L'angiogenèse est impliquée dans différents processus tels que la cicatrisation, la croissance tumorale et les maladies ischémiques. RhoA, connu pour son implication dans la prolifération et la migration des cellules, est régulé par la voie NO/PKG. Le sildenafil, inhibiteur de la phosphodiestérase 5, permet d'activer cette voie, ce qui constitue une stratégie thérapeutique intéressante dans le traitement des maladies ischémiques. Nous avon montré que le sildenafil améliore la croissance collatérale dès 7 jours de traitement, sans modifier la densité capillaire, via un mécanisme PI3K/akt-NO-dépendant et HIF/VEGF-indépendant. Ces différentes voies sont down-régulées à 21 jours. Enfin cette revascularisation s'accompagne d'un remodelage des artères de résistance, suggérant que le sildenafil favorise non pas l'angiogenèse mais l'artiogenèse. Enfin, nous avons mis en évidence un effet dose-dépendant des polyphenols du vin rouge, un autre puissant vasodilattaeur, sur la revascularisation post-ischémique : à fortes doses les densités vasculaires sont diminuées, associées à une inhibition des voies PI3K/Akt-NO et des MMPs. De faibles doses entraînent une augmentation des densités vasculaires par stimulation des voies PI3K/akt-No, sans affecter les MMPs. Par conséquent, nous avons mis en évidence un effet anti-angiogénique (fortes doses) et un effet pro-angiogenique (faibles doses) des plyphenols. Ce travail nous permet donc de mieux comprendre les mécanismes d'action de deux puissants vasodilatateurs dans revascularisation post-ischémique. Nous pouvons ainsi envisager de nouvelles stratégies thérapeutiques dans le traitement des maladies ischémiques ou du cancer.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成8年3月8日 辻井洋一郎氏の博士論文として提出された

Migraine, a neurovascular disorder, is associated with disturbances in brain stem activity during attacks. Interictal persistence of these disturbances might increase vulnerability to recurrent attacks of migraine. To explore this possibility, effects of motion sickness and pain on migrainous symptoms and extracranial vascular reponses were investigated in 27 migraine sufferers in the headache-free interval, and 23 healthy age/sex matched controls. Symptoms of migraine and motion sickness are remarkably similar. As both maladies involve reflexes that relay in the brain stem, they most probably share the same neural circuitry. Furthermore, migraineurs are usually susceptible to motion sickness and, conversely, motion sickness-prone individuals commonly experience migraine. Participants in the present study were exposed to optokinetic stimulation (OKS), a well-established way of inducing symptoms of motion sickness in susceptible individuals. Sensitivity to painful stimulation of the head and hand was also explored. Head pain is a hallmark of a migraine attack and cutaneous allodynia has been observed elsewhere in the body during attacks. The trigeminal nerve is associated with head pain in migraine, and trigeminal activity evokes reflexes that relay in the brain stem. To stimulate the trigeminal nerve, ice was applied to the temple. To stimulate nociceptors elsewhere in the body the participant immersed their fingers and palm in ice-water. Procedures used in this study were physically stressful and probably psychologically stressful. The impact of stress in relation to the development of symptomatic and vascular responses, particularly anticipatory stress-responses, was explored. This research involved one central experiment that consisted of six experimental conditions. On separate occasions participants were exposed to optokinetic stimulation and painful stimulation of the head or limb, individually and in combination. In migraine sufferers, symptomatic responses were enhanced during all procedures involving OKS and during temple pain after OKS, in the presence of residual motion sickness. During trigeminal stimulation independent of OKS, headache initially developed followed by nausea as the procedure progressed. In contrast, symptoms barely developed in controls during any of the six procedures except for slight dizziness, self-motion and visual-illusion during conditions involving OKS, and slight nausea when the temple was painfully stimulated during OKS and during OKS alone. Trigeminal stimulation during OKS intensified nausea and headache in migraine sufferers compared to during OKS alone or limb pain during OKS. However, the remaining symptomatic ratings were not affected by temple pain during OKS, suggesting a specific association between nausea and head pain. It may be that these cardinal symptoms compound one another during a migraine attack. Enhanced symptomatic responses in migraine sufferers during the headache interval may indicate activation of hypersensitive neural pathways that mediate symptoms of motion sickness or migraine. Migraineurs found procedures generally more unpleasant, and ice-induced pain ratings more intense and unpleasant, than controls, which may further indicate hyperexcitable nociception in this group, or a difference in their criterion of discomfort. Vascular responses, particularly during OKS alone, and during painful stimulation independent of OKS, were greater in migraine sufferers than in controls. The added stress of painful stimulation during OKS appeared to boost facial blood flow in controls to approach levels obtained in migraine sufferers. Enhanced vasodilatation was observed in migraineurs prior to painful stimulation, presumably due to anticipatory anxiety. For both groups ipsilateral vascular responses were greater than contralateral responses when the hand was painfully stimulated. During limb pain before OKS asymmetry was minimal in migraine sufferers but more apparent in controls. An enhanced stress response in migraineurs may have drawn ipsilateral and contralateral responses closer together. The development of symptoms during the procedures of this study provides an insight into how symptoms might develop sequentially in a migraine attack. Once the headache is in motion, nausea and headache may mutually exacerbate one another. In turn, trigemino-vascular responses and stress appear to be associated with the migraine crisis. Given the interactive nature of symptomatic, vascular, and stress responses, it may be more effective to target multiple, rather than individual, symptoms, in prophylactic or acute chemical and psychological interventions.

