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. / réalisé avec la codirection de Marek Jankowski

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-11-27T18:17:23Z No. of bitstreams: 1 Carla Patrícia Novais Luz Efeito agudo... 1997.pdf: 28638306 bytes, checksum: 690203708866521de7b4f58b702d4398 (MD5) / Made available in DSpace on 2012-11-27T18:17:23Z (GMT). No. of bitstreams: 1 Carla Patrícia Novais Luz Efeito agudo... 1997.pdf: 28638306 bytes, checksum: 690203708866521de7b4f58b702d4398 (MD5) Previous issue date: 1997 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / Trabalho realizado com o objetivo de estudar os possíveis efeitos da injeção intracerebroventricular aguda de chumbo e cádmio sobre a função renal. Ratos Wistar machos receberam duas sobrecargas hídrica oral de 5% do peso corporal com intervalo de 60 minutos. Vinte minutos após a segunda sobrecarga hídrica os animais receberam injeções de PbAc e CdCb no terceiro ventrículo em três diferentes doses (0.03, 0.3, 3.0 nmol/rato), sendo comparados ao grupo tratado com salina. Ambos os metais induziram um aumento significante na exaeção de sódio e potássio, sem nenhuma modificação no fluxo urinário. O pré-tratamento com losarían, um antagonista seletivo dos receptores aiigiotensinérgicos ATI (10,8 nmol/rato no terceiro ventrículo 10 minutos antes da injeção cenü'al dos metais), inibiu o efeito natriurético e kaliuréüco induzido pelo chumbo. Quanto ao cádmio o losarían foi capaz apenas de inibir o efeito natriurético, não interferindo na kaliurese.O pré-tralamento com gadolinio, um bloqueador dos canais de cálcio voltagem-dependentes (0.3 nmol/rato no terceiro ventrículo 20 minutos antes da injeção central dos melais), reverteu o aumento na excreção de sódio e potássio induzido pela administração central de PbAc e CdCli. Esses dados indicam que o aumento na natriurese e kaliurese é um efeito agudo da injeção central de cádmio e chumbo. A natriurese observada nos animais tratados com com esses metais parece depender da integridade funcional das vias angiotensinérgicas centrais já que esta foi revertida pelo losartan. Entretanto, a resposta kaliurética observada nos animais tratados com cádmio não é dependente do componente angiotensinérgico central, já que o losartan não foi capaz de reverter a kaliurese observada nos animais tratados com cádmio.O Gadolinio, um bloqueador dos canais de cálcio voltagem-dependentes, é capaz de reverter o efeito natriurético e kahurétíco induzido pelo cádmio e chumbo. Isso sugere, que as ações do chumbo e do cádmio dependem da integridade funcional dos canais de cálcio. Nos animais que receberam apenas a injeção central de gadolinio não foi observado nenhum efeito na exaeção de sódio e potássio. Assim, sugerimos que os metais entram na célula através dos canais de cálcio e, uma vez dentro da célula, interagem com alguns passos bioquímicos dependentes de cálcio levando a alterações na neurotransmissão que induzem a resposta aqui observada. / In the present work we studied the effects of acute intracerebroventricular injections of lead and cadmium on the central control of kidney function. Wistar, adult, male rats received an oral water load equivalent to 10% of their body weight. Twenty minutes after the water load experimental animals received third ventricle injections of PbAc or CdClj in three different doses (0.03, 0.3 and 3.0 nmol/rat) being compared to saline-treated controls. The injection of both metals induced a significant inaease in renal sodium and potassium excretion. Urine flow was not affected by the injections of the metals. Central pretreatment with losartan, a specific angiotensin II ATI receptor antagonist (10.8 nmol/rat into the third ventricle, 10 minutes before the injection of the metals) inhibited botli natriuretic and kaliuretic effects of lead administration. Losartan pretreatment was able to block the natriuretic effect of cadmium injections being unable to modify the kaliuretic effect of this metal. On the other hand, third ventricle injections of gadolinium, a voltage-dependent calcium channels blocker (0.3 nmol/rat 20 minutes before the central injection of the metals) reversed the increase in both natriuretic and kaliuretic response evoked by lead and cadmium administration. These data indicate that natriuresis and kaliuresis enhancement is an acute effect of central injections of both lead and cadmium. The inaeased renal sodium exaetion observed in animals receiving both metals seems to rely on a central angiotensin Il-dependent mechanism since it is reversed by losartan. However, the kaliuretic response observed in cadmium-treated animals is not dependent on this central angiotensinergic component, since losartan is unable to reverse the inaeased renal potassium excretion observed in animals treated with cadmium.Gadolinium, a voltage-dependent calcium channels blocker, is able to reverse the metal-induced kaliuretic and natriuretic effects here observed. Thus, we think that the present actions of lead and cadmium seem to require the functional integrity of calcium channels. The central injection of gadolinium in animals free of metals is devoid of any effect on renal sodium and potassium excretion. It is suggested that the metals enter the brain cell via calcium channels and, once inside the cells, interact with some calcium-related biochemical step leading to an altered neurotransmission state that induces the responses h^e observed.

