Diferenças entre os sexos no controle neural da pressão arterial durante o exercício isométrico

Tese (doutorado)—Universidade de Brasília, Faculdade de Educação Física, Programa de Pós-Graduação em Educação Física, 2020.O objetivo geral da presente tese foi de verificar as possíveis diferenças entre os sexos nos mecanismos neurovasculares de controle de pressão arterial (PA) durante o exercício isométrico de preensão manual e ativação isolada do metaborreflexo muscular. Para atingir tal objetivo, foram realizados três estudos, que apresentam os seguintes objetivos específicos: o Estudo 1 foi de investigar o efeito da ativação isolada do metaborreflexo muscular no barroreflexo cardíaco e caracterizar as possíveis diferenças relacionadas ao sexo nessa interação em jovens saudáveis. O Estudo 2 foi de investigar as possíveis diferenças entre homens e mulheres jovens na recuperação da frequência cardíaca (FC) e reativação vagal cardíaca no final do exercício isométrico e início da isquemia pós-exercício (IPE). Por fim, o objetivo do Estudo 3 que foi de testar a contribuição dos receptores β-adrenérgicos nas diferenças entre homens e mulheres na regulação da PA durante exercício isométrico e ativação isolada do metaborreflexo muscular. No Estudo 1, 40 voluntários jovens e saudáveis [20 homens (21 ± 0,6 anos) e 20 mulheres (23 ± 0,6 anos)] foram submetidos ao exercício isométrico de preensão manual seguido por ativação isolada do metaborreflexo muscular via IPE. A FC e PA foram medidas batimento-a-batimento, a sensibilidade do barorreflexo cardíaco espontâneo foi analisado utilizando a técnica da sequência e foi estimada a atividade autonômica cardíaca através dos índices de variabilidade da FC (VFC). Os resultados demonstraram que a sensibilidade barorreflexa cardíaca espontânea é semelhante entre homens e mulheres durante o repouso. Contudo, ela foi aumentada durante a IPE em homens, mas não em mulheres. Os dados da VFC mostraram um maior aumento da atividade vagal em homens comparado com mulheres durante a IPE. No Estudo 2, 47 voluntários jovens e saudáveis [24 homens (21 ± 2 anos) e 23 mulheres (23 ± 3 anos)] foram recrutados e submetidos ao mesmo protocolo citado anteriormente. Contudo, as análises de FC, PA e VFC foram feitas durante os últimos 30s do exercício e imediatamente após (primeiros 30s do início da IPE). Extrapolando os achados do primeiro estudo, as mulheres apresentaram uma recuperação da FC mais lenta do que os homens nos 30s iniciais da IPE, acompanhado de menores valores de atividade parassimpática para o coração. Por fim, no Estudo 3, foram recrutados 16 voluntários jovens e saudáveis [8 homens (20 ± 0,5 anos) e 8 mulheres (24 ± 1,4 anos)]. As medidas hemodinâmicas foram similares às dos estudos anteriores, adicionando as medidas de volume sistólico, DC e RVP via método Modelflow. Os participantes foram submetidos a um protocolo de exercício isométrico isquêmico seguido por IPE. Além disso, de maneira cega e randomizada, os participantes também foram submetidos à ingestão de pílula placebo e bloqueador não seletivo dos receptores β-adrenérgicos (40mg propranolol). Durante a condição de placebo, a resposta de PA ao exercício foi menor em mulheres comparada com os homens. Contudo, o β-bloqueio atenuou a resposta de PA nos homens por uma redução no DC. Por outro lado, as mulheres não apresentaram alteração na resposta de PA, pois apesar de também terem reduzido o DC, aumentaram robustamente a RVP. Em conclusão, os estudos mostraram que há diferença entre os sexos na interação entre barorreflexo cardíaco e metaborreflexo muscular. Além disso, que diferenças entre os sexos na recuperação da FC durante a ativação do metaborreflexo muscular já são pronunciadas imediatamente após a interrupção do exercício, potencialmente mediadas por diferenças na reativação vagal. Por fim, conclui-se que há diferenças entre os sexos na regulação da PA durante o exercício isométrico de preensão manual e que são mediadas, principalmente, por receptores β-adrenérgicos.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).The overall aim of the present thesis was to verify the possible sex differences in the neurovascular mechanisms of blood pressure (BP) control during isometric handgrip exercise and isolated muscle metaboreflex activation. Three studies were carried out, which present the following specific aims: Study 1 aimed to investigate the effect of isolated muscle metaboreflex activation on cardiac barroreflex activity, and also to characterize the possible sex related differences in this interaction. The aim of Study 2 was to further explore the findings from Study 1 investigating the possible sex related differences in heart rate (HR) recovery and vagal reactivation at the end of isometric exercise and onset of post-exercise ischemia (PEI). Finally, the aim of Study 3 was to test the role of β-adrenergic receptors in the differences between men and women in BP regulation during isometric exercise and isolated muscle metaboreflex activation. In Study 1, 40 young and healthy volunteers [20 men (21 ± 0.6 yr) and 20 women (23 ± 0.6 yr)] underwent an isometric handgrip exercise followed by muscle metaboreflex activation via PEI. Beat-to-beat HR and BP were continuously measured. In addition, the spontaneous cardiac baroreflex sensitivity was analyzed using the sequence technique, and cardiac autonomic activity was estimated using HR variability (HRV) indexes. The results demonstrated that spontaneous cardiac baroreflex sensitivity is similar between men and women at rest. However, it was increased during PEI in men, but not in women. HRV indexes showed a greater increase in vagal activity in men compared to women during PEI. In Study 2, 47 young and healthy participants [24 men (21 ± 2 yr) and 23 women (23 ± 3 yr)] were recruited and submitted to the same protocol of exercise and PEI. However, the HR, BP and HRV were analyzed during the last 30s of the exercise and immediately after the cessation of exercise (first 30s at the onset of PEI). Women demonstrated a slower HR recovery compared to men at the onset of PEI. This result was accompanied by a lower response in parasympathetic activity to the heart in women compared to men. In Study 3, 16 young and healthy participants [8 men (20 ± 0.5 yr) and 8 women (24 ± 1.4 yr)] were recruited. Hemodynamic measurements were similar from those previous studies with further measurements of stroke volume, CO and TPR using Modelflow method. The participants underwent an ischemic isometric exercise protocol followed by PEI. In addition, in a blind and randomized design, participants were also submitted to a placebo pill and a non-selective blocker of β-adrenergic receptors (40mg propranolol). During the placebo condition, the BP response to exercise was lower in women compared to men. During β-blockade, men showed an attenuated BP response during exercise by a reduction in CO. Even though women also demonstrated a reduction in CO during the β-blockade, the BP response was not affected because they have a robust increase in TPR. In conclusion, the studies showed that there is a sex related differences in the interaction between cardiac baroreflex and muscle metaboreflex. Furthermore, the sex differences in HR recovery during muscle metaboreflex activation are already pronounced immediately after the cessation of exercise, potentially mediated by differences in vagal reactivation. In addition, there are sex differences in BP regulation during isometric handgrip exercise, mainly mediated by β- adrenergic receptors