Arterial hypertension (AH) is a multifactorial chronic syndrome, caused by either congenital or acquired factors such as physical inactivity. To evaluate the effects of Resistance Training (RT) in arterial blood pressure, and in vascular reactivity and morphology of hypertensive rats induced by L-NAME. Male Wistar rats (200 250 g) were allocated into one of the following groups: Sedentary Normotensive (SN), Sendentary Hypertensive (SH) and Trained Hypertensive (TH) groups. To induce hypertension, L-NAME (40 mg/Kg) was given in the drinking water during 4 weeks. Mean arterial pressure (MAP) was evaluated before and after the RT. RT was performed with 50% of 1RM, 3 sets of 10 repetitions, 3 times for week, over 4 weeks. Superior mesenteric artery rings were obtained in order to establish concentration-response curves to sodium nitroprusside (SNP; 10-8 10-4 M) and phenylephrine (PHE; 10-8 10-3 M) as well for histological and stereological analysis. No changes in weight gain were observed at the end of experimental period. Resistance training inhibited the increase in mean, systolic and diastolic arterial pressures. Significative differences were not observed in Rmax (maximal response) and pD2 (potency) for SNP and PHE between SH and TH groups. Arteries demonstrated normal intima, media and adventitia layers in all groups. Stereological analysis demonstrated no significant difference in luminal, tunica media, and total areas of arteries in SH and TH groups when compared to SN. Wall to-lumen ratio of SH arteries was significant different compared to SN (p<0.05), however, not different to TH. Thus, it can be concluded that the RT, under the conditions in this study, was able to control blood pressure. This appears to involve a vasoconstrictor regulation mechanism and maintenance of luminal diameter in LNAME induced hypertensive rats. / A hipertensão arterial (HA) é uma síndrome multifatorial, crônica, causada tanto por fatores congênitos ou adquiridos, como a inatividade física. Avaliar os efeitos do treinamento físico resistido (TR) sobre pressão arterial, reatividade vascular e morfologia da artéria mesentérica superior de ratos hipertensos. Ratos Wistar machos (200-250 g) foram divididos em 3 grupos: normotenso sedentário (NS), hipertenso sedentário (HS) e hipertenso treinado (HT). HA foi induzida pela administração de L-NAME (40 mg/kg) na água de beber por 4 semanas. Após o TR, a pressão arterial, reatividade vascular para nitroprussiato de sódio e fenilefrina (FEN) foram avaliados. Além disso, foram realizadas análises histológica e estereológica dos segmentos arteriais. O TR inibiu o aumento da PAM, PAS e PAD. Foi observada uma redução significativa (p<0,01) na potência da FEN do grupo HT quando comparado com o HS (5,34±0,12 vs 6,01±0,11). A análise histológica dos segmentos arteriais evidenciou aspecto normal para as túnicas íntima, média e adventícia em todos os grupos. Não houve diferença significativa nas áreas do lúmen, da túnica média e total das artérias dos grupos HS e HT em relação ao NS. A razão parede/lúmen arterial do grupo HT não apresentou diferença significativa em relação ao HS (p <0,05), mas esta foi diferente do NS. Desta forma, pode-se concluir que o TR foi capaz de controlar a pressão arterial. Este controle parece envolver a regulação de mecanismo vasoconstritor e a manutenção do diâmetro luminal de ratos hipertensos.

