No description available.

Stress has been reported to activate the locus coeruleus (LC)-noradrenergic system. In this study, corticosterone (CORT) was orally administrated to rats for 21 days to mimic stress status. In situ hybridization measurements showed that CORT ingestion significantly increased mRNA levels of norepinephrine transporter (NET) and dopamine β-hydroxylase (DBH) in the LC region. Immunofluorescence staining and western blotting revealed that CORT treatment also increased protein levels of NET and DBH in the LC, as well as NET protein levels in the hippocampus, the frontal cortex and the amygdala. However, CORT-induced increase in DBH protein levels only appeared in the hippocampus and the amygdala. Elevated NET and DBH expression in most of these areas (except for NET protein levels in the LC) was abolished by simultaneous treatment with combination of corticosteroid receptor antagonist mifepristone and spironolactone (s.c. for 21 days). Also, treatment with mifepristone alone prevented CORT-induced increases of NET expression and DBH protein levels in the LC. In addition, behavioral tasks showed that CORT ingestion facilitated escape in avoidance trials using an elevated T-maze, but interestingly, there was no significant effect on the escape trial. Corticosteroid receptor antagonists failed to counteract this response in CORT-treated rats. In the open-field task, CORT treatment resulted in less activity in a defined central zone compared to controls and corticosteroid receptor antagonist treatment alleviated this increase. In conclusion, this study demonstrates that chronic exposure to CORT results in a phenotype that mimics stress-induced alteration of noradrenergic phenotypes, but the effects on behavior are task dependent. As the sucrose consumption test strongly suggests CORT ingestion-induced depression-like behavior, further elucidation of underlying mechanisms may improve our understanding of the correlation between stress and the development of depression.

La moxonidine, un médicament antihypertenseur sympatholytique de type imidazolinique, agit au niveau de la médulla du tronc cérébral pour diminuer la pression artérielle, suite à l’activation sélective du récepteur aux imidazolines I1 (récepteur I1, aussi nommé nischarine). Traitement avec de la moxonidine prévient le développement de l’hypertrophie du ventricule gauche chez des rats hypertendus (SHR), associé à une diminution de la synthèse et une élévation transitoire de la fragmentation d’ADN, des effets antiprolifératifs et apoptotiques. Ces effets se présentent probablement chez les fibroblastes, car l’apoptose des cardiomyocytes pourrait détériorer la fonction cardiaque. Ces effets apparaissent aussi avec des doses non hypotensives de moxonidine, suggérant l’existence d’effets cardiaques directes. Le récepteur I1 se trouvé aussi dans les tissus cardiaques; son activation ex vivo par la moxonidine stimule la libération de l’ANP, ce qui montre que les récepteurs I1 cardiaques sont fonctionnels malgré l’absence de stimulation centrale. Sur la base de ces informations, en plus du i) rôle des peptides natriurétiques comme inhibiteurs de l’apoptose cardiaque et ii) des études qui lient le récepteur I1 avec la maintenance de la matrix extracellulaire, on propose que, à part les effets sympatholytiques centrales, les récepteurs I1 cardiaques peuvent contrôler la croissance-mort cellulaire. L’activation du récepteur I1 peut retarder la progression des cardiopathies vers la défaillance cardiaque, en inhibant des signaux mal adaptatifs de prolifération et apoptose. Des études ont été effectuées pour : 1. Explorer les effets in vivo sur la structure et la fonction cardiaque suite au traitement avec moxonidine chez le SHR et le hamster cardiomyopathique. 2. Définir les voies de signalisation impliquées dans les changements secondaires au traitement avec moxonidine, spécifiquement sur les marqueurs inflammatoires et les voies de signalisation régulant la croissance et la survie cellulaire (MAPK et Akt). 3. Explorer les effets in vitro de la surexpression et l’activation du récepteur I1 sur la survie cellulaire dans des cellules HEK293. 