Obesity Contributes to an Attenuated Spontaneous Baroreflex Sensitivity in UCD-Type 2 Diabetic Rats

Previous studies suggest impaired baroreflex function in individuals with type 2 diabetes (T2D), which is critically important since it leads to an increased risk for adverse cardiovascular events. Currently, the underlying mechanisms remain poorly understood. The baroreflex, essential for maintaining blood pressure homeostasis, can also be influenced by several risk factors, one of which is obesity. Obesity has been shown to markedly decrease baroreflex sensitivity (BRS) in non-diabetic individuals, and given that the majority of T2D patients are obese, it is likely that impairment in baroreflex function in T2D is mainly driven by obesity. PURPOSE: To investigate the effects of obesity on baroreflex function in T2D rats at different phases of the disease. We hypothesized that BRS would be attenuated in T2D rats, and this would be associated with increased adiposity. METHODS: Experiments were performed on male University of California Davis (UCD)-T2D rats assigned to four experimental groups (n=6 in each group): prediabetic (PD), diabetes-onset (DO), 4 weeks after onset [recent-onset (RO)], and 12 weeks after onset [late-onset (LO)]. Age-matched healthy Sprague-Dawley rats were assigned to the same experimental groups as controls (n=6 in each). Rats were anesthetized and blood pressure was directly measured for 5 min. Hemodynamic variables were obtained on a beat-to-beat basis and spontaneous BRS was assessed using the sequence technique. Dual-energy X-ray absorptiometry (DEXA) was used to assess body composition and visceral fat was determined by identifying an abdominal region of interest. Data are presented as mean ± SD. RESULTS: Spontaneous BRS was significantly lower in T2D compared to control rats at DO (3.7 ± 3.2 ms/mmHg vs 16.1 ± 8.4 ms/mmHg; P=0.01). However, this difference was abolished by LO (13.4 ± 8.1 ms/mmHg vs 9.2 ± 6.0 ms/mmHg; P=0.16). T2D rats had the highest level of adiposity during the RO phase but it significantly decreased by LO (PD: 136 ± 14 g; DO: 175 ± 24 g; RO: 207 ± 44 g; LO: 163 ± 45 g; P=0.03). In addition, T2D rats had greater visceral fat compared to control rats regardless of the disease phase (P\u3c0.01). CONCLUSION: These findings suggest that obesity may contribute to an attenuated spontaneous BRS in T2D rats and suggests a link between metabolic and autonomic dysfunction in T2D

