Master of Science / Department of Anatomy and Physiology / Michael J. Kenney / Hyperthermia is an environmental stressor that produces marked increases in visceral sympathetic nerve discharge (SND) in young rats. The brainstem in rats contains the essential neural circuitry for mediating visceral sympathetic activation; however, specific brainstem sites involved remain virtually unknown. The rostral ventral lateral medulla (RVLM) is a key central nervous system region involved in the maintenance of basal SND and in mediating sympathetic nerve responses evoked from supraspinal sites. In the present study we tested the hypothesis that inhibition of RVLM synaptic activation at peak hyperthermia (internal body temperature, Tc, increased to 41.5°C) would affect heating-induced visceral sympathetic activation. Experiments were completed in chloralose-urethane anesthetized, baroreceptor-intact and sinoaortic-denervated, 3-6 month-old Sprague-Dawley rats. Bilateral inhibition of RVLM synaptic activation produced by muscimol microinjections (400 and 800 pmol) at 41.5°C resulted in immediate and significant reductions in peak heating-induced renal and splenic sympathoexcitation. Interruption of RVLM synaptic activation and axonal transmission by lidocaine microinjections (40 nmol) at 41.5°C produced significant reductions in hyperthermia-induced sympathetic activation to similar levels produced by RVLM muscimol microinjections. The total amount of SND inhibited by RVLM muscimol and lidocaine microinjections was significantly more during hyperthermia (41.5°C) than normothermia (38°C). These findings demonstrate that maintenance of sympathetic activation at peak hyperthermia is dependent on the integrity of RVLM neural circuits.

Motivation: Abdominal obesity (hereafter referred to as "obesity") is becoming the biggest "global epidemic" of our modern times. It is associated with a range of diseases, including cardiovascular diseases and hypertension. Recent research showed that an increase in sympathetic activity is of central importance in the pathogenesis of obesity-related diseases. Increased leptin levels and impaired baroreflex sensitivity have both been independently associated with abdominal obesity and increased sympathetic activity. A perception of poorer health may also contribute to the physiological characteristics of obesity-related diseases. A lack of data regarding sympathetic activity, leptin levels, baroreflex sensitivity and perception of health in Africans, serves as a motivation for conducting this study. Objective: To investigate the contributions of leptin levels, baroreflex sensitivity and perception of health data to increased sympathetic activity in lean and obese African women from South Africa. Methodology: The manuscript presented in Chapter 2 made use of the data obtained in the POWIRS (Profiles of Obese Women with the Insulin Resistance Syndrome) study. A group of 102 urbanized African women, living in the North-West Province of South Africa, was recruited according to body mass indexes. Only 85 subjects were included for analysis due to incomplete datasets. For this study, subjects were divided into lean and obese groups according to their waist circumferences. Anthropometric measurements were done according to standardized methods. Resting cardiovascular measurements were obtained from Finometer observations. Resting, fasting levels of leptin were calculated after radioimmunoassay analyses. Subjective perception of health was determined by means of the 28-item General Health Questionnaire. Comparisons between the groups were done using analysis of covariance (ANCOVA) whilst adjusting for cardiovascular risk factors (age. smoking, alcohol consumption and physical activity). Correlation coefficients were determined to indicate any associations between leptin, baroreflex sensitivity and perception of health with sympathetic activity (represented by heart rate) and other cardiovascular variables. The study was approved by the Ethics committee of the North-West University and all the subjects gave informed consent in writing. The reader is referred to the Methods section in Chapter 2 for a more detailed description of the subjects, study design and analytical procedures used in this dissertation. Results and conclusion: Results from this study indicate that obese African women, compared to lean African women, were older, reported higher physical activity, and exhibited higher diastolic and mean blood pressure, heart rate, cardiac output, arterial compliance, leptin and hypertension prevalence rate values. In lean African women social dysfunction was positively associated with diastolic and mean blood pressure and arterial resistance, and negatively with arterial compliance. In obese African women baroreflex sensitivity was negatively associated with diastolic blood pressure, which could be an indication of impaired baroreflex sensitivity. In this obese group a perception of social dysfunction was associated with decreased heart rate. Although leptin and heart rate were significantly higher in the obese Africans, no significant correlations existed between these variables to reflect leptin's enhancement of sympathetic activity. However, leptin correlated weakly but positively with cardiac output (p = 0.054, r = 0.32). In conclusion, baroreflex sensitivity (although similar between groups) and leptin seem to contribute to blood pressure and thus hypertension in obese African women, possibly through increased sympathetic activity and volume loading. A perception of poorer health, especially a perception of social dysfunction, could possibly contribute to this image. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.