O óxido nítrico (NO) é o principal agente vasodilatador endógeno que regula o tônus e a homeostase vascular. Dentre os compostos doadores de NO, estão os complexos nitrosilos de rutênio. No presente estudo, o doador de NO estudado, RuBPY, não apresenta citotoxicidade para células do músculo liso vascular (MLV) ao contrário do NPS. O RuBPY apresenta eficácia semelhante ao NPS em relaxar o MLV de aorta de ratos, porém o NPS é mais potente. Ambos compostos liberam NO do tipo radicalar (NO) no meio intracelular, mas o NPS libera também íon nitroxil (NO-). O sequestrador da espécie NO (hidroxocobalamina) reduziu mais a resposta relaxante estimulada com RuBPY do que com o NPS. Nenhum dos dois compostos precisa ser reduzido quimicamente para liberar NO, uma vez que houve relaxamento quando utilizamos alta concentração de KCl como agente contrátil. Porém, este relaxamento foi inibido, o que mostra a importância dos canais para K+ no relaxamento induzido pelos doadores de NO. O bloqueador não seletivo de canais para K+ (TEA), inibiu somente o relaxamento ao RuBPY. A via NO-GCs-GK é ativada por ambos doadores de NO, para induzir relaxamento. A inibição da degradação do GMPc potencializou o relaxamento estimulado com RuBPY e NPS. O armazenamento de Ca+2 no retículo sarcoplasmático (RS) via ativação da SERCA é importante somente para o relaxamento induzido com RuBPY. O composto RuBPY inibiu a resposta contrátil estimulada com fenilefrina devido ao armazenamento de Ca+2 no RS e também por inibir o influxo capacitivo de Ca+2. A presença do endotélio vascular não alterou o relaxamento induzido pelo RuBPY, porém potencializou o relaxamento induzido pelo NPS. A análise da liberação de NO por amperometria demonstrou que o RuBPY libera NO somente em presença do tecido aórtico de ratos. Portanto, não houve liberação espontânea de NO, por fotólise pela luz visível ou por redução química. É necessária a presença de heme-proteínas como a guanilil-ciclase solúvel (GCs) inibida pelo ODQ, para haver a conversão do nitrito presente no RuBPY, a NO. Pela quantificação da fluorescência emitida pela sonda DAF-2DA, RuBPY liberou cerca de 3,5 vezes mais NO do que o NPS. Pela medida do potencial de membrana, demonstramos que o RuBPY induz hiperpolarização de membrana de células isoladas do MLV da aorta de rato. RuBPY tem efeito hipotensor dose-dependente, em ratos hipertensos renais, o que não ocorre em animais normotensos. A redução da pressão arterial em ratos hipertensos é maior do que nos normotensos. Em estudos iniciais de farmacocinética, verificamos que o composto RuBPY é absorvido por via oral e é distribuído entre alguns tecidos após ser administrado aos ratos, por gavagem. / Nitric oxide (NO) is the main endogenous vasodilator agent that regulates vascular tone. Among the compounds which are able of releasing NO, are the nitrosyl ruthenium complexes. The NO donor studied, RuBPY, does not present cytotoxicity in smooth muscle cells (SMC), in contrast to SNP. RuBPY has similar efficacy to SNP in inducing rat aorta relaxation, although SNP is more potent. Both compounds release intracellular radicalar NO (NO), and SNP also release ion nitroxyl (NO-). The NO scavenger (hydroxocobalamine) had greater effect on the relaxation induced by RuBPY than by SNP. Both compounds do not need to be chemically reduced to release NO, as demonstrated in aorta relaxation after pre-contraction with high concentrations of KCl. However, this relaxation was impaired, showing the importance of K+ channels to induce relaxation by NO released from these compounds. By using non-selective blocker for K+ channels (TEA), only the relaxation induced by RuBPY was inhibited. The NO-sGC-GK pathway is activated by NO donors to induce relaxation. Inhibition of cGMP degradation, potentiated the effect of RuBPY and SNP. Storage of Ca+2 in the sarcoplasmic reticulum (SR) via activation of SERCA is important only for the relaxation induced by RuBPY. The contractile response induced by phenylephrine was inhibited by RuBPY due to the storage of Ca+2 in RS and also by inhibiting the capacitive influx of Ca+2. The presence of endothelium had no effect on the relaxation induced by RuBPY, but it potentiated the relaxation induced by SNP. RuBPY released NO only in the presence of the rat aorta. The complex RuBPY did not spontaneously release NO, by photolysis by visible light, or by chemical reduction. RuBPY requires the presence of heme-protein such as guanylyl-cyclase, inhibited by ODQ, to convert nitrite to NO. The amount of NO released from RuBPY was about 3.5 times greater than that released from SNP. RuBPY induced membrane hyperpolarization of SMC. RuBPY has hypotensive effect in renal hypertensive rats in a dose-dependent way, which does not occur in normotensive rats. The decreased of blood pressure in hypertensive rats was greater than in normotensive rats. Initial studies of pharmacokinetics demonstrated that RuBPY is orally absorbed and it is also distributed in some tissues after being administered by gavage to rats.