Sex differences in blood pressure regulation during ischemic isometric exercise : the role of the β-adrenergic receptors

We sought to investigate whether the β-adrenergic receptors play a pivotal role in sex-related differences in arterial blood pressure (BP) regulation during isometric exercise. Sixteen volunteers (8 women) performed 2 min of ischemic isometric handgrip exercise (IHE) and 2 min of postexercise circulatory occlusion (PECO). Heart rate (HR) and beat-to-beat arterial BP were continuously measured. Beat-to-beat estimates of stroke volume (ModelFlow) were obtained and matched with HR to calculate cardiac output (Q̇) and total peripheral resistance (TPR). Two trials were randomly conducted between placebo and nonselective β-adrenergic blockade (40 mg propranolol). Under the placebo condition, the magnitude of the BP response in IHE was lower in women compared with men. During PECO, the BP remained elevated and the sex differences persisted. The β-blockade attenuated the BP response during IHE in men (∆57 ± 4 vs. ∆45 ± 7 mmHg, P = 0.025) due to a reduction in Q̇ (∆3.7 ± 0.5 vs. ∆1.8 ± 0.2 L/min, P = 0.012) while TPR was not affected. In women, however, the BP response during IHE was unchanged (∆27 ± 3 vs. ∆28 ± 3 mmHg, P = 0.889), despite attenuated Q̇ (∆2.7 ± 0.4 vs. ∆1.3 ± 0.2 L/min, P = 0.012). These responses were mediated by a robust increase in TPR under β-blockade (∆−0.2 ± 0.4 vs. ∆2.2 ± 0.7 mmHg·L−1·min, P = 0.012). These findings demonstrate that the sex differences in arterial BP regulation during ischemic IHE are mediated by β-adrenergic receptors

Spontaneous baroreflex sensitivity is attenuated in male UCD-type 2 diabetes mellitus rats: A link between metabolic and autonomic dysfunction

Patients with type 2 diabetes mellitus (T2DM) have impaired arterial baroreflex function, which may be linked to the co-existence of obesity. However, the role of obesity and its related metabolic impairments on baroreflex dysfunction in T2DM is unknown. This study aimed to investigate the role of visceral fat and adiponectin, the most abundant cytokine produced by adipocytes, on baroreflex dysfunction in T2DM rats. Experiments were performed in adult male UCD-T2DM rats assigned to the following experimental groups (n = 6 in each): prediabetic (Pre), diabetes-onset (T0), 4 weeks after onset (T4), and 12 weeks after onset (T12). Age-matched healthy Sprague-Dawley rats were used as controls. Rats were anesthetized and blood pressure was directly measured on a beat-to-beat basis to assess spontaneous baroreflex sensitivity (BRS) using the sequence technique. Dual-energy X-ray absorptiometry (DEXA) was used to assess body composition. Data are presented as mean ± SD. BRS was significantly lower in T2DM rats compared with controls at T0 (T2D: 3.7 ± 3.2 ms/mmHg vs Healthy: 16.1 ± 8.4 ms/mmHg; P = 0.01), but not at T12 (T2D: 13.4 ± 8.1 ms/mmHg vs Healthy: 9.2 ± 6.0 ms/mmHg; P = 0.16). T2DM rats had higher visceral fat mass, adiponectin, and insulin concentrations compared with control rats (all P < 0.01). Changes in adiponectin and insulin concentrations over the measured time-points mirrored one another and were opposite those of the BRS in T2DM rats. These findings demonstrate that obesity-related metabolic impairments may contribute to an attenuated spontaneous BRS in T2DM, suggesting a link between metabolic and autonomic dysfunction