4. Rechercher la localisation, régulation et implication dans la croissance-mort cellulaire du récepteur I1 in vitro (cardiomyocytes et fibroblastes), en réponse aux stimuli associés au remodelage cardiaque : norépinephrine, cytokines (IL-1β, TNF-α) et oxydants (H2O2). Nos études démontrent que la moxonidine, en doses hypotensives et non-hypotensives, améliore la structure et la performance cardiaque chez le SHR par des mécanismes impliquant l’inhibition des cytokines et des voies de signalisation p38 MAPK et Akt. Chez le hamster cardiomyopathique, la moxonidine améliore la fonction cardiaque, module la réponse inflammatoire/anti-inflammatoire et atténue la mort cellulaire et la fibrose cardiaque. Les cellules HEK293 surexprimant la nischarine survivent et prolifèrent plus en réponse à la moxonidine; cet effet est associé à l’inhibition des voies ERK, JNK et p38 MAPK. La surexpression de la nischarine protège aussi de la mort cellulaire induite par le TNF-α, l’IL-1β et le H2O2. En outre, le récepteur I1 s’exprime dans les cardiomyocytes et fibroblastes, son activation inhibe la mort des cardiomyocytes et la prolifération des fibroblastes induite par la norépinephrine, par des effets différentiels sur les MAPK et l’Akt. Dans des conditions inflammatoires, la moxonidine/récepteur aux imidazolines I1 protège les cardiomyocytes et facilite l’élimination des myofibroblastes par des effets contraires sur JNK, p38 MAPK et iNOS. Ces études démontrent le potentiel du récepteur I1/nischarine comme cible anti-hypertrophique et anti-fibrose à niveau cardiaque. L’identification des mécanismes cardioprotecteurs de la nischarine peut amener au développement des traitements basés sur la surexpression de la nischarine chez des patients avec hypertrophie ventriculaire. Finalement, même si l’effet antihypertenseur des agonistes du récepteur I1 centraux est salutaire, le développement de nouveaux agonistes cardiosélectifs du récepteur I1 pourrait donner des bénéfices additionnels chez des patients non hypertendus. / Moxonidine, an antihypertensive sympatholytic imidazoline compound, reduces blood pressure by selective activation of non-adrenergic imidazoline I1-receptors (also known as nischarin) in brainstem medulla. Moxonidine prevents left ventricular hypertrophy development in hypertensive rats, associated with reduced cardiac DNA synthesis and early transient increase in DNA fragmentation. It is likely that the anti-proliferative and apoptotic effects occur in fibroblasts, as cardiomyocyte apoptosis may deteriorate cardiac function. The effects also occurred to sub-hypotensive doses, suggesting a blood-pressure-independent mechanism and pointing to a local cardiac action. Imidazoline I1-receptors have been identified in cardiac tissues, and their ex vivo activation by moxonidine stimulates ANP release, demonstrating that cardiac imidazoline I1-receptors are functional without the contribution of the central nervous system. Based on the above studies and on i) the role of natriuretic peptides in inhibition of myocardial cell apoptosis and ii) studies linking imidazoline I1-receptors to the maintenance of the extracellular matrix and PC12 cell survival, we propose that apart from centrally-mediated sympatholytic function, imidazoline I1-receptors in the heart may control cell growth and death. Activation of imidazoline receptors may delay the progression of cardiac pathologies into heart failure by inhibition of maladaptive proliferative signalling and downstream apoptotic pathways. In order to test this hypothesis studies were performed to: 1. Explore the in vivo effects of moxonidine on cardiac structure and function in SHR and cardiomyopathic hamsters. 2. Define the pathways involved in the observed changes following moxonidine treatment, specifically, on inflammatory markers and pathways involved in LVH and cardiac cell survival/death (MAPK and Akt). 3. Explore in vitro the effect of imidazoline I1-receptor activation by moxonidine, on cell survival by over-expressing nischarin in HEK293 cells, to circumvent the lack of specific imidazoline I1-receptor agonists and antagonists. 4. Investigate in vitro, imidazoline I1-receptor localization (cardiomyocytes and fibroblasts), regulation and implication in cell growth/death in response to cardiac remodelling-associated stimuli: norepinephrine, cytokines (IL-1β, TNF-α), and oxidants (H2O2). The studies reveal that hypotensive and sub-hypotensive concentrations of moxonidine improve cardiac structure and performance in SHR by mechanisms that involve inhibition of cytokines, p38MAPK, and Akt signalling pathways. In cardiomyopathic hamsters moxonidine improves cardiac performance, in association with differential inflammatory/anti-inflammatory responses that culminate in attenuated cardiomyocyte death and fibrosis and altered collagen type expression. HEK293 cells, transfected with nischarin cDNA, show increased viability/proliferation in response to moxonidine. The overall survival response is associated with moxonidine’s inhibition