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-22T15:01:31Z No. of bitstreams: 1 rafaelapinheirolacerda.pdf: 2532354 bytes, checksum: a9f84d4aefdf273756887ac76d89cfa7 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-07T19:22:32Z (GMT) No. of bitstreams: 1 rafaelapinheirolacerda.pdf: 2532354 bytes, checksum: a9f84d4aefdf273756887ac76d89cfa7 (MD5) / Made available in DSpace on 2017-08-07T19:22:32Z (GMT). No. of bitstreams: 1 rafaelapinheirolacerda.pdf: 2532354 bytes, checksum: a9f84d4aefdf273756887ac76d89cfa7 (MD5) Previous issue date: 2014-01-28 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / INTRODUÇÃO: Pacientes com hipotireoidismo subclínico (HSC) podem apresentar alterações no sistema cardiovascular. Dessa forma, o objetivo desse estudo foi avaliar a integridade do reflexo pressor do exercício físico em mulheres com HSC. MÉTODOS: Foram avaliadas dezoito mulheres com HSC (Grupo HSC) e vinte mulheres eutiroidianas (Grupo Controle), pareadas por idade (37 ± 11 vs. 38 ± 11 anos, p=0,907, respectivamente), índice de massa corporal (26 ± 5 vs. 24 ± 4 kg/m2, p=0,221, respectivamente) e nível de atividade física (6,93 ± 0,81 vs. 7,66 ± 1,14, p=0,063, respectivamente). A pressão arterial foi medida minuto a minuto pelo método oscilométrico (DIXTAL2023®), a frequência cardíaca medida continuamente pelo eletrocardiograma (DIXTAL2023®) e o fluxo sanguíneo do antebraço pela técnica de pletismografia de oclusão venosa (Hokanson®). A condutância vascular do antebraço foi calculada pela divisão do fluxo sanguíneo do antebraço pela pressão arterial média, multiplicada por 100. Registrando essas variáveis por 3 minutos de basal seguidos de 3 minutos de exercício físico, foram realizados os protocolos de exercício físico passivo, exercício físico isométrico a 10% da contração voluntária máxima do antebraço, exercício físico a 30% da contração voluntária máxima do antebraço e por 2 minutos oclusão circulatória pós-exercício físico isométrico a 30%. ANOVA de dois fatores foi utilizada para testar as diferenças, adotando significativo p<0,05. RESULTADOS: Durante o exercício físico passivo, a pressão arterial sistólica, diastólica e média sofreram diminuição significativa, porém semelhante entre os grupos HSC e Controle. A frequência cardíaca, o fluxo sanguíneo do antebraço e a condutância vascular do antebraço não apresentaram modificações ao longo do protocolo de exercício físico passivo. Durante o exercício físico de leve intensidade a pressão arterial sistólica não sofreu nenhuma alteração, a pressão arterial diastólica foi significativamente diferente entre os grupos HSC e Controle. Os valores da pressão arterial média, frequência cardíaca, fluxo sanguíneo do antebraço e condutância vascular do antebraço apresentaram aumento significativo e se comportaram similarmente. Durante o exercício físico de moderada intensidade os valores de pressão arterial sistólica, diastólica, média, fluxo sanguíneo do antebraço e condutância vascular do antebraço aumentaram significativamente e similarmente entre os grupos HSC e Controle. Entretanto a frequência cardíaca apresentou comportamento significativamente diferente entre os grupos HSC e Controle, porém, ambos os grupos apresentaram aumento significativo da frequência cardíaca em relação aos valores basais. Para a oclusão circulatória, os grupos sofreram aumento da pressão arterial sistólica, diastólica e média, porém com comportamento similar. CONCLUSÃO: Mulheres com HSC apresentam reflexo pressor do exercício físico íntegro. / INTRODUCTION: Patients with subclinical hypothyroidism (SCH) may show changes in the cardiovascular system. Thus, the aim of this study was to evaluate the integrity of the pressor reflex exercise in women with SCH. METHODS: Were evaluated eighteen women with SCH (Group SCH) and twenty euthyroid women (Group Control), matched for age (37 ± 11 vs. 38 ± 11 years; p=0.907, respectively), body mass index (26 ± 5 vs. 24 ± 4 kg/m2; p=0.221, respectively) and level of physical activity (6,93 ± 0,81 vs. 7,66 ± 1,14, p=0,063, respectively). Blood pressure was measured every minute by oscillometry (DIXTAL2023®), heart rate measured continuously by electrocardiogram (DIXTAL2023®) and forearm blood flow by the technique of venous occlusion plethysmography (Hokanson®). In forearm vascular conductance was calculated by dividing the