INTRODUÇÃO: Em pacientes com síndromes isquêmicas miocárdicas instáveis (SIMI), tanto a hiperatividade simpática quanto a resposta inflamatória exacerbada se associam a pior prognóstico. No entanto, ainda é desconhecido se existe alguma correlação entre esses dois marcadores de evolução desfavorável. OBJETIVOS: Correlacionar a atividade nervosa simpática muscular com marcadores inflamatórios nas fases precoce e tardia de pacientes portadores de SIMI. MÉTODOS: Pacientes hospitalizados com diagnóstico de SIMI e evolução favorável foram incluídos de forma prospectiva desde que apresentassem idade entre 18 e 65 anos e aterosclerose coronária comprovada por cinecoronariografia. Logo após a inclusão no estudo foram coletadas informações basais, e no quarto dia (± 1 dia) de internação os pacientes foram submetidos à avaliação da ANSM e coleta concomitante de amostra sanguínea para dosagem de proteína CReativa ultrassensível (PCR-us), interleucina-6 (IL6), e fosfolipase A2 associada à lipoproteína (Lp-PLA2). ANSM foi obtida pela técnica de microneurografia do nervo fibular. As medidas e respectivas análises de correlação foram repetidas em 1, 3 e 6 meses após a hospitalização. Correlações entre ANSM e marcadores inflamatórios foram analisadas por meio do teste de Pearson (variáveis de distribuição não-paramétrica foram transformadas logaritmicamente). Modelos de regressão linear múltipla foram criados para avaliar os efeitos independentes. RESULTADOS: Foram estudados 34 pacientes com idade média de 51,7±7,0 anos, sendo 79,4% do sexo masculino. A prevalência de hipertensão arterial foi de 64,7%, diabetes mellitus 8,8%, e doença arterial coronária prévia de 20,6%. A apresentação foi IAM com supradesnível de ST em 18 pacientes (52,9%), IAM sem supra de ST em 14 (41,2%) e angina instável em 02 pacientes (5,9%). Tanto ANSM quanto biomarcadores inflamatórios estavam elevados durante a fase aguda das SIMI e diminuíram ao longo do tempo. Na fase hospitalar, a mediana da PCR-us foi 17,75 (8,57; 40,15) mg/L, e IL-6 6,65 (4,45; 8,20) pg/ml, a Lp- PLA2 média foi 185,8 ± 52,2 nmol/min/ml, e ANSM média 64,2 ± 19,3 impulsos/100bpm. Após 6 meses, houve diminuição significativa de todas essas variáveis quando comparadas com a fase hospitalar. Entretanto, não houve correlação significativa entre a atividade simpática e qualquer dos marcadores inflamatórios analisados, em nenhuma das fases analisadas (p > 0,05), Por outro lado, ANSM se correlacionou independentemente com níveis de CKMB na fase aguda (p=0,027), e com fração de ejeção do VE na fase crônica (p=0,026). CONCLUSÃO: Apesar do aumento inicial dos níveis de marcadores inflamatórios e da atividade simpática em pacientes com SIMI, não houve correlação significativa entre esses parâmetros em nenhuma das fases analisadas, sugerindo que as alterações dessas variáveis estariam relacionadas a diferentes vias fisiopatológicas / INTRODUCTION: Previous publications have shown that both sympathetic hyperactivity and enhanced inflammatory response are associated with worse outcomes during acute coronary syndromes (ACS). However, little is known about the correlation between these two pathologic pathways. OBJECTIVE: To correlate muscle sympathetic nerve activity with inflammatory biomarkers in both acute and chronic phase of ACS. METHODS: Patients hospitalized with uncomplicated ACS were enrolled if they were 18-65 years old and have significant atherosclerosis. Baseline characteristics information were collected and at fourth day (± 1 day) of hospitalization they were submitted to muscle sympathetic nerve activity (MSNA) analysis and blood sample were collected for ultrasensitive C-reactive protein (usCRP), interleukin-6 (IL-6) and Lipoprotein-associated phospholipase A2 activity (Lp-PLA2) measurements. MSNA was recorded directly from the peroneal nerve using the microneurography technique. Measurements were repeated at 1, 3 and 6 months after hospitalization. Correlations between MSNA and inflammatory markers and baseline characteristics were made using Pearson\'s test (nonnormally distributed variables were logarithmically transformed) and multivariate regression models were performed to assess the independent effects. RESULTS: Thirty-four patients were included, 79.4% male, mean age 51.7 (SD 7.0 years). The prevalence of hypertension was 64.7%, diabetes mellitus 8.8%, and previous coronary heart disease 20.6%. The ACS presentation was STEMI in 18 patients (52.9%), NSTEMI in 14 (41.2%) and UA in 02 patients (5.9%). Both MSNA and inflammatory markers were elevated during acute phase of ACS and decreased over time. In the hospitalization phase the median usCRP was 17.75 (8.57; 40.15) mg/L, median IL-6 6.65 (4.45; 8.20), mean Lp-PLA2 185.8 ± 52.2 nmol/min/mL, and mean MSNA 64.2 ± 19.3 bursts/100heart beats. All of these variables decreased significantly over 6 months when compared to in-hospital phase. However, there were no significant correlations between the sympathetic activity and inflammatory markers in any of the analyzed phases (p>0.05). After adjusted analyzes, MSNA was independently associated with CKMB levels at acute phase (p=0.027) and with left ventricular ejection fraction at 6 months (p=0.026). CONCLUSION: Despite the increased levels of inflammatory markers and sympathetic activity among patients with ACS, there was no correlation between these assessments, suggesting that although they may be present concomitantly during an ACS they might follow different pathological pathways

Choisir entre l'action ou l'inaction est peut-être le type de décision le plus critique auquel un animal peut faire face. Une formalisation simple de ces choix consiste à évaluer les bénéfices attendus (nourriture, argent par exemple) ainsi que les coûts (punitions, pertes de temps ou d'argent) associés à chaque action et d'optimiser le rapport entre récompenses reçues et coûts assumés. Notre motivation à s'engager dans une action donnée dépend donc de la valeur de ce rapport. Dans le domaine de l'économie comportementale, l’optimisation de ce rapport bénéfices/coûts constitue le principe fondamental qui régule et explique le comportement des individus. Dans mes travaux de thèse, j'ai réalisé une implémentation de ces concepts venant de l'économie comportementale en utilisant une forme expérimentalement quantifiable de coûts: l'effort physique. Dans notre vie de tous les jours, si l'on nous demande de choisir entre deux options rapportant les même bénéfices mais demandant différents efforts (par exemple, travailler 3 ou 7 jours par semaine pour le même salaire), nous choisissons habituellement l'option qui nécessite la plus petite dépense d'énergie, en optant donc pour le moindre effort. Néanmoins, l'effort physique a été beaucoup moins étudié en comparaison à d'autres formes de coûts comme le fait de différer la récompense ou d'en augmenter l'incertitude. Le présent travail de recherche a donc pour but de mettre en lumière les bases neurales de la balance récompense / effort dans la prise de décision. Comprendre comment l'effort affecte la dévaluation des potentielles récompenses a un intérêt particulier pour la prise de décisions économiques mais aussi pour la clinique, étant donné que la diminution de la capacité à accepter d'avoir à exercer un effort est un symptôme-clé de nombreuses pathologies comme l'apathie ou la dépression. Nous faisons l’hypothèse que de tels désordres pourraient résulter de deux différents processus comportementaux: (a) une diminution de la sensibilité aux bénéfices futurs et/ou (b) une sensibilité excessive aux coûts potentiels. Ainsi, lorsqu'interrogés sur les raisons pour lesquelles ils ne veulent pas aller au cinéma regarder un film qu'ils apprécient, les patients apathiques peuvent déclarer que (a) le film n'est pas assez bon (soit une plus faible réponse à la valeur attendue), (b) le cinéma est trop loin (soit une plus forte sensibilité à l'effort anticipé). Afin de tester ces hypothèses, nous avons enregistré l'activité de neurones chez le singe pendant des tâches comportementales. Nous avons trouvé que d'une part, la dopamine encode la valeur de l'action future et oriente le comportement vers l'option demandant le moindre effort. D'autre part, la noradrénaline permet à l'individu de faire face à l'effort à venir en réduisant la sensibilité à l'anticipation de l'effort. En utilisant une approche pharmacologique, nous avons démontré que lorsque le niveau