of ERK, JNK, and p38MAPK. Nischarin also opposes the reduced cell viability in response to oxidative stimuli (TNF-α, IL-1β and H2O2), with differential responses to moxonidine. Furthermore, the imidazoline I1-receptor is expressed in cardiac fibroblasts and myocytes and its activation inhibits norepinephrine-induced cardiomyocyte death and fibroblast proliferation, through differential effects on MAPKs and Akt. Moxonidine/imidazoline I1-receptor protects cardiomyocytes and facilitates elimination of myofibroblasts in inflammatory conditions, through opposite effects on JNK, p38MAPK and iNOS activity. These studies emphasize the potential importance of imidazoline I1-receptor/nischarin as an anti-hypertrophic and anti-fibrotic target. Identification of the cardio-protective mechanisms of cardiac nischarin could result in specifically-tailored cell/gene-driven nischarin treatments, which could be important for patients with heart disease. Also, while the antihypertensive action of centrally acting compounds is appreciated, new cardiac-selective I1-receptor agonists may confer additional benefit.

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function. The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry. As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core. A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.

La dysfonction des mécanismes de régulation vasculaire, observée dans les états de choc septique (CS), hémorragique (CH) et la cirrhose (C), remet en question l’efficacité des substances vasoactives utilisées. L’objectif de ce travail est l’évaluation hémodynamique, systémique et splanchnique de l’administration d’hydrogène sulfuré [H2S], de terlipressine [TP] et de noradrénaline [NE] au cours des complications des CS, CH et C. Suite à une ischémie/reperfusion (I/R) chez le rat, le sepsis n’a pas d’impact particulier sur le rein, lors de la phase précoce, alors que le débit rénal varie en réponse aux variations de pression artérielle, incluant le phénomène d’autorégulation. Le CS est associé très précocement à une augmentation du flux sanguin dans les capillaires péritubulaires et à une dysfonction rénale limitée par la perfusion de NE. Au cours d’un CH retransfusé et réanimé par un remplissage vasculaire, l’inhibition endogène de H2S aggrave la dysfonction rénale suite à une diminution des vitesses microcirculatoires péritubulaires et favorise un syndrome de fuite capillaire. A l’inverse, l’administration exogène de H2S pourrait provoquer un rétrocontrôle négatif sur l’activité de l’enzyme principale de production de H2S endogène, la CSE. Lors d’une hypertension portale par C chez le rat, la NE augmente la pression porte à faibles doses et augmente la contraction maximale des veines portes in vitro par rapport à la vasopressine, ce qui augmente le risque hémorragique. Au contraire, la TP diminue le débit mésentérique et la pression porte, ce qui favorise la réponse hémodynamique de réduction du risque d’hémorragie digestive. / The impairment of vascular regulatory mechanisms observed in cirrhosis and shock situations, reduces the effectiveness of vasoactive substances used in treatments. The aim of this study is the hemodynamic, systemic and splanchnic assessments of vasoactive molecules proposed for the treatment of septic shock, hemorrhagic shock and cirrhosis complications (hydrogen sulfide [H2S], terlipressin [TP] and norepinephrine [NE]). In a model of ischemia/reperfusion (I/R), sepsis has no particular impact on the kidney since renal blood flow varies in response to mean arterial blood pressure variations, including an auto-regulation phenomenon. Sepsis is very rapidly associated with hypervelocity of blood flow in peritubular capillaries and renal dysfunction, both of wich are reserved by NE infusion. In hemorrhagic shock model controlled and resuscitated by Gelofusin® perfusion, we demonstrated that inhibition of endogenous H2S worsening renal dysfunction due to decreased renal peritubular microcirculatory velocities and promotes capillary leak syndrome. While the exogenous administration of H2S, could cause a negative feedback on the activity of the principal enzyme of endogenous H2S production, the CSE. During portal hypertension by cirrhosis in rats, NE increases the portal venous pressure, at low doses, and is more efficient than vasopressin on the portal veins of cirrhotic rats in vitro. However TP significantly reduces the mesenteric artery blood flow and the portal vein pressure. Taken together, TP could reduce the variceal bleeding risk associated with cirrhosis in comparison to NE.