forearm blood flow by the mean arterial pressure multiplied by 100. Registering these variables from baseline for 3 minutes followed by 3 minutes of exercise, the protocols of passive exercise, isometric exercise at 10% of maximal voluntary contraction of forearm exercise at 30% maximal voluntary contraction of the forearm were performed and circulatory occlusion for 2 minutes post-isometric physical exercise to 30%. Two-factor ANOVA was used to test differences, significant considering p< 0.05. RESULTS: During the passive exercise, systolic blood pressure, diastolic and mean suffered significant decline, but similar between SCH and Control groups. The heart rate, forearm blood flow and vascular conductance of the forearm showed no change during the protocol of passive exercise. During mild exercise systolic blood pressure did not undergo any changes, diastolic blood pressure was significantly different between the SCH and Control groups. The values of mean arterial pressure, heart rate, forearm blood flow and vascular conductance of the forearm showed a significant increase and behaved similarly. During exercise of moderate intensity values of systolic, diastolic, mean, forearm blood flow and vascular conductance of the forearm increased significantly and similarly between SCH and Control groups. However, the heart rate behavior was significantly different between the SCH and Control groups, however, both groups showed a significant increase in heart rate from baseline. To circulatory occlusion groups had an increase in systolic blood pressure, diastolic and mean, but with similar behavior. CONCLUSION: Women with SCH have pressor reflex upright exercise.

Les espèces endothermes amphibies font face à de fortes contraintes durant leurs séjours en mer dont l’augmentation des coûts de thermorégulation. La recherche alimentaire du manchot royal (Aptenodytes patagonicus) s’étend sur plusieurs jours alternant des plongées profondes de chasse et des périodes de repos à la surface de l’eau correspondant à deux stratégies de thermorégulation différentes. Durant les plongées, l’hypothermie des tissus suggère une économie d’énergie visant à augmenter la durée d’apnée. Cependant, l’utilité de la réaugmentation des températures corporelles durant les périodes de repos reste méconnue. Alors que la digestion débute durant les plongées, nous supposons que le stockage des acides gras dans les tissus adipeux périphériques ne peut se faire que par le retour à normothermie de ces tissus. Nous avons testé cette hypothèse en maintenant des individus équipés d’enregistreurs de températures (périphériques et interne) dans une piscine d’eau de mer afin d’étudier les variations de températures en fonction de l’état nutritionnel des manchots. De plus, nous avons mesuré, par respirométrie, les dépenses énergétiques en fonction des températures corporelles. Enfin, nous avons étudié les variations de flux sanguins à l’aide de thermographie infra-rouge afin de comprendre le retour à normothermie des tissus périphériques et les coûts énergétiques associés. / The energetic cost of foraging activities in King Penguin (Aptenodytes patagonicus) consists to reach favourable areas, realizes depth diving to attempt fish patch and resting in high latitude cold water. Several studies have shown that resting in cold water could be represent a more expensive cost than realized depth diving. Indeed, this paradox is probably linked with contrasting thermoregulation processes. During daylight, a general hypothermia occurs and is believed to reduce energy expenditure. At sunrise occurs a re-warming to normothermia, contributing to increase heat-loss during the night. We hypothesise an energetic conflict between thermoregulation and digestive processes. During daylight, the organism may be unable to assimilate the end product of prey digestion (free fatty acids) inside the peripheral subcutaneous adipose tissues (SAT), because skin is no more blood perfused. During the night, re-warming and re-connecting to blood circulation peripheral tissues could be inevitable to end the assimilation of FFA inside the SAT. In a first step, we have reproduced the conditions of a resting night at sea and events of rewarming skin temperature, using a sea water tank in which king penguins equipped with internal temperature loggers were maintained several days. In a second step, we have tested a generalisation of our hypothesis studying body temperature variations on penguins fast and feed. Finally, we have measured the cost to maintain normothermia in cold water with respirometry measures and investigated peripheral vasodilation with body temperature variations and infrared thermography.