de noradrénaline est augmenté, les singes exercent d'avantage d'effort. En outre, nous avons montré que les potentiels locaux de champ dans le cortex pré-frontal ventro-médian, enregistrés dans une tâche comportementale identique, sont modulés par la valeur attendue et prédisent le choix du singe. En résumé, ce travail permet de départager en partie les circuits neuronaux impliqués dans le calcul de la balance récompense / effort, principalement encodée par les neurones dopaminergiques et dans les potentiels locaux de champ au niveau du cortex pré-frontal ventro-médian. Enfin, ce travail souligne le rôle de la noradrénaline dans la mobilisation de l'énergie d'un individu afin de faire face au défi que représente l'effort physique. / There is perhaps no more critical factor for the behaviour of an animal than the way it chooses between action and inaction. A simple way to formalise such choices is to evaluate the predicted benefit (e.g. food, money) and costs (e.g. punishments, losses, delays) associated with each action and optimise the rates at which rewards are received and costs avoided. Our motivation to perform a given action depends upon such value ratio. In the current behavioural economics literature, the optimisation of the benefits/costs ratio stands as the fundamental principle that regulates and explains agents’ behaviour. In my Ph.D. studies, I implement a realistic model of such concepts from behavioural economics by using an empirical type of cost: physical effort. In our everyday life, if we are asked to choose between two options that imply the same reward but different efforts (e.g., working 3 or 7 days per week for the same salary), we usually opt for the alternative that requires the slightest energy expenditure, thus the least effort. However, physical effort has been far less studied compared to other decision costs such as delay or uncertainty. The present Ph.D. work aims at highlighting the neuronal bases of such reward/effort tradeoff. Understanding how effort cost affects the discounting of potential rewards has a clear significance for economic decisions and clinics, since the reduced willingness to exert effort is a key signature of several clinical disorders such as apathy and depression We suggest that disorders such as apathy could result from two different behavioural processes: (a) a decreased responsiveness to future benefits and/or (b) an excessive sensitivity to potential costs. For instance, when asked why they would not go see a movie they like, patients may say that (a) the movie is not good enough (i.e. low responsiveness to expected value) or that (b) the theatre is too far away (i.e. high sensitivity to anticipated effort). To test our hypothesis, we combined behavioural tasks and pharmacological approach with neuron recordings in monkeys, targeting specifically two majors actors of the rewarding and effort system, dopamine and noradrenaline. We found that dopamine and noradrenaline have distinct but complementary roles. On the one hand, dopamine tracks the reward value of future outcomes and orient the behaviour towards the least effortful options. On the other hand, noradrenaline enables subjects to face the effort at hand, reducing the sensitivity to anticipated effort. Using a pharmacological approach, we found that, when we increase noradrenaline, monkeys exerted significantly more effort. Moreover, we have found that local field potentials in the ventromedial prefrontal cortex recorded in the same task encode the expected value and predict action selection. In summary, this Ph.D. work allows to disentangle some of the neuronal circuits implicated in the computation of the reward/effort tradeoff, mainly encoded by dopaminergic neurons and in the local field potential of the ventromedial prefrontal cortex. On the other hand, this work highlights the role of noradrenaline in the energization of behaviour to face the challenge represented by the physical effort.

Orientador: Robison José Quitério / Resumo: Introdução: Em decorrência do número elevado de comorbidades associadas à Doença Arterial Coronariana (DAC), os modelos de previsão de risco para cirurgia cardíaca foram desenvolvidos com a finalidade de melhor caracterizar os fatores que influenciam os resultados deste procedimento. Além dos escores de risco utilizados mundialmente “European System for Cardiac Operative Risk Evaluation” (EUROSCORE II) e “Society of Thoracic Surgeons” (STS), a Variabilidade da Frequência Cardíaca (VFC) tem surgido como um novo instrumento de previsão do risco cardiovascular e cirúrgico. Objetivo: Caracterizar os pacientes eletivos para cirurgia de revascularização do miocárdio na região de Marília-SP-Brasil, quanto aos fatores de risco e controle neural do coração; Verificar se existe correlação entre os índices da VFC e os escores de risco cirúrgico EUROSCORE II e STS. Amostra: Foi composta por indivíduos de ambos os sexos, acima de 50 anos, eletivos para cirurgia de revascularização do miocárdio (Hospital Santa Casa de Misericórdia de Marília). O Grupo Controle (GC) foi composto por indivíduos de ambos os sexos, acima de 50 anos, saudáveis. Procedimentos do Estudo: Foi realizada a anamnese na qual foram avaliados os fatores de risco para doença cardiovascular. O registro do intervalos RR foi obtido na postura decúbito dorsal, por 20 minutos, em respiração espontânea. Os índices da VFC (lineares e não lineares) foram analisados, comparados com um grupo controle e correlacionados com valores ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Due to the high number of comorbidities associated with Coronary Artery Disease (CAD), risk prediction models for cardiac surgery were developed with the purpose of better characterizing the factors that influence the results of this procedure. In addition to the European System for Cardiac Operative Risk Evaluation (EUROSCORE II) and Society of Thoracic Surgeons (STS) worldwide, Heart Rate Variability (HRV) has emerged as a new tool for predicting cardiovascular risk and surgical. Objective: To characterize elective patients for myocardial revascularization surgery in the Marília-SP-Brazil region, regarding risk factors and neural control of the heart; To verify if there is a correlation between the HRV indices and the surgical risk scores EUROSCORE II and STS. Sample: It was composed of individuals of both sexes, over 50 years old, elective for myocardial revascularization surgery (Santa Casa de Misericórdia Hospital of Marília). The Control Group (CG) was composed of individuals of both genders, over 50 years, healthy. Study Procedures: An anamnesis was performed in which the risk factors for cardiovascular disease were evaluated. RR interval recording was obtained in the dorsal decubitus position for 20 minutes in spontaneous breathing. The HRV indices (linear and non-linear) were analyzed, compared to a control group and correlated with values obtained from EUROSCORE II and STS. The data were organized as descriptive statistics, with values of mean and stan... (Complete abstract click electronic access below) / Mestre

Anesthetics cause profound alterations in respiratory and cardiovascular systems. Our experiments demonstrated that different anesthetics caused different changes in blood pressure regulating components. The role of particular BP regulating systems was disclosed by their selective inhibition - sympathetic nervous system blocked by pentolinium (peripheral ganglionic blockade), renin-angiotensin system by captopril (angiotensin converting enzyme blocker) and nitric oxide production by L-NAME (nitric oxide synthase blocker). Components of blood pressure regulating mechanisms in conscious normotensive Wistar rats and spontaneously hypertensive rats were compared with four different groups of anesthetized rats by pentobarbital, ketamine-xylazine, chloralose-urethane and isoflurane. Each anesthesia caused different hemodynamic changes. If hemodynamic conditions should be similar to conscious rats, the most suitable anesthetic is pentobarbital. L-serine-induced effects represent endothelium-derived hyperpolarizing factor (EDHF)-mediated response, which is a type of endothelium-dependent regulation of vascular tone, independent of nitric oxide and prostacyclin production. Pronounced L-serine effects on blood pressure were shown in NO-deficient type of hypertension. Our study demonstrated its pronounced effects in...

