinoaortic denervation (SAD). The rats (n = 32) were divided into 4 groups: 16 Wistar (W) with (n = 8) or without SAD (n = 8) and 16 spontaneously hypertensive rats (SHR) with (n = 8) or without SAD (SHRSAD) (n = 8). Blood pressure (BP) and heart rate (HR) did not change between the groups with or without SAD; however, compared to W, SHR groups had higher BP levels and BP variability was increased. Exercise testing showed that SHR had better functional capacity compared to SAD and SHRSAD. Echocardiography showed left ventricular (LV) concentric hypertrophy; segmental systolic and diastolic biventricular dysfunction; indirect signals of pulmonary arterial hypertension, mostly evident in SHRSAD. The end-diastolic right ventricular (RV) pressure increased in all groups compared to W, and the end-diastolic LV pressure increased in SHR and SHRSAD groups compared to W, and in SHRSAD compared to SAD. CONCLUSIONS: Our results suggest that baroreflex dysfunction impairs cardiac function, and increases pulmonary artery pressure, supporting a role for baroreflex dysfunction in the pathogenesis of hypertensive cardiac disease. Moreover, TEE is a useful and feasible noninvasive technique that allows the assessment of cardiac function, particularly RV indices in this model of cardiac disease.
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Coração/fisiopatologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Artéria Pulmonar/fisiopatologia , Seio Aórtico/fisiopatologia , Disfunção Ventricular/fisiopatologia , Animais , Denervação Autônoma , Barorreflexo , Pressão Sanguínea , Ecocardiografia Transesofagiana , Teste de Esforço , Gânglios Parassimpáticos/fisiopatologia , Gânglios Parassimpáticos/cirurgia , Frequência Cardíaca , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Pressorreceptores/diagnóstico por imagem , Pressorreceptores/fisiopatologia , Artéria Pulmonar/diagnóstico por imagem , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Seio Aórtico/diagnóstico por imagem , Seio Aórtico/inervação , Disfunção Ventricular/diagnóstico por imagemRESUMO
We have bred a Pkd1 floxed allele with a nestin-Cre expressing line to generate cystic mice with preserved glomerular filtration rate to address the pathogenesis of complex autosomal dominant polycystic kidney disease (ADPKD) phenotypes. Hypertension affects about 60% of these patients before loss of renal function, leading to significant morbimortality. Cystic mice were hypertensive at 5 and 13 weeks of age, a phenotype not seen in noncystic controls and Pkd1-haploinsufficient animals that do not develop renal cysts. Fractional sodium excretion was reduced in cystic mice at these ages. Angiotensinogen gene expression was higher in cystic than noncystic kidneys at 18 weeks, while ACE and the AT1 receptor were expressed in renal cyst epithelia. Cystic animals displayed increased renal cAMP, cell proliferation, and apoptosis. At 24 weeks, mean arterial pressure and fractional sodium excretion did not significantly differ between the cystic and noncystic groups, whereas cardiac mass increased in cystic mice. Renal concentrating deficit is also an early finding in ADPKD. Maximum urine osmolality and urine nitrite excretion were reduced in 10-13- and 24-week-old cystic mice, deficits not found in haploinsufficient and noncystic controls. A trend of higher plasma vasopressin was observed in cystic mice. Thus, cyst growth most probably plays a central role in early-stage ADPKD-associated hypertension, with activation of the intrarenal renin-angiotensin system as a key mechanism. Cyst expansion is also likely essential for the development of the concentrating deficit in this disease. Our findings are consistent with areas of reduced perfusion in the kidneys of patients with ADPKD.
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Pressão Arterial , Proliferação de Células , Hipertensão/etiologia , Capacidade de Concentração Renal , Rim/metabolismo , Rim Policístico Autossômico Dominante/complicações , Canais de Cátion TRPP/deficiência , Animais , Apoptose , Pressão Arterial/genética , Biomarcadores/sangue , Biomarcadores/urina , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Genótipo , Taxa de Filtração Glomerular , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/patologia , Rim/fisiopatologia , Capacidade de Concentração Renal/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/fisiopatologia , Sistema Renina-Angiotensina , Canais de Cátion TRPP/genética , Fatores de TempoRESUMO
OBJECTIVES: We explored whether high blood pressure is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome. METHODS: We evaluated 135 consecutive overweight/obese patients. From this group, we selected 75 patients who were not under the regular use of medications for metabolic syndrome as defined by the current Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults criteria. The patients were divided into metabolic syndrome with and without high blood pressure criteria (≥130/≥85 mmHg). RESULTS: Compared to the 45 metabolic syndrome patients without high blood pressure, the 30 patients with metabolic syndrome and high blood pressure had significantly higher glucose, insulin, homeostasis model assessment insulin resistance index, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, uric acid and creatinine values; in contrast, these patients had significantly lower high-density lipoprotein-cholesterol values. Metabolic syndrome patients with high blood pressure also had significantly higher levels of retinol-binding protein 4, plasminogen activator inhibitor 1, interleukin 6 and monocyte chemoattractant protein 1 and lower levels of adiponectin. Moreover, patients with metabolic syndrome and high blood pressure had increased surrogate markers of sympathetic activity and decreased baroreflex sensitivity. Logistic regression analysis showed that high-density lipoprotein, retinol-binding protein 4 and plasminogen activator inhibitor-1 levels were independently associated with metabolic syndrome patients with high blood pressure. There is a strong trend for an independent association between metabolic syndrome patients with high blood pressure and glucose levels. CONCLUSIONS: High blood pressure, which may be related to the autonomic dysfunction, is associated with metabolic, inflammatory and prothrombotic dysregulation ...