Indiana University-Purdue University Indianapolis (IUPUI) / Although paclitaxel is a commonly used anti-neoplastic agent for the treatment of solid tumors, therapy often results in a number of side effects, the most debilitating of which is peripheral neuropathy. Peripheral neuropathy is defined as a pathology of peripheral nerves, and, depending on the type of nerves damaged, the neuropathy can be classified as sensory, motor, or autonomic neuropathy. In the case of peripheral neuropathy induced by paclitaxel, the symptoms are experienced in the extremities and are sensory in nature. Patients undergoing chemotherapy with paclitaxel often report sensory disturbances such as burning, tingling, numbness, a diminished sensation to pain and temperature, loss of vibration sense, loss of proprioception, and loss of deep tendon reflexes. Electrophysiological abnormalities including decreased sensory nerve action potential amplitude and conduction confirm damage to large myelinated fibers. However, the involvement of damage to small diameter sensory neurons in the etiology of paclitaxel – induced peripheral neuropathy is still controversial. Therefore, experiments were performed to determine if paclitaxel alters the function of small diameter sensory neurons and to examine the mechanisms responsible for the change in function. vi Sensory neuron mediated vasodilatation in paclitaxel – injected animals was examined as an indirect measure of calcitonin gene related peptide (CGRP) release and therefore of sensory neuron function. CGRP release was also directly measured from central terminals in the spinal cord. To examine mechanisms of paclitaxel – induced sensory neuron damage, CGRP release and neurite length was examined in paclitaxel – treated sensory neurons in culture. The results demonstrate that (1) paclitaxel decreases the ability of small diameter sensory neurons to produce an increase in blood flow in the skin; (2) paclitaxel alters the release of CGRP from the small diameter sensory neurons; (3) paclitaxel causes the neuronal processes of isolated sensory neurons to degenerate. This dissertation provides novel information showing that paclitaxel alters the function of small diameter sensory neurons and thus provides a better understanding of the mechanisms mediating the sensory disturbances characteristic of peripheral neuropathy resulting from chemotherapy with paclitaxel.

Affectant près d'un milliard de personnes dans le monde, l'hypertension artérielle représente un facteur de risque majeur de pathologies cardiovasculaires et d'insuffisance rénale et constitue l'une des principales causes de mortalité. L'identification de traitements anti-hypertenseurs efficaces et tenant compte des particularités des différentes populations du globe présente ainsi un intérêt capital en termes de santé publique. Notre travail a été consacré à l'étude de plantes anti-hypertensives de la Pharmacopée ouïghoure, principale ethnie de la Région autonome du Xinjiang, vaste territoire montagneux et désertique situé au Nord-Ouest de la Chine. L'objectif de la thèse a été d'apporter des arguments scientifiques, phytochimiques et pharmacologiques, permettant de valider et valoriser l'utilisation traditionnelle de ces plantes. La première partie du travail a démontré sur le modèle d'aortes isolées de rat l'effet vasodilatateur de Ziziphora clinopodioides Lam. (Lamiaceae). L'étude des mécanismes impliqués a permis d'identifier une action indépendante de l'endothélium vasculaire et secondaire à une modification des conductances calciques et potassiques. La réalisation d'un fractionnement bioguidé a permis l'identification de 7 métabolites vasoactifs d'origine phénolique. Dans une deuxième partie, les propriétés vasodilatatrices et hypotensives des fruits Nitraria sibirica Pall. (Nitrariaceae) ont été démontrées. L'endothélium vasculaire et la voie du monoxyde d'azote ont été identifiés comme les éléments fondamentaux de cette action vasodilatatrice. Dans une troisième partie, nos travaux ont étudié pour la première fois les effets vasorelaxants et la composition chimique d'Echinops integrifolius Kar. & Kir. (Asteraceae) et ont permis