Thèses (Ph.D.)--Université de Sherbrooke (Canada), 2001. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.

O presente estudo avaliou, em aorta de ratos, o efeito de uma sessão de exercício físico aeróbio na resposta vasoconstritora dependente e independente de receptores adrenérgicos, assim como a participação dos sistemas de síntese e remoção de óxido nítrico (NO) nestas respostas. Para isso, um grupo de ratos foi submetido a uma sessão de exercício físico em esteira rolante (grupo EX, n=14), enquanto o outro grupo permaneceu em repouso (grupo CTR, n=14), sendo que imediatamente após este período os ratos de ambos os grupos foram sacrificados e foi feita a retirada da aorta torácica para realização de medidas funcionais e bioquímicas in vitro. Resultados: pudemos observar que o grupo EX apresentou menor resposta vasoconstritora máxima à noradrenalina e ao cloreto de potássio quando comparados ao grupo CTR. Esta diferença na reatividade vascular deixou de ser observada nos anéis aórticos com o endotélio removido ou pré-incubados com um inibidor da síntese de NO. Além disso, o grupo EX apresentou maior biodisponibilidade de NO, maiores níveis vasculares de ânions superóxido, e maiores atividades das enzimas NAD(P)H oxidase e superóxido dismutase comparado ao grupo CTR. Esses resultados demonstram que uma única sessão de exercício físico aeróbio é capaz de atenuar a resposta vasoconstritora dependente e independente de receptores adrenérgicos em aorta de ratos, principalmente por aumentar a biodisponibilidade vascular de óxido nítrico, apesar de aumentar os níveis vasculares de ânions superóxido / The present study investigated, in rat aortas, the effect of one bout of aerobic exercise on the adrenergic receptor-dependent and -independent vasoconstrictor response, and the role of nitric oxide (NO) synthesis and scavenging systems on this vasomotor response. One group of rats was submitted to a single bout of exercise on a treadmill (EX group, n=14) and the other one was placed in the treadmill without running (CTR group, n=14). Immediately after this period, both groups were euthanized and the thoracic aorta was removed for functional and biochemical analysis. Results: one bout of exercise attenuated the maximal contractile response to both noradrenaline and potassium chloride compared to CTR group. These differences on vascular reactivity were not observed in aortic rings when the endothelium was removed or aortic rings pre-incubated with a nitric oxide synthesis inhibitor. Additionally, EX group increased NO bioavailability, increased vascular superoxide levels, and increased NAD(P)H oxidase and superoxide dismutase activity compared to CTR group. These results demonstrate that one bout of aerobic exercise is able to attenuate adrenergic receptor-dependent and -independent vasoconstrictor response in rat aorta, mainly by increasing vascular NO bioavailability, despite the enhanced vascular superoxide levels

The involvement of the endothelial cell in the vasoconstriction induced by angiotensin I and II (AI, AII), and norepinephrine (NE) was studied in microvessels of the hamster cheek pouch before and after the following procedures: endothelial impairment by light-dye treatment, inhibition of angiotensin-converting enzyme (ACE), blockade of endothelium-derived relaxing factor (EDRF) and inhibiting prostaglandin (PG) synthesis. The results showed that in large 2nd-order arterioles, endothelial impairment did not affect the vasoconstrictor activity of AII and NE, nor did it alter ACE activity. However, in small 4th-order arterioles, endothelial impairment significantly reduced angiotensin conversion without altering the vasoconstrictor responses to either AII or NE. Thus, the endothelium plays differential roles in the modulation of local angiotensin conversion in these distinct segments of serial-arranged arterioles. Furthermore, it is unlikely that the vasoconstrictor response to AII in these arterioles is modulated by the endothelium through a pathway involving the release of EDRF or PGs.