O transplante cardíaco permanece sendo o procedimento de escolha para a insuficiência cardíaca refratária, apresentando resultados favoráveis em termos da sintomatologia, qualidade de vida e sobrevida desses pacientes. A hipertensão arterial sistêmica aparece como a comorbidade de maior incidência neste grupo de pacientes, chegando a 95% após cinco anos. O efeito do exercício físico sobre a dinâmica do comportamento tensional na monitorização da pressão arterial ambulatorial durante 24 horas (MAPA-24h) e da rigidez arterial não tem sido estudado neste grupo de pacientes. Nós avaliamos os efeitos da atividade física aeróbia sobre a dinâmica do comportamento tensional na MAPA-24h, rigidez arterial e as variáveis cardiovasculares em indivíduos após um ano de transplante cardíaco. Trinta e nove pacientes de ambos os sexos, randomizados para grupo treino (GT) (n = 29; 45 ± 13 anos) ou grupo controle (GC) (n = 9; 51 ± 11 anos) realizaram, antes e após o período de 12 semanas de seguimento, exames de MAPA-24h, velocidade de onda de pulso carótido-femoral (VOP) e teste de esforço cardiopulmonar, com coletas de amostras sangüíneas para dosagem de norepinefrina (Nor) (repouso e pico). Treinamento físico aeróbio foi realizado três vezes por semana, sendo duas supervisionadas e uma não supervisionada, durante 40 minutos inicialmente com a frequência cardíaca monitorada em 80% do ponto de compensação respiratória. O GT apresentou redução significativa da pressão arterial sistólica nos períodos da média das 24 horas (de 120 ± 11 para 116 ± 14mmHg, p<0,05) e vigília (de 123 ± 11 para 118 ± 13mmHg, p<0,05). A pressão arterial diastólica apresentou redução significativa para os três períodos sendo na média das 24 horas (de 81 ± 9 para 74 ± 9mmHg, p< 0,001), vigília (de 83 ± 9 para 75 ± 10mmHg, p<0,001) e noturno ( de 77 ± 10 para 71 ± 10mmHg, p<0,001). A VOP não apresentou redução significativa após o período de seguimento para ambos os grupos; GT (de 10,0 ± 1,9 para 9,7 ±1,9m/s, p = ns) e GC (de 10,3 ± 2,2 para 10,4 ± 2,8m/s, p = ns), porém os níveis da Nor tiveram aumento significativo no pico do exercício no grupo GT (de 2386 ± 1274 para 3292 ± 1410 pg/ml p<0,01) e também em relação ao grupo GC pós seguimento (3292 ± 1419 versus 2178 ± 659 pg/ml, p<0,05). O treinamento físico aeróbio reduziu a pressão arterial sistólica/diastólica em 4,7/7,5 mmHg durante a vigília e em 3,5/5,8 mmHg durante o sono após TX, além de melhorar o condicionamento cardiorrespiratório com aumento do VO2pico, FCmáx e do tempo de exercício. / Cardiac transplantation remains the procedure of choice for refractory heart failure, with favorable results in terms of symptoms, quality of life and patient survival. Hypertension appears as a higher incidence of comorbidity in this group of patients, reaching 95% after five years. However, the effect of exercise training in the behavior of 24-hour ambulatory blood pressure monitoring (ABPM) and arterial stiffness has not been studied in this group of patients. We assessment the effects of aerobic physical activity in the behavior of ABPM, arterial stiffness and cardiovascular variables in patients being heart transplanted for a year or more. Thirty-nine patients of both genders were evaluated, then randomized to either training group (TG) (n = 29, 45 ± 13 years) or control group (CG) (n = 9, 51 ± 11 years) and reevaluated after 12 weeks of follow-up. Pre and post evaluations combined examinations of ABPM, carotidfemoral pulse wave velocity (PWV) and graded exercise test, with collections of blood samples for measurement of norepinephrine (Nor) (rest and peak). Aerobic exercise was performed in the TG three times-a-week, two supervised and one unsupervised for 40 minutes initially at