de caractériser 11 métabolites incluant des triterpènes, des flavonoïdes ainsi qu'une coumarine. En conclusion, notre travail de thèse a permis d'apporter, pour la première fois, des arguments expérimentaux soutenant l'usage anti-hypertensif des espèces Ziziphora clinopodioides et Nitraria sibirica. L'étude phytochimique d'Echinops integrifo/ius a également offert des informations chimiotaxonomiques utiles concernant cette espèce et le genre Echinops / Affecting nearly one billion people worldwide, hypertension is the most important risk factor for cardiovascular disease and kidney failure and it is also one of the leading causes of death. The identification of efficient antihypertensive treatments taking into account the specificities of different populations of the world is an important public-health challenge. Our work has been dedicated to the study of anti-hypertensive plants from the Uighur Pharmacopoeia, one of the major ethnie groups in the Xinjiang Autonomous Region, a large desert and mountainous area from the northwestern China. The aim of this work was to provide phytochemical and pharmacological evidences to validate and to enhance the traditional use of these plants. First, the vasodilating properties of Ziziphora clinopodioides Lam. (Lamiaceae) have been shown by using the in vitro model of isolated rat aortic rings. Our data reported an endothelium-independent effect related to changes in calcium and potassium conductances. ln addition, a bioguided fractionation has been carried out and led to the identification of seven vasorelaxant phenolic compounds. Second, the vasodilating and the hypotensive effects of the fruits of Nitraria sibirica Pail. (Nitrariaceae) have been demonstrated and the contribution of vascular endothelium and nitric oxide pathway has been pointed out. Finally, the vasorelaxant properties and the chemical composition of Echinops integrifolius Kar. & Kir. have been investigated for the first time. Eleven secondary metabolites have been isolated including triterpenes, flavonoids and coumarins. ln conclusion, our results provide scientific evidences supporting the traditional use of Ziziphora clinopodioides and Nitraria sibirica as antihypertensive therapy. Additionaly, the phytochemical study of Echinops integrifolius gives chemotaxonomical data about that species and Echinops genus

As reações de alerta e defesa compreendem ajustes cardiovasculares proporcionando um fluxo sangüíneo muscular adequado nas situações de \"luta ou fuga\". As vias centrais e os possíveis neurotransmissores envolvidos nestes ajustes permanecem ainda, em grande parte, desconhecidas. Neste estudo buscamos analisar a participação da neurotransmissão purinérgica e glutamatérgica no núcleo do trato solitário (NTS) na gênese da vasodilatação muscular durante reações de defesa e o papel das vias glutamatérgicas do NTS para o núcleo rostroventrolateral (RVL) nestas respostas. Ratos Wistar machos (250-350 g) foram anestesiados (uretana 600 mg/kg + alpha-chloralose 50 mg/kg, i.v.), paralisados (d-Tubocurarina, 0,5 mg/kg, i.v.) e ventilados artificialmente. Registramos a pressão arterial média (PAM), a freqüência cardíaca (FC) e o fluxo sangüíneo dos membros posteriores (FSMP). A condutância vascular dos membros posteriores (CVMP) foi determinada como a razão FSMP/PAM e expressa como percentagem do valor basal. A estimulação elétrica (EE; 150 MuA; 0,6 ms; 100 Hz; 6 s) do hipotálamo lateral provocou hipertensão, taquicardia e vasodilatação nos membros posteriores. A microinjeção bilateral de suramin (100 pmol/50 nl), um antagonista não específico de receptores P2x no NTS, reduziu a vasodilatação nos membros posteriores durante a EE do hipotálamo (173±19,0 vs 28±14,1% do basal) sem alterar as respostas pressora e taquicárdica. A microinjeção do agonista P2x alpha, beta-methylene ATP (100 pmol/50 nl) no NTS produziu hipotensão, bradicardia e vasodilatação dos membros posteriores. A microinjeção de suramin (100 pmol/50 nl) bloqueou a vasodilatação muscular (76±15,2 vs 9±2,1% do basal) e a hipotensão (-47±4,5 vs -6±2,0 mmHg). A microinjeção de ácido quinurênico (4 nmol/50 nl), um antagonista glutamatérgico