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1.
Am J Physiol Lung Cell Mol Physiol ; 308(7): L672-82, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25617377

RESUMO

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg(-1)·day(-1) orally), antenatal sildenafil (100 mg·kg(-1)·day(-1) orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.


Assuntos
Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Pneumopatias/prevenção & controle , Pulmão/anormalidades , Sinvastatina/uso terapêutico , Remodelação Vascular/efeitos dos fármacos , Animais , Apoptose , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Feminino , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Pulmão/irrigação sanguínea , Éteres Fenílicos , Gravidez , Ratos Sprague-Dawley , Sinvastatina/farmacologia
2.
Respir Res ; 15: 12, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24499246

RESUMO

BACKGROUND: Systemic hypertension may be associated with an increased pulmonary vascular resistance, which we hypothesized could be, at least in part, mediated by increased leptin. METHODS: Vascular reactivity to phenylephrine (1 µmol/L), endothelin-1 (10 nmol/L) and leptin (0.001-100 nmol/L) was evaluated in endothelium-intact and -denuded isolated thoracic aorta and pulmonary arteries from spontaneously hypertensive versus control Wistar rats. Arteries were sampled for pathobiological evaluation and lung tissue for morphometric evaluation. RESULTS: In control rats, endothelin-1 induced a higher level of contraction in the pulmonary artery than in the aorta. After phenylephrine or endothelin-1 precontraction, leptin relaxed intact pulmonary artery and aortic rings, while no response was observed in denuded arteries. Spontaneously hypertensive rats presented with increased reactivity to phenylephrine and endothelin-1 in endothelium-intact pulmonary arteries. After endothelin-1 precontraction, endothelium-dependent relaxation to leptin was impaired in pulmonary arteries from hypertensive rats. In both strains of rats, aortic segments were more responsive to leptin than pulmonary artery. In hypertensive rats, pulmonary arteries exhibited increased pulmonary artery medial thickness, associated with increased expressions of preproendothelin-1, endothelin-1 receptors type A and B, inducible nitric oxide synthase and decreased endothelial nitric oxide synthase, together with decreased leptin receptor and increased suppressor of cytokine signaling 3 expressions. CONCLUSIONS: Altered pulmonary vascular reactivity in hypertension may be related to a loss of endothelial buffering of vasoconstriction and decreased leptin-induced vasodilation in conditions of increased endothelin-1.


Assuntos
Endotelina-1/fisiologia , Hipertensão/fisiopatologia , Leptina/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Animais , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
3.
Pediatr Surg Int ; 29(8): 823-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23832098

RESUMO

PURPOSE: Bone morphogenetic proteins (BMP) have been shown to play crucial roles in not only lung and heart development, but also in the pathogenesis of pulmonary vascular remodeling in pulmonary hypertension (PH). We therefore hypothesized that BMP signaling could be altered in nitrofen-induced congenital diaphragmatic hernia (CDH) and associated PH. METHODS: Pregnant rats were exposed to either 100 mg nitrofen or vehicle on embryonic day (E) 9.5. On E17 and E21, fetuses were delivered by cesarean section, killed and checked for left-sided CDH. The tissue was then harvested for pathobiological evaluation. RESULTS: In nitrofen-induced CDH, pulmonary expressions of BMP4, BMP receptor (BMPR) type 2 and Id1 decreased on E17 and E21. On E17, pulmonary gremlin-1 expression increased, while BMP7 decreased. In the lungs, Id1 expression was correlated to BMP4 and BMPR2 and inversely correlated to gremlin-1 expression. Myocardial expressions of BMPR2, BMPR1A, BMP7 and SERCA-2A decreased, while gremlin-1 and noggin expressions increased on E17. On E21, myocardial expressions of Id1 and SERCA-2A decreased, while gremlin-1 expression increased. Moreover, BMPR2 and BMPR1A expressions were correlated to SERCA-2A expression and inversely correlated to pro-apoptotic Bax/Bcl2 ratio within the myocardium. CONCLUSION: Downregulation of BMP signaling seems to contribute to pulmonary and myocardial anomalies observed in nitrofen-induced CDH.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Regulação para Baixo , Hérnias Diafragmáticas Congênitas , Transdução de Sinais , Animais , Hérnia Diafragmática/induzido quimicamente , Hérnia Diafragmática/metabolismo , Éteres Fenílicos/administração & dosagem , Ratos , Ratos Sprague-Dawley
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