No description available.

INTRODUÇÃO: Não são conhecidos os mecanismos que determinam o comportamento da pressão arterial durante o sono. OBJETIVO: Investigar o papel do sistema nervoso simpático, do sistema renina-angiotensinaaldosterona e da excreção de sódio urinário no descenso da pressão arterial durante o sono. MÉTODOS: Hipertensos e normotensos foram submetidos a duas monitorizações ambulatoriais de pressão arterial (MAPA)/24h com SpaceLabs 90207, medidas de 15/15 minutos durante a vigília e de 20/20 minutos no período de sono. Na ocasião da MAPA 1 foram submetidos às dosagens laboratoriais de atividade de renina (ARP), aldosterona e catecolaminas plasmáticas e excreção em diurese de 24h de sódio (Na+u), potássio (K+u) e creatinina. Após o período médio de 50 ± 20 (média ± DP) dias a MAPA e as dosagens foram repetidas. RESULTADOS: Foram incluídos 35 hipertensos e 24 normotensos, com idade 56 ± 12 anos, 45 mulheres e 42 com cor da pele branca. Não houve diferença nos parâmetros laboratoriais na ocasião da MAPA 1 e da MAPA 2 nos normotensos e hipertensos. Mantiveram o mesmo comportamento de descenso da pressão sistólica e diastólica durante o sono nas duas MAPAs (>= 10% ou < 10%) 29 (49%) indivíduos, denominado grupo manteve (hipertensos n = 18). Mudaram o comportamento do descenso durante o sono da pressão sistólica ou diastólica (de >= 10% para < 10% ou de < 10% para >= 10%) 30 (51%) indivíduos, denominado grupo mudou (hipertensos n = 17). O grupo \"mudou\" apresentou menor Na+u na ocasião da MAPA 2 (145 ± 65 mEq/24 h vs 120 ± 46 mEq/24 h, p = 0,04). Houve correlação positiva entre: a) a diferença do descenso da pressão sistólica e a diferença dos resultados das dosagens de Na+u (r = 0,41; p = 0,01) realizadas nas MAPAs 1 e 2 em todos os indivíduos dos grupos \"manteve\" e \"mudou\"; b) a diferença do descenso da pressão sistólica e a diferença de Na+u/creatinina urinária (r = 0,67; p = 0,03) e de L dopa plasmática (r = 0,75; p = 0,003) realizadas nas MAPAs 1 e 2 no grupo \"manteve\" (>= 10%); e c) a diferença do descenso da pressão sistólica e a diferença do resultado das dosagens de ARP/Na+u realizadas nas MAPAs 1 e 2 (r = 0,81; p = 0,03) no grupo \"manteve\" (< 10%). CONCLUSÃO: Em hipertensos e normotensos, sem intervenção medicamentosa ou dietética, a diferença do descenso da pressão sistólica durante o sono entre duas MAPAs apresenta correlação positiva com a diferença da excreção de sódio urinário / INTRODUCTION: The mechanisms which determine the pattern of blood pressure during sleep are unknown. OBJECTIVE: To investigate the role of the sympathetic nervous system, renin-angiotensin-aldosterone system and urinary sodium excretion in the nocturnal blood pressure fall. METHODS: Hypertensive and normotensive subjects were submitted to two ambulatorial blood pressure monitorings (ABPM)/24h with a SpaceLabs 90207 equipment programmed to obtain measurements 15/15 minutes while awake and 20/20 minutes during sleep. Upon the ABPM 1, they were submitted to laboratory measurements of plasma renin activity (PRA), plasma aldosterone and catecholamines, as well as of the excretion of sodium (UNa+), potassium (UK+) and creatinine in 24-h-diuresis. After a mean period of 50 ± 20 days, the ABPM and the laboratory measurements were repeated. RESULTS: Included in the study were 35 hypertensive and 24 normotensive subjects, aged 56 ± 12 years, of which 45 were females and 42 Caucasian. There was no difference in the laboratory parameters measured upon ABPM 1 or 2, in either normotensive or hypertensive subjects. The same pattern of nocturnal systolic and diastolic pressure fall was maintained in both ABPMs (>=10% or <10%) by 29 (49%) subjects, named the \"maintained\" group (hypertensive n = 18). The nocturnal systolic or diastolic pressure fall changed (from >=10% to <10% or from <10% to >=10%) in 30 (51%) subjects, named the \"changed\" group (hypertensive n = 17). The \"changed\" group showed a smaller UNa+ upon the ABPM 2 (145 ± 65 mEq/24 h vs 120 ± 46 mEq/24 h; p = 0.04). There was a positive correlation between the difference in the nocturnal systolic pressure fall and the difference in the results of the UNa+ (r = 0,41; p = 0,01) measurements performed upon ABPM 1 and 2 in the normotensive or hypertensive subjects of the \"maintained\" and \"changed\" groups; b) the difference in the nocturnal systolic pressure fall and the difference in the measurements of UNa+/creatinine excretion (r = 0.67; p = 0.025) and plasma L dopa (r = 0.75; p = 0.003) carried out upon ABPM 1 and 2 in the \"maintained\" group (>=10%); and c) the difference in the nocturnal systolic pressure fall and the difference in the results of the PRA/UNa+ measurements performed upon ABPM 1 and 2 (r = 0.81; p = 0.03) in the \"maintained\" group (<10%). CONCLUSION: In hypertensive and normotensive individuals, without any pharmacological or dietary intervention, the difference in the nocturnal systolic pressure fall between the two ABPMs shows a positive correlation with the difference in urinary sodium excretion