an intensity of 80% of heart rate achieved at the respiratory compensation point. The TG showed a significant reduction in systolic blood pressure during average of 24 hours (from 120 ± 11 to 116 ± 14mmHg, p < 0.05) and diurnal cycle (from 123 ± 11 to 118 ± 13mmHg, p<0.05). Diastolic blood pressure decreased significantly for the three periods, the average of 24 hours (from 81 ± 9 to 74 ± 9mmHg, p<0.001), diurnal cycle (from 83 ± 9 to 75 ± 10mmHg, p < 0.001) and nighttime (from 77 ± 10 to 71 ± 10mmHg, p < 0.001). The PWV showed no significant reduction after the followup period for both groups; TG ( from 10.0 ± 1.9 to 9.7 ± 1.9m/s, p = ns) and CG (from10.3 ± 2.2 to 10.4 ± 2.8m/s, p = ns) and the levels of the Nor had a significantly higher peak exercise in TG (from 2386 ± 1274 to 3292 ± 1410 pg/ml p <0.01) and also in relation to the control group after follow-up (3292 ± 1419 versus 2178 ± 659 pg / ml, p <0.05). The exercise training reduced both systolic and diastolic blood pressure in 4.7 and in 7.5 mmHg during daytime, respectively. Reduction also happened during nighttime in 3.5 and in 5.8 mmHg for these variables, respectively. Exercise training improved VO2peak, HRmax and time of exercise (cardiorespiratory fitness) after follow-up, as well.

Introdução: É provável que o tratamento precoce da sepse grave e do choque séptico possa melhorar o desfecho dos pacientes. Objetivo: O objetivo deste estudo foi avaliar como o atraso no início da ressuscitação da sepse influencia a gravidade da doença, a intensidade das medidas de ressuscitação necessárias para atingir estabilidade hemodinâmica, o desenvolvimento da disfunção orgânica e a função mitocondrial. Métodos: Estudo experimental, prospectivo, randomizado e controlado, realizado em um laboratório experimental de um hospital universitário. Trinta e dois porcos submetidos à anestesia geral e ventilados mecanicamente foram randomizados (8 animais por grupo) em um grupo controle sadio ou para um de três grupos em que induziu-se peritonite fecal (instilação peritoneal de 2,0 g/kg de fezes autólogas) e, após 6 (deltaT-6h), 12 (deltaT-12h) ou 24 (deltaT-24h) horas, iniciou-se um período de 48 horas de ressuscitação protocolada. Resultados: O retardo no início da ressuscitação da sepse foi associada a sinais progressivos de hipovolemia e ao aumento dos níveis plasmáticos de interleucina-6 e do fator de necrose tumoral alfa. O atraso no início do tratamento da sepse resultou em balanço hídrico progressivamente positivo (2,1 ± 0,5 mL/kg/h, 2,8 ± 0,7 mL/kg/h e 3,2 ± 1,5 mL/kg/h, respectivamente, para os grupos deltaT-6h, deltaT-12h, e deltaT-24h, p < 0,01), maior necessidade de administração de noradrenalina durante as 48 horas de ressuscitação (0,02 ± 0,04 mcg/kg/min, 0,06 ± 0,09 mcg/kg/min e 0,13 ± 0,15 mcg/kg/min, p=0,059), redução da capacidade máxima de respiração mitocondrial cerebral dependente do Complexo II (p=0,048) e tendência a aumento da mortalidade (p=0,08). Houve redução do trifosfato de adenosina (ATP) na musculatura esquelética em todos os grupos estudados (p < 0,01), com os valores mais baixos nos grupos deltaT-12h e deltaT-24h. Conclusões: O aumento do tempo entre o início da sepse e o início das manobras de ressuscitação resultou no aumento da gravidade da doença, na maior intensidade das manobras de ressuscitação e na disfunção mitocondrial cerebral associada à sepse. Nossos resultados suportam o conceito da existência de uma janela crítica de oportunidade para ressuscitação da sepse / Introduction: Early treatment in sepsis may improve outcome. Objective: The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. Methods: Prospective, randomized, controlled experimental study performed at an experimental laboratory in a university hospital. Thirty-two anesthetized and mechanically ventilated pig were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48 hour period of protocolized resuscitation started 6 (deltaT-6 hrs), 12 (deltaT-12 hrs), or 24 (deltaT-24 hrs) hours later. Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-alfa prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 ± 0.5 mL/kg/hr, 2.8 ± 0.7 mL/kg/ hr, and 3.2 ± 1.5 mL/kg/hr, respectively, for groups deltaT-6 h rs, delta T-12 hrs, and ?T-24 hrs; p < 0.01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 ± 0.04 mcg/kg/min, 0.06 ± 0.09 mcg /kg/min, and 0.13 ± 0.15 mcg/kg/min; p=0.059), decreased maximal brain mitochondrial Complex II respiration (p=0.048), and tended to increase mortality (p=0.08). Muscle tissue adenosine triphosphate decreased in all groups (p < 0.01), with lowest values at the end in groups deltaT-12 hrs and deltaT-24 hrs. Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation

INTRODUÇÃO: Informações da literatura associam a obesidade a maior atividade simpática. A gastroplastia com derivação gastrojejunal em Y de Roux, que leva a redução rápida e intensa do peso, pode influenciar o padrão autonômico cardiovascular. O objetivo deste estudo é avaliar os efeitos dessa cirurgia sobre a modulação autonômica do coração, tolerância ortostática e excreção urinária de noradrenalina. METODOS: Trata-se de um estudo observacional longitudinal, realizado na cidade de Maringá - PR, com 71 pacientes, incluídos no período de julho de 2004 a dezembro de 2005, avaliados antes e seis meses após a cirurgia. Foram estudados 42 mulheres e 29 homens, com idade variando de 18 a 66 anos (mediana de 36 anos) e índice de massa corpórea (IMC) variando de 37,1 a 56,2 kg/m2 (mediana de 41,9 kg/m2). Do total, 28 eram hipertensos. Não foram incluídos pacientes com diagnóstico de diabetes melito. Análise da variabilidade da freqüência cardíaca no domínio do tempo através de gravações de Holter 24 horas, teste de inclinação ortostática e dosagem de noradrenalina em urina de 24 horas foram realizadas nas duas fases do estudo. Também foram avaliados glicemia e insulina de jejum, perfil lipídico, proteína C-reativa de alta sensibilidade, fibrinogênio e qualidade de vida através do questionário SF-36. RESULTADOS: A redução média do peso, seis meses após a cirurgia, foi de 25,46% e da circunferência abdominal, de 20,4%. A freqüência sinusal se reduziu significativamente, expressa pelo aumento do intervalo NN médio (p<0,001). Os índices da variabilidade da freqüência cardíaca SDNN, SDANN, SDNN index, pNN50 e rMSSD apresentaram aumento significativo (p<0,001, p<0,001, p=0,002, p=0,001 e p=0,002, respectivamente). Os homens apresentaram maior elevação do SDNN e SDANN do que as mulheres (p=0,006 e p=0,007, respectivamente). A idade foi fator significativo para a evolução do SDNN index (p=0,015) e rMSSD (p=0,002), reduzindo-se o aumento com o avanço da idade. A redução da circunferência abdominal apresentou melhor correlação com o aumento da variabilidade da freqüência cardíaca que as reduções do peso e IMC. Nenhum paciente apresentou sintoma novo de intolerância ortostática após a cirurgia. A resposta vasovagal ao teste de inclinação não apresentou diferença significativa entre as duas fases do estudo. A resposta disautonômica foi encontrada em apenas dois casos, após a cirurgia, fato que não permitiu a avaliação deste tipo de resposta. Não houve nenhum caso de hipotensão ortostática sintomática. Houve redução do número de casos de hipotensão ortostática assintomática, com razão de chance para a ocorrência após a cirurgia, em relação ao pré-operatório, de 0,10 (p=0,030). Não houve diferença nos níveis de noradrenalina urinária entre o pré e o