INTRODUCCIÓN: Los isoprostanos son compuestos similares a las Prostaglandinas (PGs) que se producen mediante una peroxidación no enzimática del ácido araquidónico inducida por radicales libres (Roberts & Morrow, 1997; Morrow y cols., 1999). Debido a su semejanza estructural con las PGs, se postula que no sean simples marcadores de la peroxidación lipídica, sino que también posean actividad específica. Se ha investigado la función biológica de los isoprostanos en animales adultos, en donde ejercen un efecto dual de predominio vasoconstrictor a nivel pulmonar y coronario. Sin embargo son muy pocos los referentes en este campo durante el período neonatal.OBJETIVOS: 1.- Estudiar los efectos contráctiles y relajantes de diversos isoprostanos sobre vasos pulmonares y sistémicos de lechones recién nacidos (12-24 h) comparado con lechones de 2 semanas (15-18 días). 2.- Dilucidar los mecanismos de transducción de las respuestas vasculares a los isoprostanos en estos tejidos.ANIMALES DE EXPERIMENTACION, MATERIAL Y MÉTODOS: Se estudió las respuestas contráctil y relajante de algunos isoprostanos (8-iso PGE1, 8-iso PGE2, 8-iso PGF1α, 8-iso PGF1β, 8-iso PGF2α, 8-iso PGF2β) y del mimético del tromboxano A2 -U46619- usando para ello el miógrafo mediante la técnica del baño de órganos. Se utilizaron anillos vasculares de la tercera rama de la arteria pulmonar (AP) y de la vena pulmonar (VP), del tronco principal de la arteria mesentérica (AM) y de la coronaria descendente anterior izquierda (AC). RRESULTADOS: - Contracción: Los isoprostanos producen una potente vasoconstricción dependiente de la concentración en AP, VP y AM (magnitudes 1,5-2 veces superiores a la respuesta de KCl 62,5 mM), pero ésta resulta ser muy inferior a la vasoconstricción desarrollada por U46619. La AP del lechón recién nacido resulta ser más sensible a la acción de 8-iso PGE2, 8-iso PGF1α, 8-iso PGF1β y 8-iso PGF2β que la AP del lechón de 2 semanas, sin que se observe un patrón ontogénico claro para el resto de los compuestos. La VP del recién nacido resulta más sensible a la acción de 8-iso PGE2 y 8-iso PGF1α y la AM del recién nacido a la acción 8-iso PGE2, 8-iso PGF1α, 8-iso PGF2α y 8-iso PGF2β que los correspondientes vasos de los animales de 2 semanas. La respuesta contráctil de todos los isoprostanos y del U46619 se revierte por SQ 29,548 (antagonista del receptor del tromboxano A2 -TP-), lo que indica que indica que la respuesta mediada por los isoprostanos implica al receptor TP. La contracción mediada por los isoprostanos se reduce en presencia de inhibidores de la tirosina cinasa (genisteína) y de la Rho cinasa (Y 27632 e hidroxifasudilo) pero no en presencia de inhibidores de la proteína cinasa C (queleritrina), de la cinasa de la proteína activadora del mitógeno (PD 98059) o de la p-38 cinasa (SB 203580). -Relajación: 8-iso PGE2 induce una relajación en AP de lechones de dos semanas precontraídas con U46619 (máxima 60.1±8,7%) superior a la obtenida tras precontraer la AP con ET-1 en presencia de SQ 29,548 o en AC precontraídas con U46619. A diferencia de otros vasos, se observa también efecto relajante en AC para los siguientes isoprostanos: 8-iso PGE1 y 8-iso PGF2α. La relajación mediada por 8-iso PGE2 en la AP se redujo en presencia del inhibidor de la óxido nítrico sintetasa (L-NAME) y del inhibidor de la guanilato ciclasa soluble (ODQ). El Misoprostol, la PGE1 y la PGE2 indujeron relajación en la AP, pero no lo hicieron ni la PGD2 ni el iloprost.CONCLUSIONES: 1.- Los isoprostanos tienen efectos contráctiles, los cuales son mayores en el recién nacido y se median por el receptor TP acoplado a la tirosina cinasa y Rho cinasa. 2.