Chronic kidney disease (CKD) is a life-threating disease which arises as a frequent consequence of diabetes and hypertension. Since it is going on silently, CKD often progresses to the end-stage renal disease. It is therefore necessary to combat this disease especially due to the fact that the world population is growing old. The aim of this work was to determine the contribution of selected vasoactive systems contributing to the maintenance of high blood pressure in the developmental and established phase of CKD. Two models of CKD were used: 5/6 nephrectomy in Ren-2 transgenic rats (TGR) and stenosis of renal artery (2K1C) in Wistar rats. We demonstrated that renin-angiotensin system does not play so important role in blood pressure maintenance in both CKD models. By contrast, a more important role has sympathetic nervous system. During both the developmental and established phase of CKD, vasoconstrictor systems prevail above vasodilator NO-synthase effects. In fact, the role of NO-dependent vasodilation gradually decreased in nephrectomized TGR rats, while it was unchanged in Wistar rats with 2K1C hypertension.

本研究嘗試檢視原發性失眠 (Primary insomnia) 患者在接受完認知行為治療後，其生理激發系統與恆定系統相關生理指標的改變，並探討其主、客觀睡眠改善與生理指標變化之間的關聯，藉以瞭解不同的生理系統在影響原發性失眠患者其主、客觀睡眠改善程度上可能的重要性。本研究透過醫師轉介，共18名原發性失眠患者 (男5人，女13人，平均年齡37.4歲) 接受7週6次的失眠認知行為治療，在接受治療的前後，分別進行一個晚上的多頻道睡眠記錄檢查與主、客觀睡眠評估。再進一步分析高頻率腦波Beta波 (14~35Hz) ，用來反應其中樞神經系統的激發，低頻率腦波Delta波 (0.5~2.5Hz) 則用來反應個案的恆定系統；另外，透過心跳變異率分析得出的參數，包括低頻率 (Low frequency，簡稱LF) 功率與高頻率 (High frequency，簡稱HF) 功率，以LF/HF的比率值測量其交感神經系統的活動，而HF/ (LF+HF) 則是測量副交感神經系統的活動。研究結果顯示個案的失眠問題在主觀睡眠評估指標上有顯著改善，而客觀睡眠評估指標與睡眠結構於入睡時間與入睡後清醒時間有顯著降低，其餘則無顯著改善。而各項生理系統指標，僅後半夜階段二的腦波的Delta波有顯著上升，其餘均無顯著地改善，而LF/HF的下降與失眠嚴重度的下降有顯著地關聯。因此，本研究顯示原發性失眠患者接受認知行為治療前後，其交感神經系統的下降與失眠嚴重度之改善有明顯關聯，推論失眠認知行為治療對於原發性失眠患者的交感神經活動的改善，可能是使其失眠嚴重度改善的關鍵。 / The present study evaluated the changes in beta and delta ranges of electroencephalogram (EEG) power and heart rate variability (HRV) after cognitive behavioural therapy for insomnia (CBT-I) to understand the effect of CBT-I on arousal system and homeostatic system. The study also examined the correlations between change of sleep measurement and the physiological index to clarify underlying mechanisms of sleep improved by CBT-I. Eighteen primary insomnia patients (5 males, 13 female, mean age = 37.4) participated in this study. The participants were scheduled to come to the sleep laboratory for polysomnographic (PSG) recording twice, one prior to CBT-I and one following CBT-I. A course of 6-session CBT-I was conducted during a period of seven weeks. Subjects’ changes in subjective ratings of sleep quality and quantity and sleep parameters in PSG were calculated. Spectrum analyses were conducted for their EEG and electrocardiogram (EKG). Beta EEG activity (14~35 Hz) was used to indicate the central nervos system (CNS) arousal level and Delta EEG activity (0.5~2.5 Hz) for the intensity of homeostatic system. Low frequency power (LF) and high frequency power (HF) of the R-R interval were calculated for heart rate variability (HRV). LF/HF ratio was used as a index of sympathetic nervous system activity and the HF/ (LF+HF) ratio as a index of parasympathetic nervous system activity. The results show subjective sleep quality of subjects were significantly improved after CBT-I. PSG shows shortened sleep onset latency and decreased wake time after sleep onset, but not in the other measures. For EEG spectrum and HRV parameters, only Delta EEG activity in stage2 of the second half of the night was significantly improved. In addition, the decrease of LF/HF significantly correlated with the improvement of the insomnia severity index. Thus, the results suggests that sleep improvements by CBT-I may be associated with the reduction of sympathetic arousal.