Exaggerated exercise pressor reflex in male UC Davis type 2 diabetic rats is due to the pathophysiology of the disease and not aging

Introduction: Studies in humans and animals have found that type 2 diabetes mellitus (T2DM) exaggerates the blood pressure (BP) response to exercise, which increases the risk of adverse cardiovascular events such as heart attack and stroke. T2DM is a chronic disease that, without appropriate management, progresses in severity as individuals grow older. Thus, it is possible that aging may also exaggerate the BP response to exercise. Therefore, the purpose of the current study was to determine the effect of the pathophysiology of T2DM on the exercise pressor reflex independent of aging. Methods: We compared changes in peak pressor (mean arterial pressure; ΔMAP), BP index (ΔBPi), heart rate (ΔHR), and HR index (ΔHRi) responses to static contraction, intermittent contraction, and tendon stretch in UCD-T2DM rats to those of healthy, age-matched Sprague Dawley rats at three different stages of the disease. Results: We found that the ΔMAP, ΔBPi, ΔHR, and ΔHRi responses to static contraction were significantly higher in T2DM rats (ΔMAP: 29 ± 4 mmHg; ΔBPi: 588 ± 51 mmHg•s; ΔHR: 22 ± 5 bpm; ΔHRi: 478 ± 45 bpm•s) compared to controls (ΔMAP: 10 ± 1 mmHg, p < 0.0001; ΔBPi: 121 ± 19 mmHg•s, p < 0.0001; ΔHR: 5 ± 2 bpm, p = 0.01; ΔHRi: 92 ± 19 bpm•s, p < 0.0001) shortly after diabetes onset. Likewise, the ΔMAP, ΔBPi, and ΔHRi to tendon stretch were significantly higher in T2DM rats (ΔMAP: 33 ± 7 mmHg; ΔBPi: 697 ± 70 mmHg•s; ΔHRi: 496 ± 51 bpm•s) compared to controls (ΔMAP: 12 ± 5 mmHg, p = 0.002; ΔBPi: 186 ± 30 mmHg•s, p < 0.0001; ΔHRi: 144 ± 33 bpm•s, p < 0.0001) shortly after diabetes onset. The ΔBPi and ΔHRi, but not ΔMAP, to intermittent contraction was significantly higher in T2DM rats (ΔBPi: 543 ± 42 mmHg•s; ΔHRi: 453 ± 53 bpm•s) compared to controls (ΔBPi: 140 ± 16 mmHg•s, p < 0.0001; ΔHRi: 108 ± 22 bpm•s, p = 0.0002) shortly after diabetes onset. Discussion: Our findings suggest that the exaggerated exercise pressor reflex and mechanoreflex seen in T2DM are due to the pathophysiology of the disease and not aging

Neurovascular coupling is not influenced by lower body negative pressure in humans

Cerebral blood flow is tightly coupled with local neuronal activation and metabolism, i.e., neurovascular coupling (NVC). Studies suggest a role of sympathetic nervous system in the regulation of cerebral blood flow. However, this is controversial, and the sympathetic regulation of NVC in humans remains unclear. Since impaired NVC has been identified in several chronic diseases associated with a heightened sympathetic activity, we aimed to determine whether reflex-mediated sympathetic activation via lower body negative pressure (LBNP) attenuates NVC in humans. NVC was assessed using a visual stimulation protocol (5 cycles of 30 s eyes closed and 30 s of reading) in 11 healthy participants (aged 24 ± 3 yr). NVC assessments were made under control conditions and during LBNP at -20 and -40 mmHg. Posterior (PCA) and middle (MCA) cerebral artery mean blood velocity (Vmean) and vertebral artery blood flow (VAflow) were simultaneously determined with cardiorespiratory variables. Under control conditions, the visual stimulation evoked a robust increase in PCAVmean (∆18.0 ± 4.5%), a moderate rise in VAflow (∆9.6 ± 4.3%), and a modest increase in MCAVmean (∆3.0 ± 1.9%). The magnitude of NVC response was not affected by mild-to-moderate LBNP (all P > 0.05 for repeated-measures ANOVA). Given the small change that occurred in partial pressure of end-tidal CO2 during LBNP, this hypocapnia condition was matched via voluntary hyperventilation in absence of LBNP in a subgroup of participants (n=8). The mild hypocapnia during LBNP did not exert a confounding influence on the NVC response. These findings indicate that the NVC is not influenced by LBNP or mild hypocapnia in humans