ionotrópico não seletivo no NTS bloqueou, de forma semelhante ao suramin, a vasodilatação durante a EE do hipotálamo (134±21,5 vs 27±12,7% do basal) sem alterar as respostas pressora ou taquicárdica. O bloqueio bilateral no RVL com microinjeções de ácido quinurênico reduziu intensamente a resposta hipotensora (-60±6,1 vs -9±3,7 mmHg) e vasodilatadora (126±16,9 vs 17±4,6% do basal) provocada pelas microinjeções de alpha, beta-methylene ATP (100 pmol/50 nl) no NTS. O agonista purinérgico A2a, CGS21680 (20 pmol/50 nl) no NTS, evocou hipotensão, bradicardia e vasodilatação muscular de longa duração. O bloqueio do RVL com ácido quinurênico (4 nmol/50 nl) reduziu a hipotensão (- 41±4,7 vs -7±1,9 mmHg), a bradicardia (-33±9 vs -10±3,1 bpm) e a vasodilatação nos membros posteriores (81±5,6 vs 8±1,5% do basal). Estes resultados sugerem que a vasodilatação muscular nas repostas de defesa depende da ativação de receptores P2x e receptores glutamatérgicos no NTS. Ajustes cardiovasculares por ativação dos receptores purinérgicos P2x e A2a no NTS provocam vasodilatação muscular que depende da liberação de glutamato no RVL, provavelmente ativando interneurônios inibitórios ali presentes. / The electrical stimulation (ES) of the hypothalamus in the rat produces a well- defined pattern of cardiovascular adjustments including hypertension, tachycardia and skeletal muscle vasodilation. These hemodynamic responses can also be observed in natural conditions during fight and/or flight behaviors. However the neural pathways and possible neurotransmitters involved remain largely unknown. In this study we sought to determine the role of purinergic and glutamatergic receptors into the nucleus tractus solitarius (NTS) in the cardiovascular responses induced by hypothalamic ES, also we aimed to analyze the role of glutamatergic neural pathways from the NTS to the rostral ventrolateral medulla (RVLM) in these responses. Male Wistar rats (250-350 g) were anesthetized (urethane 600 mg/kg + alpha-chloralose 50 mg/kg, iv), paralyzed (d-tubocurarine 0.5 mg/kg, iv) and artificially ventilated. Mean arterial blood pressure (MAP), heart rate (HR) and hindquarter blood flow (HQBF) were recorded. Hindquarter vascular conductance (HQVC) was calculated as the ratio HQBF/MAP and expressed as percentage of baseline. Hypothalamic ES (6s trains, 0.6 ms square pulses, 100 Hz, 150 MuA) evoked a transitory hypertension, tachycardia and hindlimb muscle vasodilation. After bilateral microinjections of suramin (100 pmol /50 nl), a non-specific P2x receptor antagonist, into the NTS the hindlimb vasodilation was reduced (173±19.0 vs 28±14.1% of baseline), even so the transitory hypertension and tachycardia remained unchanged. A similar vasodilation reduction (134±21.5 vs 27±12.7% of baseline) was observed after microinjections of kynurenic acid bilaterally at the same NTS sites. Microinjections of the P2x receptor agonist alpha, beta-methylene ATP (100 pmol/50 nl) into the NTS produced hypotension, bradycardia and hindlimb muscle vasodilation. Bilateral microinjections of suramin at the same NTS site reduced the hypotension (-47±4.5 vs -6±2.0 mmHg) and the vasodilation (76±15.2 vs 9±2.1% of baseline). After bilateral microinjection of kynurenic acid into the RVLM, both hypotension (-60±6.1 vs -9±3.7 mmHg) and the vasodilation response (126±16.9 vs 17±4.6% of baseline) induced by alpha, beta- methylene ATP into the NTS were reduced. The A2a agonist CGS21680 (20 pmol/50 nl) into the NTS produced a long-lasting hypotension, bradycardia and hindlimb vasodilation. Bilateral RVLM glutamatergic blockade reduced the hypotension (-41±4.7 vs -7±1.9 mmHg), the tachycardia (-33±9.0 vs -10±3.1 bpm) and the muscle vasodilation (81±5.6 vs 8±1.5% of baseline) when CGS21680 was injected into the NTS. Therefore the results suggest that in alerting defense reaction, hindquarter vasodilation is mediated by NTS P2x and also by glutamatergic receptors into the intermediate NTS. Cardiovascular responses evoked by either P2x or A2a receptors stimulation in the NTS are mediated by glutamatergic synapses into the RVLM probably through activation of inhibitory interneurones in this area.