Estudou-se o efeito do treinamento físico sobre a freqüência cardíaca (FC), a freqüência cardíaca intrínseca (FCI), o efeito vagal (EV), o tônus vagal (TV), o efeito simpático (ES) e o tônus simpático (TS), de ratos idosos em repouso volitivo, na esteira, e durante o exercício de intensidade progressiva (4 estágios de 5 min à 5; 7,5; 10 e 15 m.min-1). Verificaram-se, também, as respostas da FC à doses crescentes de agonistas ?-adrenérgico (isoproterenol) e muscarínico (metacolina). Utilizaram-se 20 ratos Wistar machos, aleatoriamente divididos em dois grupos: Treinado (T, 28+2 meses, 460+36 g), submetido a 10 semanas de treinamento físico de moderada intensidade; e Sedentário-controle (S, 28+2 meses, 461+43 g), apenas manipulado, três a cinco vezes por semana, durante nove semanas, e submetido a cinco minutos de exercício diário, na décima semana, para habituação ao pesquisador e ao ambiente experimental. Utilizaram-se duplos bloqueios farmacológicos (propranolol/atropina e atropina/propranolol) para determinação da FCI, bem como bloqueios farmacológicos autonômicos unilaterais que permitiram a medida do EV, do TV, do ES e do TS. Definições: EV = FC após atropina - FC controle, ES = FC controle - FC após propranolol, TV = FCI - FC após propranolol, TS = FC após atropina - FCI. Registros: batimento-a-batimento, 500Hz (AT/CODAS). Para comparação realizou-se análise de variância de dois caminhos para medidas repetidas, com contraste. Significância estatística, P<0,05. FC e FCI foram menores em T que S, em repouso e nos quatro estágios estudados: FC = 296+6, T vs. 325+16, S; 374+33, T vs. 420+29, S; 380+ 39, T vs. 423+29, S; 407+46, T vs. 434+25, S; 441+48, T vs. 455+30, S; e FCI = 288+28, T vs. 312+18, S; 302+27, T vs. 332+24, S; 301+30, T vs. 339+26, S; 308+30, T vs. 344+30, S; 316+31, T vs. 348+31, S. Não houve diferença na atividade vagal entre T e S, tanto considerando o EV, como o TV, em nenhuma das condições estudadas. A influência simpática para o coração se mostrou semelhante entre T e S, tanto se considerando o ES quanto o TS, em todas as condições estudadas. T e S responderam de forma semelhante aos agonistas muscarínico e adrenérgico. Tanto a FC, quanto a FCI aumentaram do repouso para o exercício, e com o aumento da intensidade do mesmo. A atividade vagal diminuiu do repouso para o exercício, mas apenas em intensidade elevada. A atividade simpática aumentou na passagem do repouso para o exercício, e com o aumento da intensidade do mesmo. Concluiu-se que, em ratos idosos: a) o treinamento físico de moderada intensidade promoveu bradicardia de repouso e atenuação da taquicardia induzida pelo exercício essencialmente à custa de redução da FCI; e b) independentemente da condição de treinamento físico, a estimulação simpática contribuiu para o aumento da FC, em resposta ao exercício, de leve à alta intensidade, enquanto a retirada vagal o fez, apenas em alta intensidade. / We studied the effect of exercise training on heart rate (HR), on intrinsic heart rate (IHR), on vagal effect (VE), on vagal tone (VT), on sympathetic effect (SE) and on sympathetic tone (ST) during both treadmill resting and exercise of progressive intensity (four 5-min stages at 5, 7.5, 10 and 15 m.min-1) in old rats. HR responses to crescent doses of ?-adrenergic (isoproterenol) and muscarinic (metacholine) agonists were also verified. We used 20 male Wistar rats randomly assigned to two groups: trained (T, 28+2 months, 460+36 g) and sedentary control (S, 28+2 months, 461+43 g) rats. T was submitted to a ten-week moderate intensity exercise training program, while S was just handled, three to five times a week, for nine weeks and submitted to five-min bouts of daily exercise during the tenth week for taming and to become accustomed to experimental environment. Double pharmacological blockades (propranolol/ methylatropine and methylatropine/propranolol) were performed in order to determine IHR. Autonomic influences on heart rate were evaluated using also unilateral autonomic pharmacological blockade, which allowed us to measure VE and VT as well as SE and ST. Definitions: VE = HR after atropine - control HR, SE = control HR - HR after propranolol, VT = IHR - HR after propranolol, ST = HR after atropine - IHR. HR was recorded on a beat-to-beat basis with a 500 Hz acquisition frequency (AT/CODAS). For statistical analysis we used two-way ANOVA for repeated measurements with contrast, considering a P<0.05 as statistically significant. T rats had lower HR as well as IHR than their sedentary counterparts both at rest and during all progressive exercise stages: HR = 296+6,T vs. 325+16,S; 374+33,T vs. 420+29,S; 380+39,T vs. 423+29,S; 407+46,T vs. 434+25,S; 441+48,T vs. 455+30,S, respectively; and IHR = 288+28,T vs. 312+18,S; 302+27,T vs. 332+24,S; 301+30,T vs. 339+26,S; 308+30,T vs. 344+30,S; 316+31,T vs. 348+31,S, respectively. Vagal activity was not significantly different between groups, either considering VE or VT. Sympathetic influence was also similar between S and T considering both SE and ST in all of the studied conditions. T and S responded similarly to both muscarinic and ?-adrenergic agonists. Both HR and IHR increased from rest to exercise and with increasing exercise intensity. Vagal activity decreased from rest to exercise but only in high intensity exercise. Sympathetic activity increased from rest to exercise and also with increasing exercise intensity. We concluded that in old rats: a) exercise training of moderate intensity led to resting bradycardia and attenuation of exercise tachycardia essentially due to the decrease in IHR; and b) independently from exercise training status, sympathetic stimulation contributed to HR increase from light to high intensity exercise while vagal withdrawal became important only at high intensity exercise

A restrição crônica de sal na dieta tem sido recomendada como medida não medicamentosa do tratamento da hipertensão arterial sistêmica. Entre os efeitos observados desta medida terapêutica tem sido descrita uma redução dos valores da pressão arterial (PA), tanto em indivíduos normotensos e pacientes hipertensos, assim como em animais de laboratório. Outros efeitos observados são alterações do metabolismo de carboidratos e de lípides. Tanto em indivíduos normotensos e pacientes hipertensos, assim como em animais de laboratório foram observadas maiores concentrações de peptídeo C e de insulina, sem alteração da glicemia e com redução da captação periférica de glicose pelos tecidos, caracterizando um estado de resistência à insulina. No metabolismo de lípides, uma outra conseqüência da restrição crônica de sal é a maior concentração plasmática de colesterol total e triacilgliceróis. Apesar da demonstração dos efeitos do sal sobre o metabolismo de carboidratos e lípides em humanos e animais existem dados conflitantes na literatura, com resultados opostos a estes descritos. Para melhor compreensão deste fenômeno, foi desenvolvido um estudo em nosso laboratório, o qual demonstrou que ratos Wistar machos que receberam restrição crônica de sal na dieta apresentaram maiores insulinemias medidas durante um teste de tolerância à glicose e sem a constatação de resistência à insulina em adipócitos isolados avaliada pela EC50 Entretanto, o que não ficou esclarecido neste estudo é se este quadro era restrito ao tecido estudado ou se ocorria no animal como um todo, ou seja, se era um fenômeno generalizado. Tendo em vista estes resultados, um outro estudo foi desenvolvido em nosso laboratório. Analisando o animal intacto, foi verificado que a restrição crônica de sal em ratos Wistar estava associada a uma menor sensibilidade à insulina medida por meio de um clamp euglicêmico hiperinsulinêmico (CLAMP) em animais anestesiados. Também foi observado maior peso corpóreo (PC) e maior massa dos tecidos adiposos. No intuito de se compreender quais eram os mecanismos envolvidos na menor sensibilidade à insulina durante a restrição de sal na dieta, também foi feito o pareamento de peso entre os animais que receberam dietas hipo (HO), normo (NR) ou hipersódica (HR) e mesmo sem diferença entre os PC, os animais sob restrição salina mantiveram-se insulino resistentes. Em uma nova etapa foi feito o bloqueio do sistema renina angiotensina com o uso de captopril (inibidor da enzima conversora de angiotensina) ou losartan (antagonista do receptor ATI de angiotensina II) tendo sido verificado que o captopril melhorou a sensibilidade à insulina, o que não ocorreu com o uso de losartan. Outra conseqüência da restrição crônica de sal na dieta é a maior atividade do sistema nervoso simpático (SNS) e uma menor atividade da via L-arginina (LA) / óxido nítrico (NO). Assim, o