More than 30% of the population suffers from obesity, which increases the risk of death and secondary health problems. Body fat [white adipose tissue (WAT) and brown adipose tissue (BAT)] are innervated and regulated by the sympathetic nervous system (SNS). WAT stores energy, while BAT generates heat for thermoregulation. Fat also has sensory innervations, but the roles of sensory nerves are still being elucidated. Hence, understanding the neuroanatomy of the SNS innervations of fat and the neural regulation of fat metabolism will be valuable for advancing obesity treatment. Using trans-synaptic tract tracers with unique fluorescent proteins, we defined and compared the SNS innervations of visceral fat [mesenteric WAT (MWAT)] and subcutaneous fat [inguinal WAT (IWAT)] and of IWAT and interscapular BAT (IBAT) in Siberian hamsters. MWAT and IWAT have moderately shared SNS innervations within the hindbrain, but separate SNS innervations in rostral regions. In contrast, IWAT and IBAT have relatively separate SNS circuitries throughout the brain yet some overlap in SNS nuclei known to regulate thermogenesis. We tested for the presence of functional coordination between IWAT and IBAT defined by overlap in IWAT SNS and IBAT SNS innervations. When IBAT function was impaired by SNS denervation, IWAT SNS drive, thermogenic activity, and beige adipocyte recruitment increased in cold exposed hamsters likely through coordination with IWAT SNS pathways. Conversely, we found that only SNS drive to IWAT increased during acute food deprivation suggesting that populations of SNS neurons singly innervating each fat depot may contribute to differential SNS drive to fat. Lastly, we demonstrated that IWAT sensory nerves mediate the functional coordination between IWAT and IBAT and the regulation of SNS drive to fat. The absence of IWAT sensory feedback via sensory denervation differentially decreased SNS drive to IBAT and IWAT itself, but not to MWAT, retroperitoneal WAT, and epididymal WAT in cold exposed hamsters. Collectively, the studies in this dissertation provide neuroanatomical evidence of separate and shared SNS brain sites likely receiving sensory signaling and regulating SNS drive to fat, and direct evidence of the roles of SNS and sensory nerves innervating fat to energetic homeostasis and thermoregulation.

Os gânglios pertencentes ao Sistema Nervoso Autônomo (SNA) estão divididos em grupos de acordo com sua localização. Os gânglios celíaco e mesentérico superior são gânglios simpáticos pré-vertebrais. Estes se localizam anteriormente à coluna vertebral e à aorta abdominal ao nível das vértebras T12 a L1. Conectando o Sistema Nervoso Central (SNC), por meio dos nervos esplênico maior e menor, ao Sistema Nervoso Periférico (SNP), formando um emaranhado de nervos denominado plexo nervoso. Ambos participam do controle da motilidade gastrointestinal, sendo assim, estão envolvidos na fisiopatologia dos distúrbios inerentes ao seu território de inervação. Foram dissecados e fixados a solução de formol a 4%, 33 blocos anatômicos de seres humanos contendo a parte abdominal da aorta e o pâncreas, obtidos de 15 indivíduos do gênero masculino e 18 do feminino com idades variando de 20 a 90 anos, divididos em três grupos: Grupo I (jovens - 20 a 40: 3 homens e 4 mulheres); Grupo II (adulto - 45 a 60: 8 homens e 6 mulheres) e Grupo III (idosos - 70 a 90: 4 homens e 8 mulheres), onde avaliou-se aspectos estruturais e ultraestruturais dos gânglios celíacos e mesentérico superior, quanto à sua topografia e componentes microscópicos por meio das colorações de Hematoxilina e Eosina, Tricromo de Masson, Violeta Cresil, Verhoff e Picro-Sirius, observou-se respectivamente, a identificação geral dos componentes ganglionares, fibra elástica e o componente colágeno ganglionar, assim como análises por método de Microscopia Eletrônica de Varredura (MET). Quanto ao aspecto macroscópico os gânglios celíacos foram contados em número de 58, sendo 25 