pós-operatório. Houve redução da glicemia e insulina de jejum, melhora do perfil lipídico e redução da proteína C-reativa de alta sensibilidade, sem modificação do fibrinogênio. A qualidade de vida apresentou melhora. CONCLUSÃO: A gastroplastia com derivação gastrojejunal modificou o padrão autonômico, aumentando a ação parassimpática sobre o nó sinusal, evidenciada pelo aumento da variabilidade da freqüência cardíaca. A mudança ocorreu sem piora clínica da tolerância ortostática e sem aumento da suscetibilidade à síncope vasovagal. / INTRODUCTION: Findings from literature associate obesity with increased sympathetic activity. Roux-en-Y gastric bypass, which promotes large and rapid weigh loss, can influence the autonomic cardiovascular activity. The aim of the present study was to evaluate the influence of surgery on the heart autonomic modulation, orthostatic tolerance and 24-hour urinary norepinephrine. METHODS: The study was a longitudinal observation carried out in Maringá - PR, embracing 71 patients, recruited from July, 2004 to December, 2005, evaluated before surgery and six months post-operatively. Forty two (42) women and 29 men were investigated, with age varying from 18 to 66 years old (median = 36 years old) and body mass index (BMI) varying from 37.1 to 56.2 kg/m2 (median = 41.9 kg/m2). Out of the total, 28 presented arterial hypertension. Patients diagnosed as diabetics were not included. The analysis of the time domain measures of heart rate variability, by using 24-hour Holter recordings, head-up tilt testing (HUT) and urinary 24-hour norepinephrine assay was performed during both phases of the study. Fasting plasma glucose and insulin, lipid profile, high sensitivity C-reactive protein, fibrinogen and quality of life were also evaluated by applying the SF-36 questionnaire, all before surgery and post-operatively. RESULTS: Six months after surgery, the average of weight loss was 25.46% and the waist circumference reduction was 20.4%. The mean of NN interval showed a significant increase (p<0,001), thus denoting a significant reduction of sinusal rate. The measures of heart rate variability, that is, SDNN, SDANN, SDNN index, pNN50 and rMSSD, showed significant increase (p<0.001, p<0.001, p=0.002 and p=0.002, respectively). Men presented greater increase of SDNN and SDANN than women (p=0,006 and p=0,007, respectively). Age was a significant factor for the evolution of SDNN index (p=0.015) and rMSSD (p=0.002) with a lower increase according to the aging process. The waist circumference reduction presented better correlation with heart rate variability increase than weight loss and BMI reduction. After surgery, no patient showed new symptom of orthostatic intolerance. The vasovagal response to HUT did not present a significant difference between both phases of the study. Dysautonomic response occurred just in two cases, after surgery, not allowing the evaluation of that kind of response. There was no case of symptomatic orthostatic hypotension. There was a significant reduction of asymptomatic orthostatic hypotension cases, with odds ratio of 0.10 (p=0.030) after surgery, in relation to the pre-operative phase. There was not a difference of urinary 24-hour norepinephrine in the period investigated. Fasting plasma glucose and insulin reduced while lipid profile improved and high sensitivity C-reactive protein reduced, without changing the fibrinogen. Quality of life improved. CONCLUSION: Gastric bypass changed the autonomic modulation, increasing the parasympathetic activity on sinus node, which was denoted by an increase in the heart rate variability. The change occurred without clinical worse in orthostatic tolerance and without increase in the susceptibility to vasovagal syncope.

