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Role of central autonomic network nuclei on the generation of sympathetic tonus in essential hypertension : an exploratory study in conscious rats
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Um dos principais contributos para o aparecimento, desenvolvimento e manutenção da hipertensão arterial é a existência e persistência de uma atividade simpática elevada. Dados de modelos experimentais de hipertensão e doentes hipertensos tornaram evidente que a simpatoexcitação excessiva, característica da hipertensão, é deletéria resultando em danos nos órgãos periféricos e aumento da morbilidade e mortalidade. Assim, a identificação da origem desta simpatoexcitação é crucial por forma a serem desenvolvidas novas intervenções terapêuticas. No entanto, até ao momento, os mecanismos exatos responsáveis pela ativação simpática na hipertensão arterial permanecem por elucidar, devido à sua complexidade e origem multifatorial.
A face rostroventrolateral do bulbo (FRVLB) é uma área bulbar simpatoexcitatória pertencente à rede autonómica central, que desempenha um papel importante na fisiopatologia da hipertensão arterial. Em termos fisiológicos, a FRVLB tem um papel fundamental na geração do tónus simpático periférico. Os seus neurónios projetam-se monosinapticamente para os neurónios simpáticos pré-ganglionares do núcleo de células da coluna intermediolateral da medula espinhal, condicionando o tónus simpático periférico para o coração e vasos. O núcleo parabraquial lateral (NPL) e a substância cinzenta periaqueductal (SCP) são outras áreas da rede autonómica central que podem estar envolvidas na geração da atividade simpática. O NPL tem um papel crítico na transmissão central de sinais do tronco cerebral relacionados com a regulação de fluidos e ingestão de eletrólitos e com a função cardiovascular, em particular aqueles que regulam a pressão arterial em resposta à hemorragia e à hipovolémia. As colunas da SCP são capazes de modular as funções cardíacas simpáticas através de uma variedade de vias indiretas que envolvem neurónios pré-motores simpáticos encontrados em locais específicos do hipotálamo, mesencéfalo, protuberância e bulbo raquidiano.
No presente trabalho, de natureza exploratória, procurámos estabelecer as consequências funcionais no tónus simpático e pressão arterial decorrentes da diminuição da excitabilidade da FRVLB e NPL e SCP em duas situações, em normotensão e em hipertensão, respetivamente.
Para tal, e em cada área central de estudo, os valores da pressão arterial, output autonómico, função baro- e quimiorreceptora foram monitorizados e os parâmetros metabólicos e comportamentais avaliados antes e depois da microinjeção do lentivírus com informação genética que codifica os canais hKir2.1.
Os resultados mostraram que a microinjeção de LVV-hKir2.1 na FRVLB de ratos normotensos provocou uma descida significativa do tónus simpático, embora esta não se tenha refletido na pressão arterial sistólica, diastólica e média. Adicionalmente, não se observaram efeitos sobre os reflexos cardiorrespiratórios, parâmetros metabólicos e atividade locomotora/exploratória. Aos 60 dias após a microinjeção lentiviral no NPL de ratos hipertensos, o tónus simpático diminuiu significativamente refletindo-se nos valores de pressão arterial e frequência cardíaca. Verificou-se também uma tendência para a diminuição da variação do reflexo quimiorreceptor; no entanto, não houve neste caso significância estatística. Além disso, o silenciamento da SCP em ratos hipertensos não teve repercussões na pressão arterial, frequência cardíaca e tónus simpático, mas o ganho do barorreflexo diminuiu. O núcleo Kolliker-Fuse, localizado na protuberância e responsável pelo controlo pôntico da respiração foi utilizado como núcleo controlo para as duas últimas áreas. Assim, com este trabalho mostramos a suposta contribuição das áreas do mesencéfalo e da rede autonómica central pôntica para a etiologia da hipertensão de causa neurogénica e fornecemos pistas para possíveis futuras intervenções terapêuticas no controlo da simpatoexcitação a nível central.