espécimes (86% dos casos) apresentaram-se bilateralmente de formato retangular, 7 (12%) estavam fusionados na linha mediana, e 1 (1,7%) no antímero esquerdo, ambos de aspecto irregular. Relativamente todos pertencentes a este antímero estavam em situação inferior aos do antímero direito. Já o gânglio mesentérico superior, de formato preferencialmente estrelado, ocorreu em 10 espécimes (30%) ele estava situado anteriormente à artéria mesentérica superior, e em 17 (51%), posteriormente a ela, em 3 casos foi encontrado um entrecruzamento de fibras nervosas espessas com presença de corpos celulares espaçados, e em 3 casos (9%), o gânglio não foi encontrado, apenas um emaranhado de feixes com fibras nervosas. Referente a parte qualitativa, notou-se que à medida que o ser humano envelhece há uma diminuição das fibras colágenas do tipo III, passando a predominar fibras do tipo I nos grupos: GII e GIII e quantitativamente, foram analisados 9 gânglios sendo 3 de cada grupo: GI (20-40: 2 homens e 1 mulher); GII (45-60: 3 homens) e GIII (70-90: 3 mulheres), embora não se tenha realizado uma análise estatística a média das áreas dos nervos do GIII foi maior em relação ao GI, por outro lado as áreas dos fascículos nervosos não exibiram diferenças aparentes. A área do corpo neuronal de GI, GII e GIII houve uma progressiva diminuição desse parâmetro nos grupos GII e GIII. O material foi fornecido pelo Sistema de Verificação de Óbito da Capital SP (SVOC-SP/USP) e após a sua coleta as peças foram processadas no Laboratório de Anatomia Funcional Aplicada a Clínica e à Cirurgia (LAFACC) do Departamento de Anatomia do Instituto de Ciências Biomédicas III da Universidade de São Paulo (ICB III USP). O estudo estrutural e ultraestrutural de gânglios simpáticos em humanos abre perspectivas futuras para pesquisas correlacionadas a morfologia e sua função. Os resultados podem ter importância para a neurociência humana, dando embasamento para tratamentos de doenças relacionadas ao trato gastrointestinal (TGI), o que pressupõe grande relevância deste estudo. / The ganglia belonging to the Autonomic Nervous System (ANS) are divided into groups according to their location. The superior celiac and mesenteric ganglia are pre-vertebral sympathetic ganglia. These are located anterior to the vertebral column and to the abdominal aorta at the level of the vertebrae T12 to L1. Connecting the Central Nervous System (CNS), via the major and minor splenic nerves, to the Peripheral Nervous System (SNP), forming a tangle of nerves called the nervous plexus. Both are involved in the control of gastrointestinal motility and are therefore involved in the pathophysiology of the disorders inherent to their territory of innervation. A total of 33 human anatomical blocks containing the abdominal part of the aorta and the pancreas, obtained from 15 male and 18 female subjects with ages varying from 20 to 90 years, divided into three groups: Group I (young - 20 to 40: 3 men and 4 women); Group II (adult - 45 to 60: 8 men and 6 women) and Group III (elderly - 70 to 90: 4 men and 8 women), where structural and ultrastructural aspects of the celiac and mesenteric superior ganglia were evaluated for their topography and microscopic components through the staining of Hematoxylin and Eosin , Masson\'s trichrome, Violet Cresil, Verhoff and Picro-Sirius, the general identification of the ganglionic components, elastic fiber and the ganglionic collagen component, as well as the Scanning Electron Microscopy (MET) method were observed. As to the macroscopic aspect, the celiac ganglia were counted in 58, 25 specimens (86% of the cases) were bilaterally rectangular, 7 (12%) were fused at the median line, and 1 (1,7%) in the antimer left, both of irregular appearance. Relatively all belonging to this antimer were inferior to those of the right antimer. The superior mesenteric ganglion, with a predominantly star-shaped shape, occurred in 10 specimens (30%), located anterior to the