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not well understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase (FAAH), PF-3845. Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. HPLC analyses of lipid extracts of MMIC culture medium revealed a 205nm-absorbing peak that showed responsiveness to PF-3845 treatment. The biologic activities of the PF-3845-induced product (PIP) isolated by HPLC were investigated in anesthetized, normotensive surgically-instrumented mice. Intramedullary and intravenous infusion of PIP at low dose rates (0.5-1 AU/10 min) stimulated diuresis and natriuresis, whereas at higher doses, these parameters returned toward baseline but mean arterial pressure (MAP) was lowered. Whereas intravenous bolus doses of PIP stimulated diuresis, GFR and medullary blood flow (MBF) and reduced or had no effect on MAP, an intraperitoneal bolus injection of PIP reduced MAP, increased MBF, and had no effect on urinary parameters. Genetic or pharmacological ablation of the cannabinoid type 1 receptors in mice completely abolished the diuretic and vasodepressor properties of intramedullary infused PIP, suggesting that the PF-3845-induced product requires the presence of CB1 receptors in order to elicit its renal effects. In a radioactive competition binding assay, using Chinese hamster ovary cells expressing CB1 receptors, PIP successfully displaced the CB1 selective inverse agonist [3H] SR141716A, revealing that the lipid extract was able to compete for binding to CB1 receptors. Finally, we investigated the tubular location of diuretic activity that the PF-3845-induced lipid fraction exhibits. In a renal function in vivo experiment, we pre-treated anesthetized mice with an intramedullary infusion of one of four well-known diuretics. This procedure was followed by an intramedullary infusion of PIP (1AU). Only inhibition of the proximal tubule sodium reabsorption diminished the diuretic activity of the PF-3845-induced product, suggesting that the lipid fraction requires a physiologically intact proximal tubular reabsorption mechanism for it to produce diuresis. These data support a model whereby PF-3845 treatment of MMICs results in increased secretion of a neutral lipid which acts directly to promote diuresis and natriuresis and indirectly through metabolites to produce vasodepression. Efforts to identify the structure of the PF-3845-induced lipid and its relationship to the previously proposed renomedullary antihypertensive lipids are ongoing.

Thesis (Ph. D.)--University of Missouri--Columbia, 1997. / Typescript. Vita. Includes bibliographical references (leaves : 117-131). Also available on the Internet.

Orientadores: José Antonio Rocha Gontijo, Konradin Metze / Tese (doutorado) - Universidade Estadual de Campinas. Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T09:14:09Z (GMT). No. of bitstreams: 1 Borges_RafaeldeCamargoPenteado_D.pdf: 2255338 bytes, checksum: 0a8e55e3d0ad46a2d03da9d085f9fc64 (MD5) Previous issue date: 2010 / Resumo: A hipertensão arterial (HA) é um dos principais fatores de risco para a elevada morbidade e mortalidade cardiovascular. O exercício físico aeróbico promove alterações fisiológicas e morfológicas importantes para o controle da HA mediados pelo sistema renina angiotensina (SRA), porém muitos destes mecanismos continuam obscuros. Foram utilizados 80 animais, SHR (n=40) e WKy (n=40), controle (c) (n=20) e exercício (e) (n=20), com acesso livre a ração padrão e água, em um ciclo dia/noite 12h cada. Os animais SHRe e WKye realizaram treinamento de natação com sobrecarga durante 8 semanas consecutivas. Ao término do período experimental, foram aferidas a freqüência cardíaca (FC), pressão arterial sistólica (PAS) e manipulação tubular de sódio. Após o período experimental os animais (n=12 por grupo) foram perfundidos para análise morfológica da aorta (Ao), artéria mesentérica (AMes) e massa cardíaca (MCard), e para análise de western blotting (WB) (n=8 por grupo) para Ao, ventrículo esquerdo (VE) e rim. Os animais