objetivo deste estudo foi verificar se o SNS e a via LA/NO são mecanismos envolvidos na menor sensibilidade à insulina durante a restrição crônica de sal. Para o desenvolvimento deste estudo, ratos Wistar machos receberam dieta HO, NR ou HR desde o desmame aos 21 dias de vida até completarem 12 semanas. Ao tornarem-se adultos, os ratos foram submetidos ao implante cirúrgico de cateteres e três a cinco dias após era realizado um CLAMP em ratos acordados. No dia do experimento, após um jejum de seis horas se realizava a coleta de sangue e medidas metabólicas e hemodinâmicas. Neste momento, um grupo de ratos recebeu prazosin e propranolol para o bloqueio do SNS e outro grupo recebeu veículo. Um terceiro grupo de animais recebeu LA e outro grupo recebeu D-arginina (DA). Um quinto grupo de animais que consumiu apenas a dieta HR recebeu diltiazem (bloqueador de canal de cálcio). Quarenta e cinco minutos após a infusão das drogas o CLAMP foi iniciado. Foram medidos PC, glicemias, insulinemias, lípides, nitrato/nitrito (NOx), PA sistólica (PAS), diastólica (PAD) e freqüência cardíaca (FC). O PC foi maior na dieta HO do que na NR e HR. Também foi observado maior PC na dieta NR do que HR. Em situação basal observaram-se maiores valores de glicemia e insulinemia durante a restrição salina em comparação aos ratos em dieta NR e HR. A PAS e PAD foram maiores na dieta HR em comparação aos ratos em dieta NR e HO, enquanto a FC foi maior nos ratos em dieta HO em comparação àqueles sob dietas NR e HR. Também foram observadas maiores concentrações plasmáticas de colesterol total (COL) e triacilgliceróis (TAG) durante a restrição salina. Os animais controle apresentaram menor sensibilidade à insulina em comparação àqueles em dieta NR ou HR. O bloqueio do SNS corrigiu o efeito do sal sobre a captação de glicose, não sendo mais observada diferença entre as dietas. O bloqueio do SNS não influenciou a glicemia mas reduziu a maior insulinemia nos ratos em dieta HO, não sendo mais observada diferença entre as dietas quanto às insulinemias ao início do CLAMP. A infusão de LA melhorou a menor captação periférica de glicose nos ratos em dieta HO, sem influência sobre os animais tratados com dieta NR ou HR. Diltiazen não modificou a sensibilidade à insulina apesar de ter reduzido a PA em intensidade semelhante ao bloqueio do SNS. O bloqueio do SNS reduziu os valores de PAS e PAD nas três dietas, com queda mais intensa dos seus valores nos animais sob sobrecarga salina, logo ao início do CLAMP. Diltiazen reduziu a PAS e PAD. DA não influenciou (p>0,05) os valores de PAS e PAD. Já a infusão de LA promoveu redução dos valores de PAS e PAD somente em ratos em sobrecarga salina e reduziu os maiores valores de FC observados nos ratos durante a restrição de sal na dieta. O bloqueio do SNS e a infusão de LA reduziram os maiores valores de TAG ao término do CLAMP, o que não foi observado nos grupos veículo e DA. Não foi observada modificação da concentração plasmática de COL entre os grupos independentemente dos fármacos ministrados. Durante a restrição salina foi observado menor concentração plasmática de NOx em comparação à sobrecarga salina. A infusão de LA promoveu um incremento na concentração plasmática de NOx ao término do CLAMP nas três dietas, o que não foi observado nos ratos tratados com DA. Ao término do CLAMP não foram observadas diferenças na concentração de NOx plasmático entre as dietas nos animais que receberam LA. A concentração plasmática de NOx nas três dietas foi menor nos ratos que receberam DA. Assim, o bloqueio do SNS e a ativação da via LA/NO melhoraram os efeitos metabólicos decorrentes da restrição crônica de sal. / Chronic dietary salt restriction is recommended as non-pharmacological measure of hypertension treatment. One of the observed effects of this therapeutic measure is the blood pressure (BP) decrease in normotensive subjects and in hypertensive patients, and also in laboratory animals. Another side effects observed are disorders of carbohydrate and lipid metabolism. Salt restriction induced higher C-peptide and insulin levels, without changes on plasma glucose, and lower glucose uptake by the tissues in normotensive subjects and in hypertensive patients, and also in laboratory animals, suggesting an insulin resistant state. Other consequences of salt restriction are higher plasma levels of cholesterol and triacylglycerols. Some studies have disclosed opposite results. With the objective to better understand these phenomena, a study was developed in our laboratory, that showed that male Wistar rats on chronic salt restriction presented higher insulin plasma levels measured during a glucose tolerance test, without insulin resistance in isolated adipocytes measured by the EC50 of the insulin - glucose uptake curve. It was not clear in this study if this phenomenon was restricted to the evaluated tissue or if it was a phenomenon in the whole animal. With these results, another study was developed in our laboratory. Analyzing the whole animal, chronic salt restriction in male Wistar rats was associated with lower insulin sensitivity measured by a euglycemic hyperinsulinemic clamp (CLAMP) in anesthetized rats. Higher body weight (BW) and adipose tissue mass was also observed. With the objective to understand the involved mechanisms in the lower insulin sensitivity due to dietary salt restriction, weight was paired among animals on low (LSD), normal (NSD) or high (HSD) salt diet, and even without BW difference, salt restricted animals were still insulin resistants. In another step, renin angiotensin system blockade with captopril (angiotensin enzyme conversion inhibitor) or losartan (angiotensin II type I receptor antagonist) was performed. It was observed that captopril, but not losartan, improved insulin sensitivity. Another consequence of salt restriction is a higher sympathetic nervous system (SNS) and a lower L-arginine (LA) / nitric oxide (NO) pathway activity. The objective of this study was to verify if SNS and LA / NO are mechanisms involved in the lower insulin sensitivity due to chronic salt restriction. Male Wistar rats received LSD, NSD, or HSD since weaning until adulthood. In the 12th week of age, catheters were inserted and three to five days latter, a CLAMP was performed in awaked rats. On the day of the experiment, after six hours fasting, blood samples were collected and metabolic and hemodynamic measures were done. At this moment, a group of rats received prazosin and propranolol for SNS blockade and another group received vehicle. A third group of animals received LA and a fourth group received D-arginine (DA). Another group of rats only on HSD received diltiazen (calcium channel blocker). Fourty five minutes after drug infusion the CLAMP was started. BW, plasma glucose, insulin, lipids, and nitrate/nitrite (NOx), systolic BP (SBP), diastolic (DBP), and heart rate (HR) were measured. BW was higher on LSD than on NSD and HSD. BW was also higher on NSD than HSD. Basal plasma glucose and insulin were higher during salt restriction than on NSD and HSD. SBP and DBP were higher on HSD than on NSD and LSD, and HR was higher on LSD than on NSD and HSD. Cholesterol (CHOL) and triacylglycerol (TAG) plasma levels were higher on salt restriction. LSD rats presented lower insulin sensitivity compared to animals on NSD or HSD. SNS blockade corrected effect of salt on glucose uptake. SNS blockade had no influence on glucose levels but reduced the higher plasma insulin in LSD rats, without differences in insulin levels between diets at the start of the CLAMP. LA improved the lower glucose uptake observed in LSD rats, with no influence on the rats on NSD or HSD. Diltiazen had no effect on insulin sensitivity. SNS blockade reduced SBP and DBP in rats on the three diets, with an intense BP fall on HSD rats at the start of the CLAMP. Diltiazen reduced SBP and DBP. DA had no influence in SBP and DBP. On the other hand, LA decreased SBP and DBP only in salt overloaded rats and reduced the higher HR observed on salt restricted rats. SNS blockade and LA infusion reduced the higher TAG concentration at the end of the CLAMP, which was not observed in vehicle and DA groups. COL level was not influenced by drug infusion. During salt restriction, lower plasma NOx was observed compared to salt overload. LA infusion promoted plasma NOx increment at the end of the CLAMP. At the end of the CLAMP, no difference was observed in plasma NOx among the rats on the three salt diets and infused with LA. Plasma NOx was lower in rats in the DA group. In conclusion, SNS blockade and LA/NO pathway activation improved the metabolic effects due to chronic dietary salt restriction.