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Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipertensão/sangue , Síndrome Metabólica/sangue , Antropometria , Biomarcadores/sangue , Glicemia/análise , Doenças Cardiovasculares/etiologia , Citocinas/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Resistência à Insulina , Modelos Logísticos , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Sobrepeso/sangue , Fatores de Risco , Trombose/sangueRESUMO
BACKGROUND: Hypercholesterolaemia may alter cardiovascular autonomic function. We investigated the autonomic cardiovascular regulation during normoxia and hypoxia in familial isolated HC patients with or without statin treatment. MATERIALS AND METHODS: Low (LF-RR) and high (HF-RR) components of spectral analysis of RR interval and systolic arterial pressure (LF-SAP) were obtained during 5 min of normoxia and isocapnic hypoxia (10% O(2) ) in 10 normotensive familial HC patients without medication, in seven HC patients after a 12-week treatment period with 40 mg of simvastatin (HC + SVT) and in eight matched normal volunteers (CO). RESULTS: The HC patients had significant impairment of cardiac autonomic modulation parameters compared with CO at normoxia, which was maintained or even accentuated during hypoxia; these parameters included lower total variance of RR, increased normalized LF-RR, decreased normalized HF-RR, increased LF-RR/HF-RR ratio, higher LF-SAP component and reduced α index. However, the HC + SVT group had a significant improvement in all parameters: the LF-RR and LF-SAP decreased (indicating a decrease in cardiac and vascular sympathetic activity), the HF-RR increased (indicating an increase in parasympathetic activity) and the spontaneous baroreflex sensitivity improved. These changes were detected at normoxia and were maintained during hypoxia. CONCLUSIONS: Our data are the first to show that isolated HC is characterized by an increase in cardiac and vasomotor sympathetic drive, a decrease in cardiac vagal modulation and baroreflex impairment during normoxia and hypoxia. In addition, our data suggest that statin treatment has a potential role in restoring the physiological cardiovascular autonomic control at baseline and during cardiovascular challenge.
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Sistema Nervoso Autônomo/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/fisiopatologia , Hipóxia/fisiopatologia , Sinvastatina/uso terapêutico , Doença Aguda , Adulto , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Reflexo/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. MAIN METHODS: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15 µg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-ß1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). KEY FINDINGS: After treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4 ± 3.2; 1867 ± 3.7 and 202.2 ± 4.3 mmHg; respectively). ACE activity (C: 0.903 ± 0.086; A: 0.654 ± 0.025, and R: 0.389 ± 0.057 mU/mg), albuminuria (C: 264.8 ± 15.4; A: 140.8 ± 13.5 and R: 102.8 ± 6.7 mg/24h), and renal cortex GLUT1 content (C: 46.81 ± 4.54; A: 40.30 ± 5.39 and R: 26.89 ± 0.79 AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). SIGNIFICANCE: We concluded that the blockade of the renin-angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Diabetes Mellitus Experimental/enzimologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Hipertensão/enzimologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHRRESUMO
OBJECTIVES: We explored whether high blood pressure is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome. METHODS: We evaluated 135 consecutive overweight/obese patients. From this group, we selected 75 patients who were not under the regular use of medications for metabolic syndrome as defined by the current Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults criteria. The patients were divided into metabolic syndrome with and without high blood pressure criteria (≥130/≥85 mmHg). RESULTS: Compared to the 45 metabolic syndrome patients without high blood pressure, the 30 patients with metabolic syndrome and high blood pressure had significantly higher glucose, insulin, homeostasis model assessment insulin resistance index, total cholesterol, low-density lipoprotein-cholesterol, triglycerides, uric acid and creatinine values; in contrast, these patients had significantly lower high-density lipoprotein-cholesterol values. Metabolic syndrome patients with high blood pressure also had significantly higher levels of retinol-binding protein 4, plasminogen activator inhibitor 1, interleukin 6 and monocyte chemoattractant protein 1 and lower levels of adiponectin. Moreover, patients with metabolic syndrome and high blood pressure had increased surrogate markers of sympathetic activity and decreased baroreflex sensitivity. Logistic regression analysis showed that high-density lipoprotein, retinol-binding protein 4 and plasminogen activator inhibitor-1 levels were independently associated with metabolic syndrome patients with high blood pressure. There is a strong trend for an independent association between metabolic syndrome patients with high blood pressure and glucose levels. CONCLUSIONS: High blood pressure, which may be related to the autonomic dysfunction, is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome.