WKye e SHRe responderam com uma redução significativa (p<0,05) da FC, sendo que, o SHRe reduziu (p<0,05) a PAS quando comparado ao SHRc. A fração de excreção de sódio e fração de excreção pós proximal de sódio apresentaram-se aumentadas (p<0,05) para SHRe e reduzidas (p<0,05) para WKye. As análises morfológicas indicaram que os animais Wkye aumentaram (p<0,05) o número de camadas da Ao e MCard, e reduziram (p<0,05) a distância média entre camadas da AMes; enquanto os SHRe aumentaram a MCard (p<0,05), porém reduziram (p<0,05) o número de camadas da Ao e a espessura total da AMes. As análises de WB demonstraram que os WKye tiveram um aumento (p<0,05) da razão AT1R/AT2R no VE e Ao, e redução (p<0,05) no rim, enquanto os SHRe tiveram um aumento (p<0,05) da razão AT1R/AT2R somente no VE, e redução (p<0,05) na Ao e rim. As alterações morfológicas da Ao no Wkye foram promovidas pelo aumento (p<0,05) das vias ERK1, ERK2 e AKT, no VE pela ERK2, e no rim mediado pela via JAK2/STAT3. Já nos animais SHRe as alterações na Ao foram mediadas pela redução (p<0,05) da via ERK1 e ERK2, no VE pelo aumento (p<0,05) da via ERK2 e no rim pelo aumento (p<0,05) das vias ERK1, ERK2 e STAT3. Este estudo evidenciou que o exercício promoveu mecanismos distintos para manipulação tubular de sódio, adaptações morfológicas da Ao, AMes e MCard mediados pela razão AT1R/AT2R e hemodinâmicas em normotensos e hipertensos, este com redução de PAS, através do SRA atuante de forma sistêmica e localizada através de sinalização intracelular mediada por AKT, ERK1 e ERK2, JAK2 e STAT3 / Abstract: Systemic hypertension is one of the main risk factors for the high morbidity and mortality. Aerobic exercise promotes important morphological and physiological changes for the hypertension control mediated by renin angiotensin system (RAS), however many of these mechanisms are still obscure. 80 animals were used, SHR (n = 40) and WKy (n = 40), (c) (n = 20) and (e) (n = 20), with free access to standard rat chow and tap water in a day/night cycle 12 each. Animals SHRe and WKye practiced swimming with overload for 8 consecutive weeks. At the end of the experimental period, was measured the heart rate (HR), systolic blood pressure (SBP) and tubular sodium handling. After the experimental period animals (n = 12 per group) have been perfused for segmentation of the aorta (Ao), mesenteric artery (MesA) and cardiac mass (CardM), and for analysis of western blotting (WB) (n = 8 per group) to the Ao, left ventricle, (LV) and kidney. Animals WKye and SHRe replied with a significant reduction (p<0,05) to HR, were, SHRe reduced (p<0,05) the SBP when compare with SHRc. The fraction of sodium excretion and fraction of post proximal sodium excretion showed a increase (p<0,05) for SHRe and reduction (p<0,05) for WKye. The morphological analysis indicated that Wkye animals increased (p<0,05) the Ao layers number and CardM, and reduced (p<0,05) the distance between layers of MesA; while the SHRe increased the CardM (p<0,05), but reduced (p<0,05) the layers number of Ao and the total thickness of MesA. The WB analysis, showed that Wkye answered with the increase (p<0,05) in AT1/AT2 ratio in LV and Ao, and a decrease (p<0,05) in kidney, during SHRe answer only with an increase (p<0,05) of AT1/AT2 ratio in LV, and reduction (p<0,05) in Ao and kidney. The morphologic alterations of Ao in WKye was promoted by increase (p<0,05) of ERK1, ERK2 and AKT stream, in the LV by ERK2, and in the kidney the increase (p<0,05) by ERK1, ERK2 and STAT3. This study showed that the exercise promoted different mechanisms for tubular sodium handling, morphological adaptations to MesA and CardM mediated by AT1R/AT2R ratio and hemodynamic in normotensive and hypertensive rats, which answer with SBP reduction by RAS acts of systemic form and located by intracellular signaling mediated AKT, ERK1 and ERK2, JAK2 and STAT3 / Doutorado / Medicina Experimental / Doutor em Fisiopatologia Medica