superior mesenteric artery, and in 17 (51%), posterior to it, in 3 cases a \"cross-linking\" of and in 3 cases (9%), the ganglion was not found, only a tangle of bundles with nerve fibers. Regarding the qualitative part, it was noticed that as the human being grows older there is a decrease of type III collagen fibers, and type I fibers predominate in the groups: GII and GIII and quantitatively, 9 glands were analyzed, 3 in each group: GI (20-40: 2 men and 1 woman); GII (45-60: 3 men) and GIII (70-90: 3 women), although no statistical analysis was performed the mean of the GIII nerve areas was higher in relation to the GI; on the other hand, the areas of the nerve fascicles showed no apparent differences. The area of the neuronal body of GI, GII and GIII showed a progressive decrease of this parameter in the GII and GIII groups. The material was supplied by the São Paulo State Capital Surveillance System (SVOC-SP / USP) and after its collection the pieces were processed in the Laboratory of Functional Anatomy Applied to Clinic and Surgery (LAFACC) of the Department of Anatomy of the Institute of Biomedical Sciences III of the University of São Paulo (ICB III - USP). The structural and ultrastructural study of sympathetic ganglia in humans opens future perspectives for research correlated with morphology and its function. The results may be important for human neuroscience, giving support to treatments of diseases related to the gastrointestinal tract (GIT), which presupposes great relevance of this study.

Hypertension affects 1 in 3 adults and is the single greatest risk factor for premature death. Salt-sensitive hypertension occurs in approximately 50% of hypertensive patients and results in a 3-fold increase in the risk of adverse cardiovascular events. However, the pathophysiology of salt-sensitive hypertension remains to be fully elucidated. There has been increased interest in the interaction between the sympathetic nervous system and the kidney and how that interaction mediates sodium excretion to drive the development of salt-sensitivity. Previous studies show that sympathetic over-activity increases expression of the sodium chloride cotransporter (NCC) resulting in increased NCC-mediated sodium reabsorption, and the development of salt-sensitive hypertension. In this thesis, I show the effect of increased norepinephrine (NE) and high salt intake in salt-resistant vs. salt-sensitive rat phenotypes on blood pressure regulation, NCC activity, and the adrenoreceptor-mediated regulatory kinase network signal transduction pathway. A high salt diet 1) exacerbates NE-induced hypertension in salt-resistant Sprague-Dawley (SD) rats and 2) results in hypertension in Dahl salt-sensitive (DSS) rats. In contrast to salt-resistant phenotypes (SD & Dahl salt-resistant), dietary sodium-evoked suppression of NCC expression and activity is prevented in salt-sensitive rats (SD-NE infusion & DSS) - I show that this occurs through a failure of a high salt intake to suppress renal OxSR1, SPAK, and WNK1 (NCC regulatory proteins). I demonstrate that α1-adrenoreceptors are responsible for mediating the salt-sensitive component of hypertension and restore dietary sodium-evoked suppression of the NCC via a predominant OxSR1 pathway. Chronic β-adrenoreceptor antagonism significantly reduces blood pressure in NE-mediated hypertension. How the body senses salt remains unknown, but my data show that selective removal of the afferent renal nerves prevents dietary sodium-evoked suppression of NCC expression and activity resulting in salt-sensitive hypertension, suggesting that the afferent renal nerves play an important role as a sodium-sensing mechanism. Overall, these data demonstrate that attenuated afferent renal nerve feedback drives renal efferent nerve release of NE to prevent the downregulation of the NCC via an α1-adrenergic receptor-gated WNK1-OxSR1 signal transduction pathway to evoke the development of salt-sensitive hypertension.