A restrição crônica de sal na dieta tem sido recomendada como medida não medicamentosa do tratamento da hipertensão arterial sistêmica. Entre os efeitos observados desta medida terapêutica tem sido descrita uma redução dos valores da pressão arterial (PA), tanto em indivíduos normotensos e pacientes hipertensos, assim como em animais de laboratório. Outros efeitos observados são alterações do metabolismo de carboidratos e de lípides. Tanto em indivíduos normotensos e pacientes hipertensos, assim como em animais de laboratório foram observadas maiores concentrações de peptídeo C e de insulina, sem alteração da glicemia e com redução da captação periférica de glicose pelos tecidos, caracterizando um estado de resistência à insulina. No metabolismo de lípides, uma outra conseqüência da restrição crônica de sal é a maior concentração plasmática de colesterol total e triacilgliceróis. Apesar da demonstração dos efeitos do sal sobre o metabolismo de carboidratos e lípides em humanos e animais existem dados conflitantes na literatura, com resultados opostos a estes descritos. Para melhor compreensão deste fenômeno, foi desenvolvido um estudo em nosso laboratório, o qual demonstrou que ratos Wistar machos que receberam restrição crônica de sal na dieta apresentaram maiores insulinemias medidas durante um teste de tolerância à glicose e sem a constatação de resistência à insulina em adipócitos isolados avaliada pela EC50 Entretanto, o que não ficou esclarecido neste estudo é se este quadro era restrito ao tecido estudado ou se ocorria no animal como um todo, ou seja, se era um fenômeno generalizado. Tendo em vista estes resultados, um outro estudo foi desenvolvido em nosso laboratório. Analisando o animal intacto, foi verificado que a restrição crônica de sal em ratos Wistar estava associada a uma menor sensibilidade à insulina medida por meio de um clamp euglicêmico hiperinsulinêmico (CLAMP) em animais anestesiados. Também foi observado maior peso corpóreo (PC) e maior massa dos tecidos adiposos. No intuito de se compreender quais eram os mecanismos envolvidos na menor sensibilidade à insulina durante a restrição de sal na dieta, também foi feito o pareamento de peso entre os animais que receberam dietas hipo (HO), normo (NR) ou hipersódica (HR) e mesmo sem diferença entre os PC, os animais sob restrição salina mantiveram-se insulino resistentes. Em uma nova etapa foi feito o bloqueio do sistema renina angiotensina com o uso de captopril (inibidor da enzima conversora de angiotensina) ou losartan (antagonista do receptor ATI de angiotensina II) tendo sido verificado que o captopril melhorou a sensibilidade à insulina, o que não ocorreu com o uso de losartan. Outra conseqüência da restrição crônica de sal na dieta é a maior atividade do sistema nervoso simpático (SNS) e uma menor atividade da via L-arginina (LA) / óxido nítrico (NO). Assim, o objetivo deste estudo foi verificar se o SNS e a via LA/NO são mecanismos envolvidos na menor sensibilidade à insulina durante a restrição crônica de sal. Para o desenvolvimento deste estudo, ratos Wistar machos receberam dieta HO, NR ou HR desde o desmame aos 21 dias de vida até completarem 12 semanas. Ao tornarem-se adultos, os ratos foram submetidos ao implante cirúrgico de cateteres e três a cinco dias após era realizado um CLAMP em ratos acordados. No dia do experimento, após um jejum de seis horas se realizava a coleta de sangue e medidas metabólicas e hemodinâmicas. Neste momento, um grupo de ratos recebeu prazosin e propranolol para o bloqueio do SNS e outro grupo recebeu veículo. Um terceiro grupo de animais recebeu LA e outro grupo recebeu D-arginina (DA). Um quinto grupo de animais que consumiu apenas a dieta HR recebeu diltiazem (bloqueador de canal de cálcio). Quarenta e cinco minutos após a infusão das drogas o CLAMP foi iniciado. Foram medidos PC, glicemias, insulinemias, lípides, nitrato/nitrito (NOx), PA sistólica (PAS), diastólica (PAD) e freqüência cardíaca (FC). O PC foi maior na dieta HO do que na NR e HR. Também foi observado maior PC na dieta NR do que HR. Em situação basal observaram-se maiores valores de glicemia e insulinemia durante a restrição salina em comparação aos ratos em dieta NR e HR. A PAS e PAD foram maiores na dieta HR em comparação aos ratos em dieta NR e HO, enquanto a FC foi maior nos ratos em dieta HO em comparação àqueles sob dietas NR e HR. Também foram observadas maiores concentrações plasmáticas de colesterol total (COL) e triacilgliceróis (TAG) durante a restrição salina. Os animais controle apresentaram menor sensibilidade à insulina em comparação àqueles em dieta NR ou HR. O bloqueio do SNS corrigiu o efeito do sal sobre a captação de glicose, não sendo mais observada diferença entre as dietas. O bloqueio do SNS não influenciou a glicemia mas reduziu a maior insulinemia nos ratos em dieta HO, não sendo mais observada diferença entre as dietas quanto às insulinemias ao início do CLAMP. A infusão de LA melhorou a menor captação periférica de glicose nos ratos em dieta HO, sem influência sobre os animais tratados com dieta NR ou HR. Diltiazen não modificou a sensibilidade à insulina apesar de ter reduzido a PA em intensidade semelhante ao bloqueio do SNS. O bloqueio do SNS reduziu os valores de PAS e PAD nas três dietas, com queda mais intensa dos seus valores nos animais sob sobrecarga salina, logo ao início do CLAMP. Diltiazen reduziu a PAS e PAD. DA não influenciou (p>0,05) os valores de PAS e PAD. Já a infusão de LA promoveu redução dos valores de PAS e PAD somente em ratos em sobrecarga salina e reduziu os maiores valores de FC observados nos ratos durante a restrição de sal na dieta. O bloqueio do SNS e a infusão de LA reduziram os maiores valores de TAG ao término do CLAMP, o que não foi observado nos grupos