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Current state-of-the-art thermoregulatory models do not predict body temperatures with the accuracies that are required for the development of automatic cooling control in liquid cooling garment (LCG) systems. Automatic cooling control would be beneficial in a variety of space, aviation, military, and industrial environments for optimizing cooling efficiency, for making LCGs as portable and practical as possible, for alleviating the individual from manual cooling control, and for improving thermal comfort and cognitive performance. In this study, we adopt the Fiala thermoregulatory model, which has previously demonstrated state-of-the-art predictive abilities in air environments, for use in LCG environments. We validate the numerical formulation with analytical solutions to the bioheat equation, and find our model to be accurate and stable with a variety of different grid configurations. We then compare the thermoregulatory model s tissue temperature predictions with experimental data where individuals, equipped with an LCG, exercise according to a 700 W rectangular type activity schedule. The root mean square (RMS) deviation between the model response and the mean experimental group response is 0.16°C for the rectal temperature and 0.70°C for the mean skin temperature, which is within state-of-the-art variations. However, with a mean absolute body heat storage error (e_BHS_mean) of 9.7 W·h, the model fails to satisfy the ±6.5 W·h accuracy that is required for the automatic LCG cooling control development. In order to improve model predictions, we modify the blood flow dynamics of the thermoregulatory model. Instead of using step responses to changing requirements, we introduce exponential responses to the muscle blood flow and the vasoconstriction command. We find that such modifications have an insignificant effect on temperature predictions. However, a new vasoconstriction dependency, i.e. the rate of change of hypothalamus temperature weighted by the hypothalamus error signal (DThy·dThy/dt), proves to be an important signal that governs the thermoregulatory response during conditions of simultaneously increasing core and decreasing skin temperatures, which is a common scenario in LCG environments. With the new DThy·dThy/dt dependency in the vasoconstriction command, the e_BHS_mean for the exercise period is reduced by 59% (from 12.9 W·h to 5.2 W·h). Even though the new e_BHS_mean of 5.8 W·h for the total activity schedule is within the target accuracy of ±6.5 W·h, e_BHS fails to stay within the target accuracy during the entire activity schedule. With additional improvements to the central blood pool formulation, the LCG boundary condition, and the agreement between model set-points and actual experimental initial conditions, it seems possible to achieve the strict accuracy that is needed for automatic cooling control development.

La méthode d'auto-assemblage développée dans notre laboratoire a permis de mettre au point une prothèse vasculaire de faible diamètre composée uniquement de cellules humaines. Cette prothèse possède plusieurs caractéristiques propres aux vaisseaux sanguins natifs. Un des rôles principaux des vaisseaux sanguins est la régulation du tonus musculaire par la contraction et la relaxation suite à l'action de différentes hormones. La technique d'auto-assemblage permet la reconstruction de chacune des différentes tuniques du vaisseau indépendamment les unes des autres. La modulation du tonus vasculaire médiée par les cellules musculaires lisses de la média a pu tout d'abord être évaluée. L'endothéline est le vasopresseur le plus puissant connu à ce jour et est impliquée dans la régulation du tonus musculaire et de la résistance périphérique. La présence d'un système endothélinergique fonctionnel sur la média de la prothèse vasculaire a été étudiée. Les résultats montrent que la média de cette prothèse possède un système endothélinergique fonctionnel et identique à celui retrouvé dans le tissu d'origine des cellules prélevées pour reconstruire la prothèse vasculaire. De plus, suite à ces résultats, différentes prothèses vasculaires possédant une expression différentielle des récepteurs aux endothélines ont été créées. Le rôle de l'adventice dans la régulation du tonus vasculaire n'est pas bien établi. Par la technique d'auto-assemblage, une média, une adventice et une media+une adventice ont pu être reconstruites afin d'étudier l'implication de l'adventice dans la vasoréactivité du vaisseau sanguin. Les résultats montrent une implication directe de l'adventice dans la réponse vasoactive du vaisseau. De plus, un nouveau modèle pharmacologique d'adventice a été créé. Ainsi, la technique d'auto-assemblage constitue un substitut vasculaire fonctionnel de choix pour la recherche fondamentale et pharmacologique.

Ginger (Zingiber Officinale) has been used in Asia for centuries to treat various ailments. Ginger has been reported to alleviate migraine pain via four bioactive compounds that can reduce nitric oxide synthase (NOS) resulting in the inhibition of nitric oxide (NO). The inhibition of nitric oxide results in the vasoconstriction of the intracranial blood vessels alleviating migraine pain. It is hypothesized that ginger has structural similarities to vasoconstrictor drugs causing similar receptor interactions. A review of the bioactive compounds in ginger and popular vasoconstrictor drugs was done to determine structural similarities. The results of this study show that the compounds in ginger share no structural similarities with vasoconstrictor drugs used in the treatment of migraine headaches.