Orientador : Jose Antonio Rocha Gontijo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T14:12:40Z (GMT). No. of bitstreams: 1 Oliveira_PauloCesarde_D.pdf: 2188887 bytes, checksum: 309e674186fe399fd0cfec935fee1d78 (MD5) Previous issue date: 2009 / Resumo: No presente estudo, foi investigado os efeitos da administração intracerebroventricular (i.c.v) aguda de insulina sobre os mecanismos centrais responsáveis pela regulação da excreção tubular renal de sódio após injeção prévia de NG-nitro-1-arginine methylester (LNAME) em ratos não anestesiados. Ratos Wistar-Hannover Masculinos foram radomizados em cinco grupos: a) injeção i.c.v. de 0.15 M de NaCl em ratos (controle, N = 10), b) injeção i.c.v. de dose-resposta (1.26, 12.6 e 126 ng/3µL) em ratos (N = 10), c) Injeção i.c.v. de 60µg de L-NAME associada com NaCl (N = 10) ou d) com insulina 126ng (N = 10), e e) Injeção de insulina subcutânea em ratos (N = 5). A insulina injetada centralmente no ventrículo lateral direito de ratos promoveu uma elevação da excreção urinária de sódio (NaCl: 855.6 ± 85.1?%/min; 126 ng de insulina: 2055 ± 310.6?%/min; P = 0.005) e potássio (NaCl: 460.4 ± 100?%/min; 126ng insulina: 669.2 ± 60.8?%/min; P = 0.025). A excreção urinaria de sódio elevada observada após a microinjeção i.c.v. de 126 ng de insulina foi atenuada significativamente com administração prévia de L-NAME (126 ng insulina: 1935 ± 258.3?%/min; L-NAME + 126 ng de insulina do: 582.3 ± 69.6?%/min; P = 0.01). A natriurese induzida pela insulina i.c.v. ocorreu através da elevação da excreção tubular renal de sódio nos segmentos pós-proximais, a despeito de uma filtração glomerular inalterada. Embora o racional para a redução da excreção urinária de sódio induzida pela prévia administração i.c.v. de L-NAME seguida da administração de insulina i.c.v. permanece ainda desconhecida, podemos sugerir que um dos gatilhos responsáveis pela sinalização eferente da insulina no SNC possa ser de natureza nitrérgica / Abstract: In the present study, we investigated the effects of acute intracerebroventricular (icv) insulin administration on central mechanisms regulating urinary sodium excretion in simultaneously centrally NG-nitro-L-arginine methylester (L-NAME)-injected unanesthetized rats. Male Wistar-Hannover rats were randomly assigned to one of five groups: a) icv 0.15 M NaCl-injected rats (control, N = 10), b) icv dose-response (1.26, 12.6 and 126 ng/3 µL) insulin-injected rats (N = 10), c) rats icv injected with 60 µg L-NAME in combination with NaCl (N = 10) or d) with insulin (N = 10), and e) subcutaneously insulininjected rats (N = 5). Centrally administered insulin produced an increase in urinary output of sodium (NaCl: 855.6 ± 85.1 ?%/min; 126 ng insulin: 2055 ± 310.6 ?%/min; P = 0.005) and potassium (NaCl: 460.4 ± 100 ?%/min; 126 ng insulin: 669.2 ± 60.8 ?%/min; P = 0.025). The urinary sodium excretion response to icv 126 ng insulin microinjection was significantly attenuated by combined administration of L-NAME (126 ng insulin: 1935 ± 258.3 ?%/min; L-NAME + 126 ng insulin: 582.3 ± 69.6 ?%/min; P = 0.01). Insulin induced natriuresis occurred by increasing post-proximal sodium excretion, despite an unchanged glomerular filtration rate. Although the rationale for decreased urinary sodium excretion induced by combined icv L-NAME and insulin administration is unknown, it is tempting to suggest that perhaps one of the efferent signals triggered by insulin in the CNS may be nitrergic in nature / Doutorado / Clinica Medica / Doutor em Clínica Médica

INTRODUÇÃO: Não são conhecidos os mecanismos que determinam o comportamento da pressão arterial durante o sono. OBJETIVO: Investigar o papel do sistema nervoso simpático, do sistema renina-angiotensinaaldosterona e da excreção de sódio urinário no descenso da pressão arterial durante o sono. MÉTODOS: Hipertensos e normotensos foram submetidos a duas monitorizações ambulatoriais de pressão arterial (MAPA)/24h com SpaceLabs 90207, medidas de 15/15 minutos durante a vigília e de 20/20 minutos no período de sono. Na ocasião da MAPA 1 foram submetidos às dosagens laboratoriais de atividade de renina (ARP), aldosterona e catecolaminas plasmáticas e excreção em diurese de 24h de sódio (Na+u), potássio (K+u) e creatinina. Após o período médio de 50 ± 20 (média ± DP) dias a MAPA e as dosagens foram repetidas. RESULTADOS: Foram incluídos 35 hipertensos e 24 normotensos, com idade 56 ± 12 anos, 45 mulheres e 42 com cor da pele branca. Não houve diferença nos parâmetros laboratoriais na ocasião da MAPA 1 e da MAPA 2 nos normotensos e hipertensos. Mantiveram o mesmo comportamento de descenso da pressão sistólica e diastólica durante o sono nas duas MAPAs (>= 10% ou < 10%) 29 (49%) indivíduos, denominado grupo manteve (hipertensos n = 18). Mudaram o comportamento do descenso durante o sono da pressão sistólica ou diastólica (de >= 10% para < 10% ou de < 10% para >= 10%) 30 (51%) indivíduos, denominado grupo mudou (hipertensos n = 17). O grupo \"mudou\" apresentou menor Na+u na ocasião da MAPA 2 (145 ± 65 mEq/24 h vs 120 ± 46 mEq/24 h, p = 0,04). Houve correlação positiva entre: a) a