- Los isoprostanos tienen efectos relajantes que son mayores en animales de 2 semanas y que se median a través de la vía NO-GMPc. / "Effects of Isoprostanes in Pulmonary and Sistemic Vascular Reactivity during Neonatal Period".BACKGROUND: Isoprostanes are prostaglandin (PG)-like compounds produced non enzymatically by free radical-catalyzed peroxidation of arachidonic acid. The vascular effects of these compounds in neonatal vasculature are poorly known.OBJECTIVE: We aimed to study the effects of several E-ring and F-ring isoprostanes on mechanical activity in pulmonary arteries (PA), pulmonary veins (PV) and in mesenteric arteries (MA) from newborn and 2-week-old piglets. DESIGN/METHODS: The contractile and relaxant responses to 8-iso PGE1, 8-iso PGE2, 8-iso PGF1α, 8-iso PGF1β, 8-iso PGF2α, 8-iso PGF2β, and the thromboxane A2 mimetic U46619 were studied using organ bath techniques. RESULTS: Isoprostanes produced powerful concentration-dependent contractions of PA, PV and MA. Neonatal PA were more sensitive to 8-iso PGE2, 8-iso PGF1α, 8-iso PGF1β and 8-iso PGF2β than 2- week-old PA, but a clear ontogenic pattern was not observed for the rest of the compounds. Neonatal PV were more sensitive to 8-iso PGE2 and 8-iso PGF1α, and neonatal MA were more sensitive to 8-iso PGE2, 8-iso PGF1α, 8-iso PGF2α and 8-iso PGF2β than the corresponding 2-week-old vessels. The sensitivity to U46619-decraesed with postnatal age in MA but did not change in PA and PV. The contractile responses to all the isoprostanes and to U46619 were reverted by the thromboxane A2 receptor (TP) antagonist SQ 29,548. Moreover, isoprostanes-evoked contractions were blocked by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and hydroxy-fasudil). 8-iso-PGE2 induced modest dose-dependent relaxations (maximal relaxation of 60.1±8,7%) in 2-week-old PA. In CA, 8-iso PGE2 was the most potent vasodilator but relaxant responses evoked by 8-iso PGE1 y 8-iso PGF2α were also observed. 8-iso PGE2 -evoked PA relaxation was markedly impaired by the nitric oxide (NO) synthase inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ. Misoprostol, PGE1 and PGE2 fully relaxed U46619-contracted PA, while no relaxation was observed in response to PGD2 or iloprost.CONCLUSIONS: 1. Isoprostanes produce constriction of neonatal porcine pulmonary and mesenteric vascular smooth muscle which involve TP receptors coupled to tyrosine kinases and Rho kinases. 2. Isoprostanes produce modest or absent relaxant responses in piglet vascular smooth muscles. 8-iso-PGE2-evoked relaxation of piglet PA is likely to be mediated by NO.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-02-14T11:54:11Z No. of bitstreams: 1 arquivo total.pdf: 1993500 bytes, checksum: afc116c8137450f5a4f1743f6804afd0 (MD5) / Made available in DSpace on 2017-02-14T11:54:11Z (GMT). No. of bitstreams: 1 arquivo total.pdf: 1993500 bytes, checksum: afc116c8137450f5a4f1743f6804afd0 (MD5) Previous issue date: 2015-04-07 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The fruit of S. cumini is considered source of phenolic compounds with beneficial effects important for health, especially for its antioxidant potential. This work aimed to investigate the effects of the fruit skin hydro-alcoholic extract of S. cumini (EHAPS) compared to the changes related to the consumption of high calorie diet in rats. The total phenolic content and total antioxidant capacity were evaluated for standardization of the extract. The animals were treated orally, with EHAPS, for 6 weeks, in two doses (100 and 300 mg / kg) and the control of normocaloric diets (NCT) and hypercaloric (HCT) received saline. Was monitored weight, food and water consumption and