<p>A comprehensive understanding of the mechanisms regulating vascular structure and function may assist in designing effective strategies to decrease cardiovascular disease risk. The current studies were designed to investigate a) relationships between collagen markers and arterial stiffness and markers of vasoconstriction and inflammation and endothelial function in humans with a wide range of vascular health, including overweight women, elderly healthy men, individuals with coronary artery disease, individuals with spinal cord injury and young healthy men and b) changes in arterial structure and function and circulating serum markers of type I collagen synthesis and degradation, vasoconstriction and inflammation in overweight pre-menopausal women before and after a 16- week diet and exercise intervention. Resting brachial artery flow mediated dilation (FMD), upper limb and/or central pulse wave velocity (PWV_c-r and PWV_c-f) and carotid artery distensibility were assessed at baseline in all groups and, in the overweight population, after the 16-week intervention. Pro-collagen type I C-peptide (PIP), C-telopeptide of type I collagen (CTX), markers of collagen synthesis and degradation respectively, endothelin-1 (ET-1) a vasoconstrictor and interleukin-6 (IL-6) an inflammatory marker were measured. In the spectrum of vascular health, a negative relationship exists between collagen markers and central PWV (CTX–PWV_c-f: r = -0.41, p = 0.001 and PIP – PWV_c-f: r = -0.32, p = 0.01) and a positive relationship between markers and carotid distensibility (CTX: r = 0.59, pc-r increased over time in the overweight population (FMD pre: 4.1 ± 0.5 % vs. post: 6.9 ± 0.7 %, pc-r pre: 8.1 ± 0.3 m/s vs. post: 8.9 ± 0.3 m/s, p</p> / Doctor of Philosophy (PhD)

Nous avons montré : a) qu’il existe un lien entre la consommation de cannabis et la présence de sténoses artérielles intracrâniennes multifocales chez le jeune adulte victime d’infarctus cérébral, b) que la prévalence des sténoses artérielles intracrâniennes atteint un tiers des cas dans une cohorte de 159 infarctus cérébraux du jeune adulte, c) que 13% des infarctus cérébraux dans cette série répondent aux critères angiographiques du syndrome de vasoconstriction cérébrale réversible déclenché majoritairement par la consommation de cannabis, d) que le tétrahydrocannabinol (THC, le principal produit actif du cannabis) inhibe in vitro la chaîne respiratoire mitochondriale de cerveau de rat, et induit une génération significative de peroxyde d’hydrogène. La génération de radicaux libres pourrait être un des mécanismes possibles de toxicité cérébrale du THC en jeu lors d’un infarctus cérébral. / We showed that: a) there was a link between cannabis use and intracranial arterial multifocal stenosis in a series of ischemic stroke in the young, b) the prevalence of intracranial arterial stenosis was up to 31% in a series of 159 ischemic strokes in the young, c) 13% of the patients in this series sustained the angiographic criteria of reversible cerebral vasoconstriction syndrome, and that the precipitating factor was the use of cannabis in 67% of cases, d) tetrahydrocannabinol (THC, the main active component in cannabis) inhibits the respiratory mitochondrial chain of the brain in rats and induces a significant production of hydrogen peroxide. These results suggest that one of the mechanisms of brain toxicity induced by cannabis in ischemic stroke patients, may be the high rate of generation of free radicals induced by THC