Made available in DSpace on 2016-06-02T19:22:58Z (GMT). No. of bitstreams: 1 5255.pdf: 814726 bytes, checksum: 0e3f245d1d018cf30cdf30bf84e42fed (MD5) Previous issue date: 2013-05-13 / Universidade Federal de Sao Carlos / The reactive oxygen species (ROS), produced endogenously in central areas may act by modulating autonomic and behavioral responses. Recent studies have shown that a reactive oxygen species, hydrogen peroxide (H2O2), injected into the lateral ventricle (LV) reduces pressor response induced by central injection of angiotensin II. In the present study we investigated the effects of H2O2 on the dipsogeni and pressor responses and on the changes in renal excretion induced by the increases in plasma osmolality by intragastric administration (ig) of 2 M NaCl (2 ml). Holtzman rats (280 - 320 g) with stainless steel cannula implanted in the LV were used. H2O2 or PBS injections were made in the LV. Injections of H2O2 (2.5 or 5 &#956;mol/1 &#956;l) in the LV reduced water intake induced by ig 2 M NaCl (3.1 ± 0.7 and 3.5 ± 1.1 ml, vs. PBS: 8.6 ± 1.0 and 7.6 ± 0.5 ml/2h, P <0.05, respectively) and natriuresis (609.2 ± 82.9 and 1290.7 ± 80.5, vs. PBS: 876.4 ± 129.5 and 1443.6 ± 67.5 &#956;Eq/2 h, p < 0.05, respectively). However, diuresis and pressor response after ig 2 M NaCl were not altered by the pre-treatment with H2O2. The present data suggest a inhibitory role of central H2O2 in water intake and natriuresis without changing the pressor response induced by plasma hyperosmolarity. / As espécies reativas de oxigênio (EROs), produzidas endogenamente podem atuar em áreas centrais modulando respostas autonômicas e comportamentais. Estudos recentes demonstraram que uma espécie reativa de oxigênio, o peróxido de hidrogênio (H2O2), injetado no ventrículo lateral (VL) reduz resposta pressora induzida pela injeção central de angiotensina II. No presente estudo investigamos os efeitos do H2O2 sobre a resposta dipsogênica, pressora e sobre as alterações na excreção renal induzidas por aumento da osmolaridade plasmática pela administração intragástrica (ig) de NaCl 2 M (2 ml) . Ratos Holtzman (280 320 g) com cânulas de aço inoxidável implantadas no VL foram utilizados. Injeções de H2O2 ou PBS foram realizadas no VL. As injeções de H2O2 (2,5 ou 5 &#956;mol/1 &#956;l) no VL reduziu a ingestão de água induzida por NaCl 2 M ig (3,1 ± 0,7 e 3,5 ± 1,1 ml, vs. PBS: 8,6 ± 1,0 e 7,6 ± 0,5 ml/2 h, p < 0,05, respectivamente) e a natriurese (609,2 ± 82,9 e 1290,7 ± 80,5, vs. PBS: 876,4 ± 129,5 e 1443,6 ± 67,5 &#956;Eq/2 h, p < 0,05, respectivamente). Por outro lado a diurese e a resposta pressora após gavagem de NaCl 2 M não foram alteradas pelo tratamento prévio com H2O2. Nossos dados sugerem um papel inibitório para o H2O2 agindo centralmente na ingestão de água e na natriurese, sem alterar a resposta pressora induzida por hiperosmolaridade plasmática.

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.

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