blood pressure during the treatment At the end, murinométricas measures were taken, collected up the plasma and some organs for analysis. The EHAPS showed high antioxidant capacity, with a total phenolic content of 5440.86 mg GAE / 100g and EC50 value of 59 mg / mL. At the end of the six weeks of treatment HCT group had the highest percentage of weight gain relative to the NCT, 26 ± 3.9 and 15.3 ± 1.7 respectively. The hypercaloric diet also increased calorie intake, waist circumference, the adiposity index and blood glucose levels. In addition to damage the vascular response to drugs such as phenylephrine, acetylcholine, sodium nitroprusside, and raise levels of oxidative stress. The treatment decreased the percentage weight gain of the group HCT of 19.7 ± 2.6 to 13.3 ± 1.1 and 12.5 ± 1.5 in groups H100 and H300, respectively, from the 4th week of treatment. The treatment with EHAPS showed improvements in vascular response and reduction of oxidative stress in the treated animals. There has been no significant change in blood pressure levels between the groups and no significant reduction in visceral adiposity index and blood glucose in animals after treatment. The results suggest that phenolic compounds present in the fruit skin S. cumini reduce the deleterious effects of a hypercaloric diet, preventing weight gain and improving the total antioxidant capacity and the vascular response in animal models. / O fruto da S. cumini é considerado fonte de compostos fenólicos apresentando efeitos benéficos importantes para a saúde, com destaque para seu potencial antioxidante. Dessa forma, objetivou-se investigar os efeitos de um extrato hidroalcoólico da pele do fruto de S. cumini (EHAPS) mediante às alterações relacionadas ao consumo de dieta hipercalórica em ratos. O teor de fenólicos totais e capacidade antioxidante total foram avaliados para padronização do extrato. Os animais foram tratados por via oral, com o EHAPS, durante 6 semanas, em duas doses (100 e 300 mg/Kg) e o controle das dietas normocalórica (NCT) e hipercalórica (HCT) receberam solução salina. Foi monitorado o peso, o consumo alimentar e hídrico e a pressão arterial ao longo do tratamento. Ao final foram tomadas medidas murinométricas, coletou-se o plasma e alguns órgão para análises. O EHAPS apresentou elevada capacidade antioxidante, com um teor de fenólicos totais de 5.440,86 mg EAG/ 100g de amostra e valor de CE50 de 59 μg/mL. Ao final das seis semanas de tratamento o grupo HCT apresentou um ganho percentual de peso mais elevado em relação ao NCT, 26 ± 3,9 e 15,3 ± 1,7, respectivamente. A dieta hipercalórica também aumentou o consumo de calorias, a circunferência abdominal, o índice de adiposidade e os níveis glicêmicos, além de prejudicar a resposta vascular às drogas como fenilefrina, acetilcolina, nitroprussiato de sódio, e elevar os níveis de estresse oxidativo. O tratamento foi capaz de diminuir o ganho de peso percentual do grupo HCT de 19,7 ± 2,6 para 13,3 ± 1,1 e 12,5 ± 1,5 nos grupos H100 e H300, respectivamente, a partir da 4° semana de tratamento. Ao final do tratamento observou-se melhora da resposta vascular e diminuição do estresse oxidativo nos animais tratados. Não foi observada nenhuma alteração significativa dos níveis de pressão arterial entre os grupos e não houve redução significativa do índice de adiposidade visceral e glicemia sanguínea nos animais após o tratamento. Os resultados sugerem que os compostos fenólicos presentes na pele do fruto de S. cumini diminuem os efeitos deletérios de dietas hipercalóricas, prevenindo o ganho de peso corporal e melhorando a capacidade antioxidante total e a resposta vascular em modelos animais.