O sistema nervoso simpático (SNS) desempenha importante papel sobre o controle da pressão arterial assim como o endotélio, pela liberação de fatores de relaxamento e contração que atuam sobre a modulação do tônus vascular. A hipertensão renovascular (2R-1C) está associada à elevada produção de espécies reativas de oxigênio, hiperatividade do SNS e disfunção endotelial. A hipótese deste trabalho é de que os agonistas adrenérgicos noradrenalina (NOR) e adrenalina (ADR), catecolaminas endógenas, promovam efeito anti-contrátil devido à ativação da eNOS em aorta de ratos 2R-1C. Este estudo teve por objetivo investigar se a ativação de adrenoceptores (AR) com NOR ou ADR leva à maior ativação da eNOS em aortas de ratos 2R-1C do que em 2R e os mecanismos relacionados. Realizamos curvas concentração-efeito para NOR ou ADR, em aortas com ou sem endotélio de ratos 2R e 2R-1C em ausência (controle) ou presença dos antagonistas ?-AR (propranolol), ?2-AR (ioimbina), e inibidor não seletivo da NOS (L-NAME). Por western blot, verificamos a fosforilação do resíduo de ativação da enzima eNOS, Serina1177 (Ser1177), via ativação de ?-AR ou ?-AR, pela NOR ou ADR em aortas com endotélio, de ratos 2R e 2R-1C e se a via PI3K/AKT e o H2O2 estariam envolvidos nesse processo. Avaliamos a produção de NO pelas células endoteliais isoladas de ratos 2R e 2R-1C, por citometria de fluxo. Realizamos a dosagem de NOR e ADR plasmática e tecidual (adrenais) por meio de HPLC. Nos estudos de reatividade vascular avaliamos a potência (pD2) e eficácia (Emax) dos agonistas em induzir contração. O Emax da NOR foi menor na contração de aorta de ratos 2R-1C comparada a 2R, provavelmente devido à maior atividade da eNOS evidenciada pelo efeito do L-NAME em aorta de 2R-1C. A particularidade mais significativa da resposta da NOR é de que em aorta de ratos 2R-1C, a NOR promove a maior fosforilação de Ser1177 via ?-AR, e esta envolve a participação da via PI3K/AKT e do H2O2, não havendo alteração dos níveis plasmáticos e tecidual de NOR entre 2R e 2R-1C. O estímulo com ADR, em aorta de 2R-1C, promoveu aumento da atividade da eNOS, certificada pelo efeito do L-NAME, que pode contribuir para o menor Emax da ADR em 2R-1C do que em 2R. Entretanto, a ADR promoveu maior fosforilação de Ser1177 via ?-AR, em aorta de ratos 2R-1C, e esta não envolve participação da via PI3K/AKT e do H2O2. Os níveis teciduais de ADR foram semelhantes entre 2R e 2R- 1C, mas a concentração plasmática de ADR foi menor em 2R-1C do que em 2R. Não houve diferença na produção de NO pelas células endoteliais entre 2R e 2R-1C. Os resultados obtidos sugerem que a ativação de ?-AR com NOR envolve participação de H2O2 e da via PI3K/AKT para maior ativação da eNOS em aortas de ratos 2R-1C, mecanismo que pode contribuir para o menor Emax da NOR em aorta de 2R-1C. A ADR ao ativar ?-AR leva à maior ativação da eNOS, porém sem participação efetiva de H2O2 e da via PI3K/AKT em aortas de ratos 2R-1C. / The sympathetic nervous system (SNS) plays important role on the arterial pressure control as well the vascular endothelium by relaxing and contractile factors release that modulates the vascular tone. The renovascular hypertension (2K-1C) is related to the increased production of oxygen reactive species, SNS hyperactivity and endothelium dysfunction. The hypothesis of this work is that the adrenoceptor (AR) agonists noradrenaline (NOR) and adrenaline (ADR), the endogenous catecholamine promote anti-contractile effect due to eNOS activation in 2K-1C rat aorta. This study aimed to investigate if AR activation by NOR or ADR leads to the increased activation of eNOS in 2K-1C rat aorta, and the mechanisms activated by these agonists. Concentration-effect curves were constructed for NOR or ADR, in intactendothelium or denuded aortas isolated from 2K-1C and 2K rats in the absence (control) or in the presence of the AR antagonists propranolol (?-AR) or yohimbine (?2-AR), or the non-selective NOS inhibitor, L-NAME. By using western blot, we have veryfied the the effects of activation of ?-AR ou ?-AR and the phosphorylation of NOS activation site Serine1177 (Ser1177) by NOR or ADR in intact endothelium aorta from 2K and 2K-1C and also whether the PI3K/AKT pathway and hydrogen peroxide (H2O2) are related to this phosphorylation. We evaluated by flow cytometry the NO production in the isolated endotelial cells from 2K and 2K-1C. Plasma and tissue (adrenal) levels of NOR and ADR were measured by HPLC. In the vascular reactivity studies, we evaluated the potency (pD2) and efficacy (Emax) of the agonists in inducing contraction. The Emax induced by NOR was lower in 2K-1C than in 2K rat probably due to the higher activity of eNOS as shown by the effect of L-NAME. The most interesting finding was in 2K-1C aorta that NOR increases the Ser1177 phosphorylation via ?-AR activation that involves the signaling trough PI3K/AKT and H2O2. There is no differences in NOR at the plasma and tissue levels between 2K-1C and 2K. ADR activates more eNOS in 2K-1C rat aorta as shown by the effect of LNAME. It could contribute to the lower Emax of ADR in 2K-1C than in 2K. However, ADR increased Ser1177 phosphorylation via ?-AR activation in 2K-1C rat aorta, which does not involve PI3K/AKT and H2O2 pathway. The tissue levels of ADR were not different between 2K-1C and 2K, but the plasma concentration of ADR was lower in 2K-1C than in 2K. There was no difference in the NO production in the endothelial cells from 2K-1C and 2K. Taken together, our results suggest that ?-AR activation by NOR involves H2O2 and PI3K/AKT that activates eNOS in 2K-1C rat aorta that could contribute to the lower contractile effect induced by NOR in 2K-1C. ?-AR activation by ADR leads to the eNOS activation without activation of H2O2 and PI3K/AKT pathway in 2K-1C rat aorta.