veículo e DA. Não foi observada modificação da concentração plasmática de COL entre os grupos independentemente dos fármacos ministrados. Durante a restrição salina foi observado menor concentração plasmática de NOx em comparação à sobrecarga salina. A infusão de LA promoveu um incremento na concentração plasmática de NOx ao término do CLAMP nas três dietas, o que não foi observado nos ratos tratados com DA. Ao término do CLAMP não foram observadas diferenças na concentração de NOx plasmático entre as dietas nos animais que receberam LA. A concentração plasmática de NOx nas três dietas foi menor nos ratos que receberam DA. Assim, o bloqueio do SNS e a ativação da via LA/NO melhoraram os efeitos metabólicos decorrentes da restrição crônica de sal. / Chronic dietary salt restriction is recommended as non-pharmacological measure of hypertension treatment. One of the observed effects of this therapeutic measure is the blood pressure (BP) decrease in normotensive subjects and in hypertensive patients, and also in laboratory animals. Another side effects observed are disorders of carbohydrate and lipid metabolism. Salt restriction induced higher C-peptide and insulin levels, without changes on plasma glucose, and lower glucose uptake by the tissues in normotensive subjects and in hypertensive patients, and also in laboratory animals, suggesting an insulin resistant state. Other consequences of salt restriction are higher plasma levels of cholesterol and triacylglycerols. Some studies have disclosed opposite results. With the objective to better understand these phenomena, a study was developed in our laboratory, that showed that male Wistar rats on chronic salt restriction presented higher insulin plasma levels measured during a glucose tolerance test, without insulin resistance in isolated adipocytes measured by the EC50 of the insulin - glucose uptake curve. It was not clear in this study if this phenomenon was restricted to the evaluated tissue or if it was a phenomenon in the whole animal. With these results, another study was developed in our laboratory. Analyzing the whole animal, chronic salt restriction in male Wistar rats was associated with lower insulin sensitivity measured by a euglycemic hyperinsulinemic clamp (CLAMP) in anesthetized rats. Higher body weight (BW) and adipose tissue mass was also observed. With the objective to understand the involved mechanisms in the lower insulin sensitivity due to dietary salt restriction, weight was paired among animals on low (LSD), normal (NSD) or high (HSD) salt diet, and even without BW difference, salt restricted animals were still insulin resistants. In another step, renin angiotensin system blockade with captopril (angiotensin enzyme conversion inhibitor) or losartan (angiotensin II type I receptor antagonist) was performed. It was observed that captopril, but not losartan, improved insulin sensitivity. Another consequence of salt restriction is a higher sympathetic nervous system (SNS) and a lower L-arginine (LA) / nitric oxide (NO) pathway activity. The objective of this study was to verify if SNS and LA / NO are mechanisms involved in the lower insulin sensitivity due to chronic salt restriction. Male Wistar rats received LSD, NSD, or HSD since weaning until adulthood. In the 12th week of age, catheters were inserted and three to five days latter, a CLAMP was performed in awaked rats. On the day of the experiment, after six hours fasting, blood samples were collected and metabolic and hemodynamic measures were done. At this moment, a group of rats received prazosin and propranolol for SNS blockade and another group received vehicle. A third group of animals received LA and a fourth group received D-arginine (DA). Another group of rats only on HSD received diltiazen (calcium channel blocker). Fourty five minutes after drug infusion the CLAMP was started. BW, plasma glucose, insulin, lipids, and nitrate/nitrite (NOx), systolic BP (SBP), diastolic (DBP), and heart rate (HR) were measured. BW was higher on LSD than on NSD and HSD. BW was also higher on NSD than HSD. Basal plasma glucose and insulin were higher during salt restriction than on NSD and HSD. SBP and DBP were higher on HSD than on NSD and LSD, and HR was higher on LSD than on NSD and HSD. Cholesterol (CHOL) and triacylglycerol (TAG) plasma levels were higher on salt restriction. LSD rats presented lower insulin sensitivity compared to animals on NSD or HSD. SNS blockade corrected effect of salt on glucose uptake. SNS blockade had no influence on glucose levels but reduced the higher plasma insulin in LSD rats, without differences in insulin levels between diets at the start of the CLAMP. LA improved the lower glucose uptake observed in LSD rats, with no influence on the rats on NSD or HSD. Diltiazen had no effect on insulin sensitivity. SNS blockade reduced SBP and DBP in rats on the three diets, with an intense BP fall on HSD rats at the start of the CLAMP. Diltiazen reduced SBP and DBP. DA had no influence in SBP and DBP. On the other hand, LA decreased SBP and DBP only in salt overloaded rats and reduced the higher HR observed on salt restricted rats. SNS blockade and LA infusion reduced the higher TAG concentration at the end of the CLAMP, which was not observed in vehicle and DA groups. COL level was not influenced by drug infusion. During salt restriction, lower plasma NOx was observed compared to salt overload. LA infusion promoted plasma NOx increment at the end of the CLAMP. At the end of the CLAMP, no difference was observed in plasma NOx among the rats on the three salt diets and infused with LA. Plasma NOx was lower in rats in the DA group. In conclusion, SNS blockade and LA/NO pathway activation improved the metabolic effects due to chronic dietary salt restriction.