diferença do descenso da pressão sistólica e a diferença dos resultados das dosagens de Na+u (r = 0,41; p = 0,01) realizadas nas MAPAs 1 e 2 em todos os indivíduos dos grupos \"manteve\" e \"mudou\"; b) a diferença do descenso da pressão sistólica e a diferença de Na+u/creatinina urinária (r = 0,67; p = 0,03) e de L dopa plasmática (r = 0,75; p = 0,003) realizadas nas MAPAs 1 e 2 no grupo \"manteve\" (>= 10%); e c) a diferença do descenso da pressão sistólica e a diferença do resultado das dosagens de ARP/Na+u realizadas nas MAPAs 1 e 2 (r = 0,81; p = 0,03) no grupo \"manteve\" (< 10%). CONCLUSÃO: Em hipertensos e normotensos, sem intervenção medicamentosa ou dietética, a diferença do descenso da pressão sistólica durante o sono entre duas MAPAs apresenta correlação positiva com a diferença da excreção de sódio urinário / INTRODUCTION: The mechanisms which determine the pattern of blood pressure during sleep are unknown. OBJECTIVE: To investigate the role of the sympathetic nervous system, renin-angiotensin-aldosterone system and urinary sodium excretion in the nocturnal blood pressure fall. METHODS: Hypertensive and normotensive subjects were submitted to two ambulatorial blood pressure monitorings (ABPM)/24h with a SpaceLabs 90207 equipment programmed to obtain measurements 15/15 minutes while awake and 20/20 minutes during sleep. Upon the ABPM 1, they were submitted to laboratory measurements of plasma renin activity (PRA), plasma aldosterone and catecholamines, as well as of the excretion of sodium (UNa+), potassium (UK+) and creatinine in 24-h-diuresis. After a mean period of 50 ± 20 days, the ABPM and the laboratory measurements were repeated. RESULTS: Included in the study were 35 hypertensive and 24 normotensive subjects, aged 56 ± 12 years, of which 45 were females and 42 Caucasian. There was no difference in the laboratory parameters measured upon ABPM 1 or 2, in either normotensive or hypertensive subjects. The same pattern of nocturnal systolic and diastolic pressure fall was maintained in both ABPMs (>=10% or <10%) by 29 (49%) subjects, named the \"maintained\" group (hypertensive n = 18). The nocturnal systolic or diastolic pressure fall changed (from >=10% to <10% or from <10% to >=10%) in 30 (51%) subjects, named the \"changed\" group (hypertensive n = 17). The \"changed\" group showed a smaller UNa+ upon the ABPM 2 (145 ± 65 mEq/24 h vs 120 ± 46 mEq/24 h; p = 0.04). There was a positive correlation between the difference in the nocturnal systolic pressure fall and the difference in the results of the UNa+ (r = 0,41; p = 0,01) measurements performed upon ABPM 1 and 2 in the normotensive or hypertensive subjects of the \"maintained\" and \"changed\" groups; b) the difference in the nocturnal systolic pressure fall and the difference in the measurements of UNa+/creatinine excretion (r = 0.67; p = 0.025) and plasma L dopa (r = 0.75; p = 0.003) carried out upon ABPM 1 and 2 in the \"maintained\" group (>=10%); and c) the difference in the nocturnal systolic pressure fall and the difference in the results of the PRA/UNa+ measurements performed upon ABPM 1 and 2 (r = 0.81; p = 0.03) in the \"maintained\" group (<10%). CONCLUSION: In hypertensive and normotensive individuals, without any pharmacological or dietary intervention, the difference in the nocturnal systolic pressure fall between the two ABPMs shows a positive correlation with the difference in urinary sodium excretion

réalisé avec la codirection de Marek Jankowski / Introduction: L’ocytocine (OT) était connue pour ses effets lors de la parturition et de la lactation. Depuis quelques années, d’autres rôles de l’OT ont été proposés. Ainsi, la découverte de l’OT et de son récepteur (OTR) dans le cœur a suggéré le rôle fonctionnel de cette hormone dans cet organe. Aujourd’hui, il existe une controverse concernant l’implication de l’OT dans la régulation de la pression artérielle (PA). Des études additionnelles sont donc requises pour préciser le rôle de l’OT dans le contrôle de la PA. C’est dans ce cadre que se situe la présente étude. Méthodes: Deux types d’expériences ont été faites: Une pour l’étude des paramètres métaboliques et l’autre pour les paramètres cardiovasculaires. Pour la première, l’OT (0.04 mg/kg) a été testée pour son effet métabolique. Les rats SD sont injectés avec l’OT et immédiatement placés dans des cages métaboliques individuelles et adaptées pour recueillir les urines. Les urines recueillies sur 3 heures nous ont permis de mesurer la diurèse, la natriurèse et la kaliurèse chez les