A hipóxia crônica intermitente (HCI) promove hipertensão arterial e aumento da atividade simpática em ratos jovens. Nestes animais, o aumento da atividade simpática ocorre durante uma fase específica da respiração e está correlacionada com o aumento da atividade expiratória. Estas evidências mostram que, após a HCI, os ratos jovens desenvolvem alterações no acoplamento simpático-respiratório, um mecanismo que pode contribuir, pelo menos em parte, para o desenvolvimento da hipertensão observada nestes animais. Em diversos modelos experimentais de hipertensão, os níveis de pressão arterial são menores nas fêmeas do que nos machos, portanto elas são resistentes ao desenvolvimento da hipertensão. Levando em conta essas informações, a hipótese do presente projeto foi a seguinte: fêmeas submetidas à HCI seriam resistentes ao desenvolvimento da hipertensão arterial. Para tanto, ratas jovens e adultas foram submetidas à HCI e seus parâmetros cardiovasculares e respiratórios foram avaliados na condição dos animais acordados e com livre movimentação. Além disso, as alterações na atividade simpática e respiratória também foram avaliadas na preparação coração tronco-cerebral isolados. Os resultados mostram que as fêmeas desenvolvem hipertensão semelhante aos machos submetidos ao mesmo protocolo, contudo as alterações no acoplamento entre a atividade simpática e respiratória são diferentes entre os sexos. Estes dados sugerem que embora os machos e fêmeas desenvolvam um nível similar de hipertensão após a HCI, os mecanismos envolvidos na geração da atividade simpática podem ser diferentes. / Chronic intermittent hypoxia (CIH) produces hypertension and sympathetic overactivity in juvenile male rats. The increase in sympathetic activity occurs during the expiratory phase of respiration, which is correlated with an augmented expiratory activity. This information indicates that after CIH, juvenile rats develop changes in the respiratory sympathetic-coupling, which could explain, at least in part, the hypertension observed in these animals. Female rats are known to be more resistant to the development of hypertension in several experimental models of this pathology. Take in consideration these facts, we hypothesized that female rats exposed to CIH were resistant to the development of hypertension. To test this hypothesis, we studied the cardiovascular and respiratory changes in female rats after the CIH in awake freely moving condition. In another group of animals, we studied the sympathetic and respiratory activity in female rats after the CIH, using for this, the working heartbrainstem preparation. The results show that juvenile female rats develop hypertension similarly to that observed in juvenile male rats submitted to the same protocol. However, juvenile female rats presented changes in the respiratory-sympathetic coupling different from that observed in juvenile male rats. Together, these results suggest that even if the level of hypertension after CIH is similar between males and females, the mechanisms underlying the generation of sympathetic overactivity are different.

Introdução: Avaliar a relação do custo e da efetividade da radiofrequência (RF) em relação ao bloqueio seqüencial na Síndrome Dolorosa Complexa Regional-tipo I (SDCR-I). Métodos: 15 pacientes com dor somática e autonômica cervical foram submetidos a bloqueio torácico simpático, combinado com bloqueio facetário cervical bilateral por 4 semanas. Esta seqüência foi repetida quando a dor atingiu VAS 4 cm, e este período foi definido como tempo de analgesia. Posteriormente, os mesmos pacientes foram submetidos a um bloqueio teste seguido de modulação de RF do gânglio simpático torácico e ablação de ramos facetários medianos cervicais. Os pacientes atuaram como seu próprio controle relacionado à analgesia, atividades rotineiras e padrão de sono. Resultados: 13 pacientes completaram o estudo. O tempo de analgesia após a sequência de 4 bloqueios foi de 4 ± 1 mês e o custo anual R$ 15.000,00. O tempo de analgesia após RF foi de 13 ± 2 meses (p <0,001) e os custos foram reduzidos em 26% no primeiro ano e 34% -38% nos anos seguintes, com extrapolação. A qualidade de vida melhorou para ambos os tratamentos (p> 0,05). Não houve efeitos adversos. Discussão: A RF resultou em analgesia de 13 meses comparada a 4 meses após os bloqueios clássicos e melhora na capacidade física e no padrão de sono. Além disso, a RF foi rentável e reduziu as taxas em 23% durante a avaliação do primeiro ano, seguida de uma redução de custos de 32% a 36% nos anos seguintes, com extrapolação. / Objectives: To evaluate cost-effectiveness of radiofrequency (RF) compared to sequential block in Complex Regional Pain Syndrome-I (CRPS). Methods: 15 patients with cervical somathic and autonomic pain were submitted to a 4- weekly sympathetic thoracic block, combined to bilateral cervical facetary block. This sequence was repeated when pain reached VAS 4-cm, and this period was defined as time of analgesia. Thereafter, same patients were submitted to a test block followed by RF modulation of thoracic sympathetic ganglion and ablation of facetary cervical median branches. Patients acted as their own control related to analgesia, routine activities, sleep pattern and costs. Results: 13 patients completed the study. The analgesia time after the 4-block sequence was 4±1 months and the annual costs USA$5000. Analgesia time after RF was 13±2 months (p<0.001) and costs were reduced by 26% in the first year and 34%-38% in the following years extrapolation. Quality of life improved for both treatments (p> 0.05). There were no adverse effects. Discussion: RF resulted in 13-month compared to 4-month analgesia after the classical 4- weekly blocks, and improved physical capacity and sleep pattern. Besides that, RF was costeffective, and reduced rates by 23% during the first-year evaluation, followed by 32%-36% cost reduction in following years, by extrapolation.