Sympathetic nervous system hyperactivity is a major contributor to the onset, development and maintenance of essential arterial hypertension. Taking into account data from experimental models of hypertension and from hypertensive patients, it is evident that the excessive sympathoexcitation that characterizes hypertension is deleterious leading to organ damage and increasing morbidity and mortality. Thus, is essential to identify the origin of the sympathoexcitation in order to develop new therapeutic interventions. However, until the moment, the precise mechanisms responsible for the sympathetic activation in essential hypertension remain to be elucidated, since they are complex and multifactorial. The rostral ventrolateral medulla (RVLM) is a medullar sympathoexcitatory area of the central autonomic network, which plays a crucial role in essential hypertension pathophysiology. Physiologically, RVLM has a key role in peripheral sympathetic tone generation. Its neurons monosynaptically project to the sympathetic preganglionic ones in the intermediolateral column of the spinal cord, conditioning peripheral sympathetic tone to the heart and vessels. Other areas of the central autonomic network that could also be involved in the generation of sympathetic activity are the lateral parabrachial nucleus (LPBN) and the periaqueductal gray matter (PAG). LPBN plays a critical role in relaying signals related to the regulation of fluid and electrolyte intake and cardiovascular function from the brainstem to the forebrain, in particular those regulating blood pressure in response to hemorrhages and hypovolemia. PAG columns are capable of modulating cardiac sympathetic functions through a series of indirect pathways involving sympathetic premotor neurons found in specific sites of the hypothalamus, midbrain, pons and medulla oblongata. In the present work, of exploratory nature, we sought to establish the functional consequences on sympathetic tone and arterial blood pressure of decreasing the excitability of RVLM and LPBN and PAG in normotension and hypertension, respectively. For that, blood pressure, autonomic output, circadian blood pressure, baro and chemoreceptor function were monitored and metabolic plus behavioral parameters evaluated before and after microinjection in each area of genetic information encoding hKir2.1 channels through a lentivirus. Results show that LVV-hKir2.1 microinjection into the RVLM of normotensive rats promoted a significant decrease in sympathetic tone, however it did not affect systolic, diastolic and mean blood pressure values. Additionally, no deleterious effects on cardiorespiratory reflexes, metabolic parameters and locomotor plus exploratory activity were observed. In hypertensive conditions, 60 days post lentiviral microinjection into the LPBN, sympathetic outflow decreased significantly and reflect itself on blood pressure and heart rate values as well. A tendency towards chemoreflex variation attenuation was also observed, however statistical significance was not attained. In addition, PAG silencing had no repercussions on arterial blood pressure, heart rate and sympathetic tone but decreased cardiac baroreflex gain. Has a control area for these functional modifications on physiological parameters, we also microinjected the lentiviral vector at the Kolliker –Fuse nucleus, a pontine nucleus which controls respiration. Hence, with this exploratory work we unravelled the putative contribution of areas of the midbrain and pontine central autonomic network for the etiology of neurogenic hypertension and provide clues to possible future therapeutic interventions to control sympathoexcitation.
Sympathetic nervous system hyperactivity is a major contributor to the onset, development and maintenance of essential arterial hypertension. Taking into account data from experimental models of hypertension and from hypertensive patients, it is evident that the excessive sympathoexcitation that characterizes hypertension is deleterious leading to organ damage and increasing morbidity and mortality. Thus, is essential to identify the origin of the sympathoexcitation in order to develop new therapeutic interventions. However, until the moment, the precise mechanisms responsible for the sympathetic activation in essential hypertension remain to be elucidated, since they are complex and multifactorial. The rostral ventrolateral medulla (RVLM) is a medullar sympathoexcitatory area of the central autonomic network, which plays a crucial role in essential hypertension pathophysiology. Physiologically, RVLM has a key role in peripheral sympathetic tone generation. Its neurons monosynaptically project to the sympathetic preganglionic ones in the intermediolateral column of the spinal cord, conditioning peripheral sympathetic tone to the heart and vessels. Other areas of the central autonomic network that could also be involved in the generation of sympathetic activity are the lateral parabrachial nucleus (LPBN) and the periaqueductal gray matter (PAG). LPBN plays a critical role in relaying signals related to the regulation of fluid and electrolyte intake and cardiovascular function from the brainstem to the forebrain, in particular those regulating blood pressure in response to hemorrhages and hypovolemia. PAG columns are capable of modulating cardiac sympathetic functions through a series of indirect pathways involving sympathetic premotor neurons found in specific sites of the hypothalamus, midbrain, pons and medulla oblongata. In the present work, of exploratory nature, we sought to establish the functional consequences on sympathetic tone and arterial blood pressure of decreasing the excitability of RVLM and LPBN and PAG in normotension and hypertension, respectively. For that, blood pressure, autonomic output, circadian blood pressure, baro and chemoreceptor function were monitored and metabolic plus behavioral parameters evaluated before and after microinjection in each area of genetic information encoding hKir2.1 channels through a lentivirus. Results show that LVV-hKir2.1 microinjection into the RVLM of normotensive rats promoted a significant decrease in sympathetic tone, however it did not affect systolic, diastolic and mean blood pressure values. Additionally, no deleterious effects on cardiorespiratory reflexes, metabolic parameters and locomotor plus exploratory activity were observed. In hypertensive conditions, 60 days post lentiviral microinjection into the LPBN, sympathetic outflow decreased significantly and reflect itself on blood pressure and heart rate values as well. A tendency towards chemoreflex variation attenuation was also observed, however statistical significance was not attained. In addition, PAG silencing had no repercussions on arterial blood pressure, heart rate and sympathetic tone but decreased cardiac baroreflex gain. Has a control area for these functional modifications on physiological parameters, we also microinjected the lentiviral vector at the Kolliker –Fuse nucleus, a pontine nucleus which controls respiration. Hence, with this exploratory work we unravelled the putative contribution of areas of the midbrain and pontine central autonomic network for the etiology of neurogenic hypertension and provide clues to possible future therapeutic interventions to control sympathoexcitation.
Descrição
Tese de mestrado, Neurociências, Faculdade de Medicina, Universidade de Lisboa, 2015
Palavras-chave
Face rostroventrolateral do bulbo Núcleo parabraquial lateral Substância cinzenta periaqueductal Hipertensão Reflexo barorreceptor Quimiorreflexo Vector lentiviral Teses de mestrado - 2015