rats. Pour le 2ème type, des rats spontanément hypertendus (SHR) et des Sprague-Dawley (SD) ont subi une chirurgie pour l’implantation de la sonde de télémétrie. Après 10 jours de récupération, nous avons commencé l’expérience qui s’est déroulée en 2 séries: la série des injections intraveineuses (i.v.) (0.04, 0.08, 0.1, 0.2 et 0.4 mg/kg en une seule injection) et la série des injections sous-cutanées (s.c.) (0.5 et 1 mg/kg/jour pendant 5 jours d’injection). La pression artérielle (PA), la fréquence cardiaque (FC) et de l’activité des rats ont été mesurées continuellement pendant toute l’expérience. Résultats: En i.v. la plus petite dose d’OT (0.04 mg/kg/0.3 ml) utilisée pour les effets rénaux a amené une diurèse significative, montre une tendance de natriurèse et de diminution de kaliurèse. Cette dose et celle d’OT (0.08 mg⁄kg⁄0.3 ml) sont sans effets sur la PA mais diminuent la FC des SHR et des SD (seulement les nuits). Pour les doses élevées en i.v. (0.1, 0.2 et 0.4 mg/kg d’OT), à l’exception de l’effet vasopresseur transitoire observé avec OT 0.4 mg/kg chez SD, l’OT 0.1 et 0.2 mg/kg ont diminué la PA. Les doses (0.2 et 0.4 mg/kg) d’OT ont diminué la PA chez les SHR. Elles ont augmenté la FC en journée aussi bien chez les SD que chez les SHR pendant que 0.1 mg/kg l’a diminuée. Pendant les nuits, c’est seulement la dose de 0.4 mg/kg qui a un effet sur la FC qu’elle diminue aussi bien chez les SD que les SHR. Les doses de 0.5 et 1 mg/kg injectées en s.c. ont diminué significativement la PA chez les SHR. Mais, chez les SD c’est l’OT à la dose de 1 mg/kg qui a amené une baisse de PA. À l’exception de OT 0.5 mg/kg/jour qui a augmenté la FC et l’activité chez les SHR en journée et ce au cours des injections, l’OT en s.c. a également entraîné une diminution de la FC et de l’activité. Conclusion: Ces résultats démontrent que l’OT intervient dans la régulation de la PA et la FC et les effets de l’OT dépendent de la souche de rats, de la dose, de la voie d’administration et du moment d’enregistrement des paramètres cardiovasculaires (jour ou nuit). Parlant de dépendance des résultats en fonction des voies d’administration, force est de signaler qu’avec les injections s.c. l’effet hypotenseur de l’OT est puissant et sans équivoque. Cela serait dû au fait que la duré de vie de l’OT est très courte (5 à 10 minutes) quand elle entre dans le sang. Ainsi, contrairement à la voie i.v., l’efficacité de l’OT en s.c. résulterait de sa libération lente dans le sang et donc toute la quantité administrée en s.c. ne se dégrade pas d’un seul coup. / Introduction: Oxytocin (OT) is known for its effects during parturition and lactation. In recent years, new roles of OT have been brought to light. Thus, the discovery of OT and its receptors (OTR) in the heart suggest a functional role in the body. Nowadays, the involvement of OT in blood pressure (BP) regulation is still controversial. Additional studies are therefore required to accurately determine the role of OT in the control of BP. Methods: Two types of experiments were carried out: Diuretic effect: conscious male, Sprague-Dawley rats were administered OT intravenously (0.04 mg/kg) and immediately placed in metabolic and individual cage; urine was collected and measured every hour for 3 hours. Urine measurement allowed diuresis, natriuresis and kaliuresis to be determined Telemetry: telemetry implants and catheters were inserted into the abdominal aorta of spontaneously hypertensive (SHR) and Sprague-Dawley (SD) rats. After 10 days (of necessary recovery), heart rate (HR), BP and animal locomotor activities were measured continuously. The same experiment was done on two batches of rats. Different doses of OT: 0.04; 0.08; 0.1, 0.2 or 0.4 mg/kg were injected once by intravenous (i.v) route. After each injection, we waited for the normalization of BP and HR before the next dose. Further more, 5 consecutive injections of OT were made (0.5 and 1 mg/kg) subcutaneously (s.c.). Results: The dose of 0.04 mg/kg of OT administrated for renal effects led to significant diuresis, a tendancy in natriuresis and kaliuresis decreased with no effect on BP. That dose as well as 0.08 mg/kg decreased HR in SHR and SD rats (only in the night). Whereas the highest doses in i.v. (0.1, 0.2 et 0.4 mg/kg d’OT), except a transient vasopressor effect observed with the OT 0.4 mg/kg in SD rats, OT 0.1 and 0.2 mg/kg decreased BP. OT 0.2 and 0.4 mg/kg decreased BP in SHR but increased HR during the days in both strains. The dose of 0.4 mg/kg led to a decrease of HR in SHR