Dados recentes mostram que o remodelamento ósseo está sujeito ao controle do SNC, com o SNS. Para tanto, avaliamos o (CLO) e a morfologia da (LE) do fêmur de camundongos de 21 dias de idade selvagens (WT) e Knockout (KO) para a2CAR, tratados, para mimetizar o hipertiroidismo (Hiper) ou tratados para indução do hipotiroidismo (Hipo). Os animais KO eutiroideos (Eut) apresentaram uma desorganização da ZP e aumento do número de CHM da LE. Nos animais WT, o Hipo promoveu redução do CLO, desorganização da ZP e diminuição do número de CHM. O Hipo promoveu efeitos contrários na LE dos animais KO em relação aos animais WT, sendo capaz de reverter, parcialmente, a desorganização da ZP dos camundongos KO Eut, além de resultar em maior número de CHM, em relação aos animais WT Hipo. Já o Hiper levou a aumento do número de CH nos animais WT e redução nos animais KO. Os animais KO Hiper apresentaram diminuição de CHM, quando comparados aos animais WT Hiper. Esses achados reforçam as hipóteses de que o SNS regula o CLO via a2CAR e que o HT e SNS interagem para regular o CLO. / Recent data show that bone remodeling is under control of the CNS, with the SNS. Thus, we evaluated the bone growth and the morphology of the femoral EGP of 21- day old female wild-type (WT) and a2CAR-/- mice (KO), treated to mimic hyperthyroidism (Hyper), or treated for hypothyroidism (Hypo). The euthyroid KO mice had a disorganization of PZ and increase in the number of MHC of the EGP. In WT animals, Hypo promoted a significant reduction in the BLG, PZ disorganization and a decreased number of MHC. Hypo promoted opposite effects in EGP of KO compared to WT mice. Hypo was able to partially revert the PZ disorganization observed in euthyroid KO, and resulted in a greater number of MHC compared to WT Hypo. On the other hand, Hyper caused an increase in the number of HC in WT mice and a reduction in KO mice. Furthermore, Hyper KO animals showed a reduction in the number of MHC, when compared to the Hyper WT mice. These findings support the hypothesis that the SNS regulates the BLG via a2CAR and that the interaction between SNS and TH can regulate the BLG.