Hintergrund. Sibutramin ist ein Medikament, das häufig zur Gewichtsreduktion eingesetzt wird. Es hemmt die Wiederaufnahme von Noradrenalin und Serotonin. Noradrenalin-Wiederaufnahme-Hemmung könnte zu arterieller Hypertonie führen. Methoden. In einer doppelt-blinden, randomisierten Cross-Over Studie untersuchten wir 11 junge, gesunde Probanden (7 Männer, 4 Frauen, Alter 27±2 Jahre, BMI 23.1±0.7Kg/m2). Sie nahmen 26 Stunden (h) und 14h vor Studienbeginn 10mg Sibutramin ein, und 2h vor Untersuchungsbeginn 20mg. Die Wirkung verglichen wir mit Placebo und der Kombination von Sibutramin und 200mg des Beta1-Adrenorezeptor-Blockers Metoprolol. Autonome Reflextests, eine graduelle Kipptischuntersuchung, Plasmakatecholamin-Bestimmungen und eine indirekt kalorimetrische Messung wurden durchgeführt. Herzfrequenz- und Blutdruckbestimmungen erfolgten kontinuierlich und nichtinvasiv. Wir zeichneten das Schlagvolumen, das Herzzeitvolumen und den peripheren Widerstand impedanzkardiografisch auf. Ergebnisse. Sibutramin verursachte einen leichten Anstieg der Herzfrequenz in Ruhe (p / Background. Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesitytreatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension andpromote cardiovascular disease. Methods. In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m2), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Results. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine (P

Après un traumatisme de la moelle épinière (TM), l’ischémieest un facteur d’aggravation des lésions. Cette ischémie peut être aggravée par l’augmentation depression du liquide cérébro-spinal (LCS) par le biais d’un effet tamponnade. Or chez l’homme,après un TM avec préservation de l’intégrité de la dure-mère, la pression de LCS augmentesignificativement. On suppose donc que le maintien d’une pression de LCS à des valeursphysiologique pourrait être une méthode de limitation de l’ischémie post-traumatique et doncd’amélioration du pronostic fonctionnel. Afin de pouvoir réaliser une étude expérimentale de cesphénomènes, nous avons consacré la première partie expérimentale de cette thèse à la mise au pointd’un modèle de TM à dure-mère intacte chez le rat permettant la mesure simultanée de la pressionde LCS et de la perfusion médullaire. Nous avons confirmé expérimentalement que la pression deLCS augmente après TM. Dans la seconde partie expérimentale, nous avons mis au point unetechnique expérimentale de quantification spatiale et temporelle de la perfusion médullaire grâce àl’échographie de contraste. Cette technique permettait aussi un suivi en temps réel de l’évolution dusaignement intra-parenchymateux induit par le TM. Dans la troisième partie expérimentale, nousavons utilisé notre modèle couplé avec l’échographie de contraste et le laser Doppler pour évaluerles effets de la noradrénaline injectée à la phase aigüe d’un TM sur la perfusion médullaire et lesaignement intra-parenchymateux. Nous avons montré que la noradrénaline augmentait trèslégèrement le flux sanguin superficiel mais pas le flux sanguin profond et qu’elle augmentait lataille du saignement. / After spinal cord injury (SCI), ischaemia aggravates lesions.Increase in cerebrospinal fluid (CSF) pressure can worsens ischaemia through a tamponnade effect.In humans, it has been shown that after SCI with intact dura mater, CSF pressure significantlyincreases. Therefore, preserving CSF pressure within a physiological range may limit post-traumaischaemia and improve neurological outcome. In order to experimentally study these phenomenon,we have dedicated the first part of that work to create a model of SCI in rats preserving dura’sintegrity and allowing simultaneous measurement of spinal cord blood flow (SCBF) and CSFpressure. We have confirmed that CSF pressure increases after SCI with intact dura. In the secondexperimental part, we have developed a technique allowing to perform spatial and temporalmeasurement of SCBF thanks to contrast enhanced ultrasonography (CEU). Moreover, thistechnique allows real-time measurement of the size of the parenchymal hemorrhage. In the thirdexperimental part, we have used our experimental model in association with CEU and LaserDoppler to assess the effects of early injection of norepinephrine on SCBF and parenchymalhemorrhage. We found that norepinephrine induces a slight increase in superficial SCBF while itdoesn’t modify deep SCBF and significantly increases the size of parenchymal hemorrhage.