and in SD rats. The s.c. injections (0.5 and 1 mg/kg) of OT led to a significant decrease in BP in SHR, whereas in SD rats the lowering was only significant with a dose OT 1 mg/kg. HR significantly decreased in both strain with 1 mg/kg, whereas with 0.5 mg/kg, HR increased in SHR only and during the day. Conclusion: These results demonstrate that oxytocin acts on blood pressure and heart rate depending on strain, dose and route of administration. It’s important to point out that with s.c. injections the hypotensive effect of OT is powerful and unequivocal. This is probably because OT administered s.c. is slowly released into the bloodstream. Therefore the entire amount administered s.c. does not degrade at once and leads to the effectiveness of s.c. results.

Introdução/Objetivo: Este estudo teve como objetivo testar a hipótese de que a atividade e/ou expressão da dipeptidil peptidase IV (DPPIV), uma enzima que inativa peptídeos com ações cardioreno protetoras, como o peptídeo-1 semelhante ao glucagon (GLP-1) e o peptídeo natriurético cerebral (BNP), estaria associada a um pior prognóstico na insuficiência cardíaca (HF). Métodos: Injúria do miocárdio foi realizada através da ablação do ventrículo esquerdo (VE) por radiofrequência em ratos Wistar machos (200-250 g). Os ratos foram divididos em três grupos: Sham, HF e HF + inibidor de DPPIV (sitagliptina 200mg/kg/b.i.d). Seis semanas após a cirurgia, os animais foram alojados individualmente em gaiolas metabólicas durante 3 dias para avaliação da função renal. Atividade e expressão da DPPIV no plasma e coração foram medidas por espectrofotometria e por immunoblotting, respectivamente. Para a avaliação da função cardíaca um cateter de pressão-volume foi posicionado dentro da cavidade do VE. A análise histológica foi realizada para os parâmetros morfométricos. A atividade da DPPIV no plasma também foi medida em pacientes com HF (n = 190). Resultados: A atividade DPPIV e sua abundância estavam aumentadas em animais com HF em comparação com Sham. Além disso, a atividade de DPPIV no plasma se correlacionou positivamente com o volume diastólico final (R = 0,517; p < 0,001) e o peso do pulmão/peso corporal (R = 0,492; p < 0,01). Uma correlação negativa entre a atividade DPPIV plasmática e a fração de ejeção também foi observada (R = 0,602; p < 0,001). Curiosamente, os animais HF também exibiram um aumento da expressão/atividade de DPPIV no tecido cardíaco, especialmente em células endoteliais. Seis semanas de tratamento com o inibidor de DPPIV sitagliptina atenuou a disfunção cardíaca, fibrose intersticial, congestão pulmonar e infiltração de macrófagos. O tratamento com sitagliptina também elevou os níveis plasmáticos de GLP-1 ativo, e aumentou a ativação de vias de sinalização cardioprotetoras como PKA e Akt; e reduziu os níveis de apoptose e marcadores pró-inflamatórios em comparação com ratos não tratados. Ratos com HF apresentaram maiores níveis circulantes de BNP, contudo a atividade da PKG renal foi mais baixa nesses animais em comparação com o grupo tratado com sitagliptina, sugerindo uma diminuição da razão BNP ativo/total. A função renal não diferiu entre os grupos, mas o ritmo de filtração glomerular estava ligeiramente aumentado no grupo tratado em comparação com os animais HF. Pacientes com HF apresentaram uma maior atividade plasmática da DPPIV e correlações foram encontradas com a com a fração de ejeção (R = -0,20; p = 0,009) e a quimiocina Ccl2 (R² =0,30; p < 0.01). Conclusões: Em conjunto, nossos resultados demonstram que a atividade plasmática da DPPIV se correlaciona com um pior prognóstico em pacientes e animais com HF e que a DPPIV possui um papel importante na fisiopatologia desta doença / Aim: The present study aimed to test the hypothesis that the activity and/or expression of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates cardiorenal protective peptides including glucagon-like peptide-1 (GLP-1) and brain natriuretic peptide (BNP), would be associated with poorer outcomes in heart failure (HF). Methods: Experimental HF was induced in male Wistar rats (200-250 g) by left ventricular (LV) myocardial injury after radiofrequency catheter ablation. Rats were divided in three groups: Sham, HF and HF+DPPIV inhibitor (sitagliptin 200mg/kg/b.i.d). Six weeks after surgery, animals were individually housed in metabolic cages during 3 days for assessment of renal function. Plasma and heart DPPIV activity/expression were measured spectrophotometrically and by immunoblotting respectively. For evaluation of cardiac