Embora seja bem estabelecido que a exposição a baixas temperaturas resulte em ativação simpática e hiperglicemia, os mecanismos moleculares envolvidos na regulação neural da produção hepática de glicose ainda não são bem conhecidos. Portanto, o objetivo do presente estudo foi investigar o papel da inervação simpática na regulação de genes e enzimas chaves da neoglicogênese hepática, em roedores expostos agudamente ao frio. Para isso, foram utilizados dois modelos experimentais de desnervação simpática: a simpatectomia química em camundongos induzida pelo tratamento com 6-hidroxidopamina (100 mg.kg-1.dia-1; 1º, 2º e 7º dia de vida pós-natal; i.p). e a desnervação local dos nervos hepáticos por fenol (95%) em ratos. A exposição de camundongos ao frio (4ºC), durante 1, 3 e/ou 6h, induziu hiperglicemia, hipotermia, depleção do conteúdo de glicogênio hepático e ativação da neoglicogênese, estimada pela elevada expressão gênica e atividade das enzimas glicose-6-fosfatase e fosfoenolpiruvato carboxiquinase (PEPCK). Em paralelo, verificou-se que a exposição ao frio induziu um drástico aumento na expressão do RNAm do Nr4a1 e do PGC1-?, dois genes-alvos de CREB que participam do complexo de ativação transcricional dos genes que codificam as enzimas neoglicogênicas estudadas. A simpatectomia não afetou a depleção dos estoques de glicogênio hepático induzida pelo frio, mas reduziu o aumento do conteúdo hepático de noradrenalina e AMPc e acentuou a hipotermia, bem como preveniu a hiperglicemia, sendo este efeito associado ao bloqueio da expressão gênica e atividade da glicose-6-fosfatase e da PEPCK e do RNAm do Nr4a1, em todos os tempos estudados. Resultados bastante semelhantes foram observados em ratos submetidos à lesão dos nervos hepáticos com fenol e expostos ao frio durante 24h. Tanto a adrenalectomia como a adrenodemedulação (remoção da medula da adrenal) não alteraram o efeito estimulatório do frio na atividade e expressão gênica das enzimas neoglicogênicas de camundongos. Porém, em ratos expostos ao frio, a adrenodemedulação bloqueou aIII hiperglicemia e reduziu parcialmente a hiperexpressão dos genes da glicose-6-fosfatase e PEPCK. Estes resultados mostram a importância fisiológica da inervação simpática do fígado de roedores na estimulação do programa gênico da neoglicogênese, durante o estresse térmico agudo. / Although it is well established that exposure to low temperatures leads to sympathetic activation and hyperglycemia, the molecular mechanisms related to the neural regulation of hepatic glucose production remain elusive. Therefore, the goal of the present study was to investigate the role of sympathetic innervation in the regulation of genes and key enzymes of hepatic gluconeogenesis in liver of rodents exposed to acute cold. For this, two experimental models of sympathetic denervation were used: the chemical sympathectomy in mice induced by 6-hydroxydopamine treatment (100 mg.kg-1.day-1; 1º, 2º and 7ºdays of neonatal life; i.p.) and local denervation of hepatic nerves by phenol (95%) in rats. Exposure of mice to cold (4° C) for 1, 3 and / or 6 h induced hyperglycemia, hypothermia, depletion of hepatic glycogen content and activation of gluconeogenesis, estimated by high gene expression and activity of the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK). In parallel, it was found that exposure to cold induced a dramatic increase in Nr4a1 and PGC1-? mRNA expression, two CREB target genes that participate in the transcriptional activation complex of the genes encoding the gluconeogenesis enzymes studied. The sympathectomy did not affect the depletion of cold-induced hepatic glycogen stores but reduced the hepatic content of noradrenaline and cAMP and increased hypothermia, as well as prevented hyperglycemia, and this effect was associated with the blockade of gene expression and enzymatic activity of glucose-6-phosphatase and PEPCK and Nr4a1 mRNA levels, at all time intervals investigated. Similar results were observed in rats submitted to hepatic nerve damage with phenol and exposed to cold for 24h. Either adrenalectomy or adrenodemedullation (surgical removal of the adrenal medulla) did not alter the stimulatory effect of cold on the activity and gene expression of the gluconeogenesis enzymes of mice. However, in cold-exposed rats, adrenodemedullation blocked hyperglycemia and partially reduced overexpression of the glucose-6-phosphatase and PEPCK mRNA.V These results show the physiological role of the hepatic sympathetic innervation in the transcriptional program associated with gluconeogenesis, during acute thermal stress.