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Hipertensão/sangue , Síndrome Metabólica/sangue , Adulto , Antropometria , Biomarcadores/sangue , Glicemia/análise , Doenças Cardiovasculares/etiologia , Citocinas/sangue , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Resistência à Insulina , Modelos Logísticos , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Sobrepeso/sangue , Fatores de Risco , Trombose/sangueRESUMO
PURPOSE: To evaluate the effect of inspiratory muscle training (IMT) on cardiac autonomic modulation and on peripheral nerve sympathetic activity in patients with chronic heart failure (CHF). METHODS: Functional capacity, low-frequency (LF) and high-frequency (HF) components of heart rate variability, muscle sympathetic nerve activity inferred by microneurography, and quality of life were determined in 27 patients with CHF who had been sequentially allocated to 1 of 2 groups: (1) control group (with no intervention) and (2) IMT group. Inspiratory muscle training consisted of respiratory exercises, with inspiratory threshold loading of seven 30-minute sessions per week for a period of 12 weeks, with a monthly increase of 30% in maximal inspiratory pressure (PI(max)) at rest. Multivariate analysis was applied to detect differences between baseline and followup period. RESULTS: Inspiratory muscle training significantly increased PI(max) (59.2 ± 4.9 vs 87.5 ± 6.5 cmH(2)O, P = .001) and peak oxygen uptake (14.4 ± 0.7 vs 18.9 ± 0.8 mL·kg(-1)·min(-1), P = .002); decreased the peak ventilation (VE)/carbon dioxide production (VCO(2)) ratio (35.8 ± 0.8 vs 32.5 ± 0.4, P = .001) and the VE/VCO(2) slope (37.3 ± 1.1 vs 31.3 ± 1.1, P = .004); increased the HF component (49.3 ± 4.1 vs 58.4 ± 4.2 normalized units, P = .004) and decreased the LF component (50.7 ± 4.1 vs 41.6 ± 4.2 normalized units, P = .001) of heart rate variability; decreased muscle sympathetic nerve activity (37.1 ± 3 vs 29.5 ± 2.3 bursts per minute, P = .001); and improved quality of life. No significant changes were observed in the control group. CONCLUSION: Home-based IMT represents an important strategy to improve cardiac and peripheral autonomic controls, functional capacity, and quality of life in patients with CHF.
Assuntos
Insuficiência Cardíaca/psicologia , Hipertensão/psicologia , Inalação , Debilidade Muscular , Qualidade de Vida/psicologia , Sistema Nervoso Simpático , Sistema Nervoso Autônomo , Teste de Esforço , Terapia por Exercício , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estatísticas não Paramétricas , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Exacerbated oxidative stress is thought to be a mediator of arterial hypertension. It has been postulated that creatine (Cr) could act as an antioxidant agent preventing increased oxidative stress. The aim of this study was to investigate the effects of nine weeks of Cr or placebo supplementation on oxidative stress and cardiovascular parameters in spontaneously hypertensive rats (SHR). FINDINGS: Lipid hydroperoxidation, one important oxidative stress marker, remained unchanged in the coronary artery (Cr: 12.6 ± 1.5 vs. Pl: 12.2 ± 1.7 nmol·mg-1; p = 0.87), heart (Cr: 11.5 ± 1.8 vs. Pl: 14.6 ± 1.1 nmol·mg-1; p = 0.15), plasma (Cr: 67.7 ± 9.1 vs. Pl: 56.0 ± 3.2 nmol·mg-1; p = 0.19), plantaris (Cr: 10.0 ± 0.8 vs. Pl: 9.0 ± 0.8 nmol·mg-1; p = 0.40), and EDL muscle (Cr: 14.9 ± 1.4 vs. Pl: 17.2 ± 1.5 nmol·mg-1; p = 0.30). Additionally, Cr supplementation affected neither arterial blood pressure nor heart structure in SHR (p > 0.05). CONCLUSIONS: Using a well-known experimental model of systemic arterial hypertension, this study did not confirm the possible therapeutic effects of Cr supplementation on oxidative stress and cardiovascular dysfunction associated with arterial hypertension.