function a pressure-volume catheter was positioned into the LV cavity. Histological analysis was performed for morphometric parameters. Plasma DPPIV activity was also measured in patients (n = 190) with heart failure. Results: Plasma DPPIV activity and abundance were increased in animals with HF compared to Sham. Additionally, plasma DPPIV activity positively correlated with ventricular end diastolic volume (R² =0.517; p < 0.001) and lung/body weight (R² =0.492; p < 0.01). A negative correlation between plasma DPPIV activity and ejection fraction was also observed (R² =0.602; p < 0.001). Interestingly, HF animals also exhibited an increase of expression and activity of DPPIV in heart tissue, especially in endothelial cells. Six-week treatment with the DPPIV inhibitor sitagliptin attenuated cardiac dysfunction, mitigated cardiac hypertrophy, interstitial fibrosis, lung congestion and macrophage infiltration. Sitagliptin also raised the plasma levels of active GLP-1, increased activation of cardioprotective signaling pathways including PKA, and Akt; and reduced the levels of apoptosis and pro-inflammatory biomarkers compared to non-treated HF rats. Despite the higher circulating total BNP, renal PKG activity was lower in HF rats compared with sham and sitagliptin-treated rats, suggesting a decrease in active/total BNP ratio. Renal function did not differ between groups, but glomerular filtration rate was modestly, but significantly increased by Sitagliptin compared to HF. Plasma DPPIV activity in patients was also increased compared to healthy subjects and correlations was found with ejection fraction (R² =-0.20; p=0.009) and the chemokine Ccl2 (R² =0.30; p < 0.01). Conclusions: Taken together, our results demonstrate that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental HF and might play an important role in the pathophysiology of HF.

Hypertension and salt-sensitivity are independent risk factors for cardiovascular disease. Although both conditions are idiopathic, they develop due to a complex interplay between susceptibility genes and environmental factors. Given that the kidney plays an important role in regulating blood pressure, in particular, by maintaining sodium and water balance via pressure-natriuresis, it is not surprising that disturbances in the proper functioning of this intrarenal mechanism have been linked to these conditions. Although direct coupling of changes in renal arterial pressure (RAP) to renal interstitial hydrostatic pressure (RIHP) and consequent sodium excretion is well established, few studies have characterized the moment-to-moment aspects of this process. Thus, the main focus of the research presented herein was to characterize the moment-to-moment RAP-RIHP relationship, and assess the functioning of this intrarenal mechanism in various animal models of genetic and environmentally-induced hypertension and/or salt-sensitivity. In adult normotensive rats, the response time of RIHP to acute changes in RAP was rapid (<2 seconds), and the moment-to-moment RAP-RIHP relationship was linear over a wide range of pressures. Additionally, the functioning of this relationship was not affected by inhibition of the renin-angiotensin system and autonomic nervous system. Further, the acute RAP-RIHP relationship was impaired in hypertension and/or salt-sensitivity. Specifically, animals with a hypertensive phenotype (i.e. young spontaneously hypertensive rats [SHR] and pro-atrial natriuretic peptide gene-disrupted mice [ANP -/-]) displayed a rightward shift in the moment-to-moment pressure-natriuresis curve towards higher RAP. This rightward shift was associated with increased structurally-based vascular resistance properties in the hindlimb of young SHR versus their normotensive controls. Salt-sensitive phenotypes were associated with a blunting of this acute mechanism. Specifically, this blunting was evident in both the ANP -/-, a transgenic model of salt-sensitive hypertension, and in adult perinatal iron deficient (PID) rats, a developmentally programmed model of salt-sensitivity. It appears that a blunting in the RAP-RIHP relationship is influenced by an imbalance of key blood pressure modulating factors (e.g. ANP). Further, visceral obesity was associated with salt-sensitivity in PID rats; however the mechanism(s) are yet to be elucidated. Novel methodologies (MRI, abdominal girth) were developed for non-invasive assessment of visceral obesity to aid future research. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2010-05-12 10:11:21.197