A privação do sono é um problema sério nos tempos atuais e pode ter graves conseqüências para a fisiologia humana. De fato, a redução no tempo de sono tem sido associada a um notável aumento na incidência de hipertensão arterial, diabetes mellitus, infarto do miocárdio, acidente vascular cerebral e estresse, porém os mecanismos envolvidos são pobremente compreendidos. Objetivos: Avaliar o impacto da privação parcial do sono na função endotelial venosa e no controle autonômico cardiovascular em homens saudáveis. Métodos: Treze voluntários do sexo masculino, saudáveis e com idade média de 31±2 anos, tiveram o sono monitorado por diário de sono e actigrafia de pulso durante 12 noites consecutivas, nas quais foram divididas em 2 dois períodos. Um período de 5 noites denominado de privação parcial do sono (dormir<5h por noite) e outro de 5 noites denominado de sono controle (dormir>7h por noite). Entre estes períodos, foi interposto por 2 noites de sono irrestrito (com pelo menos de 7 horas de sono por noite). A escolha do período inicial de sono foi randomizada. Ao término de cada período de 5 dias, foi analisada a reatividade vascular venosa (com a técnica da veia do dorso da mão, Dorsal Hand Vein), a sonolência diurna excessiva (através da Escala de Sonolência de Epworth), realizada avaliação hemodinâmica e autonômica (no momento em repouso e mediante o teste de inclinação postural tilt test), exames de sangue e dosagem de norepinefrina plasmática. A freqüência cardíaca e pressão arterial de batimento a batimento na posição supina e com a manobra de \"tilt test\" foi monitorado com intervalo (RR) e variabilidade de pressão arterial. Resultados: Os indivíduos dormiram em média 8.0 h durante o período de sono controle e 4.5 h no período de privação parcial do sono, sendo a diferença significativa entre os mesmos (p<0.01). O período privação de sono não mudou a frequência cardíaca e a pressão arterial basal significativamente, mas promoveu um aumento significante em baixas freqüências cardíacas e variabilidade da pressão arterial, como também na norepinefrina plasmática. O \"tilt test\" promoveu uma queda em PA sistólica depois da privação parcial do sono, que foi significativamente maior depois do período de sono controle (p<0.05). A privação parcial do sono causou uma redução significantiva na venodilatação endotélio-dependente e não mudou venodilatação endotélio-independente. Conclusão: Privação parcial do sono durante só 5 noites já é o suficiente para causar disfunção endotelial venosa, um aumento significantivo na atividade simpática e no prejuízo do controle da pressão arterial / Background: Sleep curtailment is a serious and common problem in western societies and can have significant consequences in the human physiology. In fact epidemiological studies showed that sleep deprivation (reduction in sleeping time) is associated with increased blood pressure, higher incidence of diabetes mellitus, myocardial heart attack, strokes in the brain, and stress, however the mechanisms are poorly understood. Objectives: Evaluate the impact of partial sleep deprivation in the venous endothelial function and the autonomic cardiovascular autonomic control in healthy men. Methods: Thirteen healthy male volunteers (average age: 31±2 years) had their sleep monitored by sleep diary and wrist actigraphy during 12 consecutive nights, these were divided into two periods. The subjects were randomized and crossed over to 5 nights of control sleep (> 7hs) and 5 nights of partial sleep deprivation (<5hs), interposed by 2 nights of unrestricted sleep (at least 7 hours sleep per night). The choice of the initial sleeping period was randomized. At the end of each period of 5 days heart rate and beat-to-beat blood pressure in the supine position and head up tilt test maneuver were monitored with off line determination of RR-interval and blood pressure variability. In addition, serum norepinephrine and venous endothelial functions were measured by dorsal hand vein technique; also we performed the evaluation of excessive day sleepiness (evaluated through the Epworth Sleepiness Scale), hemodynamic and autonomous evaluation (during sleep and through the tilt test). Results: The subjects slept 8.0 and 4.5 hs during control and partial sleep deprivation periods, respectively (p<0.01). Sleep deprivation did not change significantly the resting heart rate and blood pressure but promoted a significant increase in the low frequency bands of heart rate and blood pressure variability as well as serum norepinephrine. Tilt test promoted a significantly greater drop in systolic BP after partial sleep deprivation than after control sleep (p<0.05). Partial sleep deprivation caused a considerable reduction of acetylcholine induced venodilatation (endothelium dependent) and did not change sodium nitroprusside venodilatation (independent from the endothelium). Conclusion: Partial sleep deprivation for only 5 nights is sufficient to cause significant increase in sympathetic activity, impairment of blood pressure control and endothelial dysfunction