Introduction – Objectives. The cardiovascular system is in direct and constant interaction with its environment. Exposure to various environmental parameters, such as low temperature, air pollution and tobacco smoke, has been strongly associated with serious or even fatal cardiovascular outcomes. Arterial stiffening and greater wave reflection are age-related vascular modifications that lead to an increased risk of cardiovascular events. The aim of this work was to explore the relationship between selected environmental factors and arterial elastic properties in an effort to elucidate the underlying mechanisms that link these factors to increased cardiovascular mortality.<p><p>Study 1: Effects of cold exposure on central and peripheral vascular tone. Our first study explored the effects of cold exposure on aortic stiffness and peripheral microvascular tone. We observed that cold exposure, in addition to its chronotropic effects, provoked an increase in aortic stiffness, as assessed by aortic pulse wave velocity, as well as significant vasoconstriction of peripheral arterioles in the microcirculation. Moreover, we explored the magnitude of this effect in a different population (Black subjects of African origin), which is traditionally characterized by exaggerated reactions to adrenergic stimuli. We noted that the vascular reactions, in terms of both aortic stiffness and microvascular vasoconstriction, were more profound in Black Africans than in age-matched Caucasian-Whites. These results argue for a direct effect of cold exposure on arterial stiffness and peripheral vascular tone, probably through activation of the orthosympathetic system.<p><p>Study 2: Exposure to ambient particulate matter and arterial stiffness. We explored the effects of acute exposure to outdoor particulate matter on aortic stiffness and aortic wave reflection. We studied the relationship between central hemodynamic parameters and ambient concentration of particulate matter in a population of patients who attended the Hypertension Clinics of Athens University. After statistical correction for a number of potential confounders, we did not observe an association between ambient concentrations of particulate matter and aortic stiffness. However, in men, particulate matter concentration was related to the amplitude of the reflected wave reaching the aorta from the periphery. These results suggest a direct acute interaction between particulate matter concentration and vascular tone, leading to an enhanced arterial wave reflection.<p><p>Study 3: The role of nicotine on the vascular effects of environmental tobacco smoke. Environmental tobacco smoke is considered as the most important source of particulate matter in the indoor environment. We recently demonstrated that exposure to tobacco smoke augmented wave reflection, an effect that was not seen after equivalent exposure to the smoke of non-tobacco, herbal cigarettes. We also noticed that the increased wave reflection was proportional to the plasma concentrations of nicotine. However, a direct causal effect between nicotine, arterial wave reflection and aortic stiffness has never been clearly demonstrated. We observed that increasing nicotine plasma concentration to levels comparable to those seen after extensive exposure to environmental tobacco smoke, provoked an increase in both aortic stiffness and arterial wave reflection after correction for heart rate and blood pressure changes. These results confirm the significant participation of nicotine in the vascular effects of passive smoking.<p><p>Conclusions. Globally, our results reveal the deleterious effects of cold, particulate matter exposure, and nicotinic stimulation on arterial stiffness, peripheral microcirculation and aortic wave reflection. The hemodynamic modifications associated with these effects may at least partially explain the causal relation between cold exposure, ambient air pollution and cardiovascular mortality.<p><p>Introduction-Objectifs. Le système cardiovasculaire est en relation directe et constante avec l’environnement. L’exposition au froid, la pollution atmosphérique et le tabagisme passif sont associés à des événements cardiovasculaires aigus graves et même fatals. La rigidification des artères et l’intensification de la réflexion de l’onde de pouls au niveau de l’aorte accompagnent le vieillissement et prédisent un risque cardiovasculaire accru. Nous avons testés l’hypothèse que les effets cardiovasculaires délétères des facteurs environnementaux comportent une altération des propriétés élastiques artérielles. Ceci pourrait être un des mécanismes physiopathologiques qui lie la mortalité cardiovasculaire aux variables environnementales.<p><p>Étude 1 :Exposition au froid ;effets centraux et périphériques. Notre première étude portait sur l’effet de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artérioles périphériques. Nous avons démontré que l’exposition au froid, hormis ses effets chronotropes, provoquait une augmentation de la rigidité artérielle – mesuré par la vitesse de l’onde de pouls au niveau de l’aorte - ainsi qu’une vasoconstriction importante au niveau des artérioles de la microcirculation. Nous avons ensuite déterminé l’amplitude de cet effet dans une autre population (sujets Africains-Noirs) qui se caractérise par des réactions plus prononcées aux différentes stimulations adrénergiques. Nous avons observé que les réactions vasculaires, tant au niveau de la rigidité aortique qu’au niveau de la microcirculation, étaient plus marquées chez les Africains-Noirs que chez les Caucasiens. Ces résultats révèlent un effet délétère de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artères périphériques, probablement via une activation du système orthosympathique.<p><p>Étude 2 :Exposition aux microparticules atmosphériques et rigidité artérielle. Nous avons ensuite investigué les effets de la pollution atmosphérique sur la rigidité artérielle et la réflexion de l’onde de pouls vers l’aorte. Nous avons étudié la relation entre les paramètres hémodynamiques centraux et la concentration atmosphérique de microparticules dans une population de patients qui ont consulté la Clinique Universitaire d’Hypertension Artérielle d’Athènes. Après correction statistique pour les facteurs confondants, nous n’avons pas observé de corrélation entre la rigidité artérielle et le taux de microparticules atmosphériques dans l’ensemble de la population investiguée. Par contre, si on restreint l’analyse aux résultats obtenus chez les sujets masculins, on s’aperçoit que la concentration atmosphérique de microparticules était associée de façon significative avec l’amplitude de l’onde réfléchie par la périphérie vers l’aorte et la pression pulsée aortique. Ces résultants suggèrent un effet direct des microparticules au niveau de la microcirculation. L’augmentation de l’amplitude de l’onde réfléchie consécutive à une vasoconstriction périphérique, modifie vraisemblablement les pressions au niveau de l’aorte chez le sujet masculin lors de pics de pollution.<p><p>Etude 3 :Le rôle de la nicotine dans les effets vasculaires du tabagisme passif. Le tabagisme passif est considéré comme la source la plus importante d’émission de microparticules au niveau domestique. Cependant, la composition chimique des particules semble jouer un rôle essentiel sur les ondes de réflexion. Nous avons démontré récemment que l’exposition passive à la fumée des cigarettes du tabac augmente l’intensité de la réflexion de l’onde de pouls. Ceci n’a pas été observé avec l’exposition à la fumée des cigarettes non tabagiques, en dépit d’une concentration ambiante tout à fait comparable de microparticules. Par ailleurs, nous avons observé que l’augmentation de l’incidence de l’onde de pouls au niveau de l’aorte était fortement associée à la concentration plasmatique de la nicotine. Un lien causal entre la nicotine, réflexion de l’onde de pouls et rigidité artérielle n’avait jamais clairement été établi. Nous avons testé cette hypothèse en administrant la nicotine pure chez des sujets sains. Nous avons observé que l’augmentation des taux plasmatiques de la nicotine à des valeurs comparables à celles qui surviennent après une exposition intensive au tabagisme passif, intensifiait la réflexion de l’onde de pouls et augmentait la rigidité artérielle. La correction statistique pour l’augmentation de la fréquence cardiaque et l’augmentation de la pression artérielle en réponse à la nicotine ne modifiait pas ces conclusions. Nos résultats démontrent ainsi les effets cardiovasculaires importants de faibles concentrations de nicotine, similaires à ceux qui sont atteints en cas d’exposition à un tabagisme passif.<p><p>Conclusions. Nos résultats révèlent les effets néfastes de l’exposition au froid et aux microparticules atmosphériques sur la rigidité artérielle, la microcirculation périphérique et la réflexion de l’onde de pouls. Nous avons pu également démontrer le rôle de la stimulation nicotinique dans les effets vasculaires aigus du tabagisme passif, comme en témoigne l’augmentation de la réflexion de l’onde de pouls au niveau aortique. Ces modifications hémodynamiques favorisent l’ischémie myocardique, et constituent un des mécanismes par lesquels l’exposition au froid et à la pollution atmosphérique favorisent la pathologie cardiovasculaire.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished