Doctor of Philosophy / Department of Kinesiology / Craig A. Harms / The overall aim of this dissertation is to further understand sex differences in the cardiopulmonary responses during exercise in younger and older individuals. Emphasis is directed towards the influence of sex in modulating respiratory muscle blood flow and the inspiratory muscle metaboreflex. The first investigation of this dissertation (Chapter 2) demonstrated that sex differences do not alter respiratory muscle blood flow at rest or during exercise. The second investigation (Chapter 3) demonstrated that sex differences exist in the cardiovascular consequences of the inspiratory muscle metaboreflex. Specifically, premenopausal women, compared to age-matched men, exhibited attenuated increases in mean arterial pressure and limb vascular resistance as well as decreases in limb blood flow during inspiratory muscle metaboreflex activation. In Chapter 4, we demonstrated that postmenopausal, compared to pre-menopausal, women exhibit greater increases in mean arterial pressure and limb vascular resistance and decreases in limb blood flow during activation of the inspiratory muscle metaboreflex. Furthermore, no differences in the cardiovascular consequences were present between older men and women or younger and older men with activation of the inspiratory muscle metaboreflex. These data suggest that the tonically active inspiratory muscle metaboreflex present during maximal exercise will result in less blood flow redistribution away from the locomotor muscles in pre-menopausal women compared to postmenopausal women, as well as younger and older men. In conclusion, sex differences in young adults incur a major impact in the cardiovascular consequences during inspiratory muscle metaboreflex activation, while not modifying respiratory muscle blood flow.

Acute (~2 min) baroreceptor unloading was reported to modulate metaboreflex control of postexercise cutaneous blood flow, but not sweating. We examined whether sustained changes in baroreceptor loading status during prolonged postexercise recovery can alter the metaboreceptors’ influence on heat loss. Thirteen young males performed a 1-min isometric handgrip exercise (IHG) at 60% maximal voluntary contraction followed by 2-min of forearm ischemia (to activate metaboreceptors) before and 15, 30, 45 and 60-min after a 15-min intense treadmill running exercise (>90% maximal heart rate) in the heat (35°C). This procedure was repeated on three separate days with the application of lower-body positive (LBPP, +40 mmHg), negative (LBNP, -20 mmHg), or no pressure (Control) postexercise. Sweat rate (ventilated capsule; forearm, chest, upper back) and cutaneous vascular conductance (CVC; forearm, upper back) were measured. Relative to pre-IHG levels, sweating at all sites increased during IHG and remained elevated during ischemia at baseline and similarly at 30, 45, and 60-min postexercise (site average sweat rate increase during ischemia: Control, 0.13±0.02; LBPP, 0.12±0.02; LBNP, 0.15±0.02 mg·min-1·cm-2; all P<0.01), but not at 15-min (all P>0.10). LBPP and LBNP application did not modulate the pattern of sweating to IHG and ischemia (all P>0.05). At 15-min postexercise, forearm CVC was reduced from pre-IHG levels during both IHG and ischemia under LBNP only (ischemia: 3.9±0.8 %CVCmax; P<0.02). Therefore, we show metaboreceptors modulate postexercise sweating in the mid-to-late stages (30-60 min) of recovery, independent of baroreceptor loading status and similarly between skin sites. In contrast, metaboreflex modulation of forearm but not upper back CVC occurs only in the early stages of recovery (15 min) and depends upon baroreceptor unloading.

INTRODUÇÃO: A hipertensão arterial tem sido associada à hipersensibilidade quimiorreflexa arterial. A consequência dessa disfunção autonômica nessa população é a ativação simpática e vasoconstrição. De fato, a atividade nervosa simpática está aumentada e o fluxo sanguíneo muscular diminuído, em repouso e durante manobras fisiológicas como o exercício, em pacientes hipertensos. Contudo, o papel dos quimiorreceptores periféricos na resposta neurovascular durante o exercício não tem sido investigado nesses pacientes. OBJETIVO: Avaliar a influência dos quimiorreceptores periféricos no controle neurovascular da atividade nervosa simpática muscular (ANSM), condutância vascular no antebraço e pressão arterial em repouso, durante o exercício e a oclusão circulatória em pacientes com hipertensão arterial. MÉTODOS: Vinte e cinco sujeitos, na faixa etária entre 25 e 60 anos, sedentários, com índice de massa corporal menor que 30kg/m2 e não engajados em tratamento farmacológico participaram do estudo. Os participantes foram divididos em dois grupos, de acordo com o nível de pressão arterial clínica e classificados como hipertensos ou normotensos. Foram avaliados a ANSM (microneurografia), o fluxo sanguíneo muscular (pletismografia de oclusão venosa), a pressão arterial (oscilométrica), a frequência cardíaca (eletrocardiograma) e respiratória (cinta piezoelétrica) e a saturação de pulso de oxigênio (oxímetro). Todas as avaliações foram realizadas em repouso, durante o exercício de preensão de mão (30% da contração voluntária máxima) e durante a oclusão circulatória pós-exercício, em condições de normóxia (inalação de níveis ambientes com 21% de oxigênio) e hiperóxia (manobra que desativa os quimiorreceptores arteriais através da inalação da concentração de 100% de oxigênio). Em repouso, também foram avaliadas a variabilidade da frequência cardíaca e da pressão arterial e o ganho do controle barorreflexo da frequência cardíaca. Foi considerada diferença significativa quando P<0,05. RESULTADOS: No repouso, a desativação dos quimiorreceptores periféricos diminuiu a ANSM (38±3 vs. 34±3 disparos/minuto, P=0,02), aumentou o fluxo sanguíneo muscular (2,2±0,3 vs. 2,4±0,3 ml/min/100ml, P=0,02) e tendeu a aumentar a condutância vascular do antebraço (P=0,06) nos pacientes hipertensos. Além disso, a desativação dos quimiorreceptores periféricos aumentou o ganho do controle barorreflexo da frequência cardíaca (8±2 vs. 10±2 ms/mmHg, P=0,03) nesses pacientes tornando-os semelhantes ao grupo normotenso, quando comparados em condição de hiperóxia. Durante o exercício físico, a desativação dos quimiorreceptores periféricos diminuiu a resposta da ANSM nos pacientes hipertensos (A.S.C.= 131±8 vs. 116±9 disparos, P=0,005). No entanto, nenhuma modificação significativa foi observada na condutância vascular do antebraço e na pressão arterial. Interessantemente, durante a oclusão circulatória, manobra que isola os metaborreceptores musculares, a desativação dos quimiorreceptores periféricos aumentou a ANSM no primeiro e segundo minuto de oclusão (?= -2±2 vs. 3±1 disparos/min; ?= -4±2 vs. 3±1 disparos/min, P(grupo)= 0,02). CONCLUSÃO: Em pacientes hipertensos, a desativação dos quimiorreceptores periféricos: 1- Diminui a ANSM e aumenta o fluxo sanguíneo muscular e o ganho do controle barorreflexo da frequência cardíaca em repouso; 2-Diminui a resposta da ANSM durante o exercício e; 3- Normaliza o controle metaborreflexo da ANSM. Analisados em conjunto, esses resultados demonstram a participação do mecanismo quimiorreflexo periférico no controle neurovascular não só em repouso, mas também, durante a manobra fisiológica de exercício nos pacientes hipertensos / INTRODUCTION: Hypertension has been associated with augmented arterial chemoreflex sensitivity. The consequence of this autonomic dysfunction is an increased sympathetic outflow and vasoconstriction. Indeed, sympathetic nerve activity is increased and forearm blood flow is decreased at rest and during physiological maneuvers such as exercise, in hypertensive patients. However, the role of peripheral chemoreceptors in neurovascular response during exercise has not been investigated in these patients. OBJECTIVES: To evaluate the influence of peripheral chemoreceptors on neurovascular control of muscle sympathetic nerve activity (MSNA), forearm vascular conductance and blood pressure at rest, during exercise and postexercise circulatory arrest in patients with hypertension. METHODS: Twenty-five subjects, age between 25 and 60 years old, sedentary, with body mass index less than 30 kg/m2 and not engaged in pharmacological treatment participated in the study. The participants were divided into two groups according to their clinical blood pressure levels and were classified as hypertensive or normotensive. Were evaluated MSNA (microneurography), forearm blood flow (venous occlusion plethysmography), blood pressure (oscillometric), heart rate (electrocardiogram), respiratory rate (piezoelastic strap) and oxygen saturation (oxymeter). The evaluations were performed at rest, during a handgrip exercise (30% of the maximal voluntary contraction) and during postexercise circulatory arrest, in normóxia (breathing ambient air, containing 21% of oxygen) and hyperoxia (breathing air containing 100% oxygen, maneuver that deactivates the peripheral chemoreceptors). At rest, the variability of heart rate and blood pressure and the baroreflex control of heart rate were also evaluated. Significant differences were assumed to be when P<0.05. RESULTS: At rest, the deactivation of the peripheral chemoreceptors decreased the MSNA (38±3 vs. 34±3 bursts/min, P=0.02), increased forearm blood flow (2.2±0.3 vs. 2.4±0.3 ml/min/100ml, P=0.02) and tended to increase forearm vascular conductance (P=0.06) in hypertensive patients. Besides, the deactivation of the peripheral chemoreceptors increased the baroreflex control of heart rate (8±2 vs. 10±2 ms/mmHg, P=0.03) in these patients, toward to the normotensive group levels, when compared during hyperoxia condition. During exercise, the deactivation of peripheral chemoreceptors decreased the MSNA response in hypertensive patients (A.U.C.= 131±8 vs. 116±9 bursts, P=0.005). However, no significant changes were observed in forearm vascular conductance and blood pressure responses. Interestingly, during postexercise circulatory arrest, when the metaboreflex control is isolated, the deactivation of peripheral chemoreceptors increased the MSNA during the first and second minute of circulatory arrest (?= -2±2 vs. 3±1 bursts/min; ?= -4±2 vs. 3±1 bursts/min, P(group)=0.02). CONCLUSION: In hypertensive patients, the deactivation of the peripheral chemoreceptors: 1- Decreases the MSNA and increases the forearm blood flow and baroreflex control of heart rate at rest; 2- Decreases the MSNA response during exercise; 3- Normalizes the metaboreflex control of MSNA. Taken together, these results demonstrate the participation of the peripheral chemorreflex mechanism in the neurovascular control not only at rest, but also during the physiological maneuver of exercise in hypertensive patients

INTRODUÇÃO: A hipertensão arterial tem sido associada à hipersensibilidade quimiorreflexa arterial. A consequência dessa disfunção autonômica nessa população é a ativação simpática e vasoconstrição. De fato, a atividade nervosa simpática está aumentada e o fluxo sanguíneo muscular diminuído, em repouso e durante manobras fisiológicas como o exercício, em pacientes hipertensos. Contudo, o papel dos quimiorreceptores periféricos na resposta neurovascular durante o exercício não tem sido investigado nesses pacientes. OBJETIVO: Avaliar a influência dos quimiorreceptores periféricos no controle neurovascular da atividade nervosa simpática muscular (ANSM), condutância vascular no antebraço e pressão arterial em repouso, durante o exercício e a oclusão circulatória em pacientes com hipertensão arterial. MÉTODOS: Vinte e cinco sujeitos, na faixa etária entre 25 e 60 anos, sedentários, com índice de massa corporal menor que 30kg/m2 e não engajados em tratamento farmacológico participaram do estudo. Os participantes foram divididos em dois grupos, de acordo com o nível de pressão arterial clínica e classificados como hipertensos ou normotensos. Foram avaliados a ANSM (microneurografia), o fluxo sanguíneo muscular (pletismografia de oclusão venosa), a pressão arterial (oscilométrica), a frequência cardíaca (eletrocardiograma) e respiratória (cinta piezoelétrica) e a saturação de pulso de oxigênio (oxímetro). Todas as avaliações foram realizadas em repouso, durante o exercício de preensão de mão (30% da contração voluntária máxima) e durante a oclusão circulatória pós-exercício, em condições de normóxia (inalação de níveis ambientes com 21% de oxigênio) e hiperóxia (manobra que desativa os quimiorreceptores arteriais através da inalação da concentração de 100% de oxigênio). Em repouso, também foram avaliadas a variabilidade da frequência cardíaca e da pressão arterial e o ganho do controle barorreflexo da frequência cardíaca. Foi considerada diferença significativa quando P<0,05. RESULTADOS: No repouso, a desativação dos quimiorreceptores periféricos diminuiu a ANSM (38±3 vs. 34±3 disparos/minuto, P=0,02), aumentou o fluxo sanguíneo muscular (2,2±0,3 vs. 2,4±0,3 ml/min/100ml, P=0,02) e tendeu a aumentar a condutância vascular do antebraço (P=0,06) nos pacientes hipertensos. Além disso, a desativação dos quimiorreceptores periféricos aumentou o ganho do controle barorreflexo da frequência cardíaca (8±2 vs. 10±2 ms/mmHg, P=0,03) nesses pacientes tornando-os semelhantes ao grupo normotenso, quando comparados em condição de hiperóxia. Durante o exercício físico, a desativação dos quimiorreceptores periféricos diminuiu a resposta da ANSM nos pacientes hipertensos (A.S.C.= 131±8 vs. 116±9 disparos, P=0,005). No entanto, nenhuma modificação significativa foi observada na condutância vascular do antebraço e na pressão arterial. Interessantemente, durante a oclusão circulatória, manobra que isola os metaborreceptores musculares, a desativação dos quimiorreceptores periféricos aumentou a ANSM no primeiro e segundo minuto de oclusão (?= -2±2 vs. 3±1 disparos/min; ?= -4±2 vs. 3±1 disparos/min, P(grupo)= 0,02). CONCLUSÃO: Em pacientes hipertensos, a desativação dos quimiorreceptores periféricos: 1- Diminui a ANSM e aumenta o fluxo sanguíneo muscular e o ganho do controle barorreflexo da frequência cardíaca em repouso; 2-Diminui a resposta da ANSM durante o exercício e; 3- Normaliza o controle metaborreflexo da ANSM. Analisados em conjunto, esses resultados demonstram a participação do mecanismo quimiorreflexo periférico no controle neurovascular não só em repouso, mas também, durante a manobra fisiológica de exercício nos pacientes hipertensos / INTRODUCTION: Hypertension has been associated with augmented arterial chemoreflex sensitivity. The consequence of this autonomic dysfunction is an increased sympathetic outflow and vasoconstriction. Indeed, sympathetic nerve activity is increased and forearm blood flow is decreased at rest and during physiological maneuvers such as exercise, in hypertensive patients. However, the role of peripheral chemoreceptors in neurovascular response during exercise has not been investigated in these patients. OBJECTIVES: To evaluate the influence of peripheral chemoreceptors on neurovascular control of muscle sympathetic nerve activity (MSNA), forearm vascular conductance and blood pressure at rest, during exercise and postexercise circulatory arrest in patients with hypertension. METHODS: Twenty-five subjects, age between 25 and 60 years old, sedentary, with body mass index less than 30 kg/m2 and not engaged in pharmacological treatment participated in the study. The participants were divided into two groups according to their clinical blood pressure levels and were classified as hypertensive or normotensive. Were evaluated MSNA (microneurography), forearm blood flow (venous occlusion plethysmography), blood pressure (oscillometric), heart rate (electrocardiogram), respiratory rate (piezoelastic strap) and oxygen saturation (oxymeter). The evaluations were performed at rest, during a handgrip exercise (30% of the maximal voluntary contraction) and during postexercise circulatory arrest, in normóxia (breathing ambient air, containing 21% of oxygen) and hyperoxia (breathing air containing 100% oxygen, maneuver that deactivates the peripheral chemoreceptors). At rest, the variability of heart rate and blood pressure and the baroreflex control of heart rate were also evaluated. Significant differences were assumed to be when P<0.05. RESULTS: At rest, the deactivation of the peripheral chemoreceptors decreased the MSNA (38±3 vs. 34±3 bursts/min, P=0.02), increased forearm blood flow (2.2±0.3 vs. 2.4±0.3 ml/min/100ml, P=0.02) and tended to increase forearm vascular conductance (P=0.06) in hypertensive patients. Besides, the deactivation of the peripheral chemoreceptors increased the baroreflex control of heart rate (8±2 vs. 10±2 ms/mmHg, P=0.03) in these patients, toward to the normotensive group levels, when compared during hyperoxia condition. During exercise, the deactivation of peripheral chemoreceptors decreased the MSNA response in hypertensive patients (A.U.C.= 131±8 vs. 116±9 bursts, P=0.005). However, no significant changes were observed in forearm vascular conductance and blood pressure responses. Interestingly, during postexercise circulatory arrest, when the metaboreflex control is isolated, the deactivation of peripheral chemoreceptors increased the MSNA during the first and second minute of circulatory arrest (?= -2±2 vs. 3±1 bursts/min; ?= -4±2 vs. 3±1 bursts/min, P(group)=0.02). CONCLUSION: In hypertensive patients, the deactivation of the peripheral chemoreceptors: 1- Decreases the MSNA and increases the forearm blood flow and baroreflex control of heart rate at rest; 2- Decreases the MSNA response during exercise; 3- Normalizes the metaboreflex control of MSNA. Taken together, these results demonstrate the participation of the peripheral chemorreflex mechanism in the neurovascular control not only at rest, but also during the physiological maneuver of exercise in hypertensive patients