RESUMO
In the present study, we analysed possible alterations in adrenergic, nitrergic and sensory functioning in mesenteric arteries from rats at 1 and 21 months after partial portal vein ligation, and the mechanisms involved in these alterations, if any. For this purpose, we analysed the vasoconstrictor response to EFS (electrical field stimulation) and the effect of the α-antagonist phentolamine, the NOS (nitric oxide synthase) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester) and the CGRP (calcitonin gene-related peptide) receptor antagonist CGRP-(8-37) in mesenteric segments from ST (short-term; 1 month) and LT (long-term; 21 months) SO (sham-operated) and pre-hepatic PH (portal hypertensive) rats. The vasomotor responses to NA (noradrenaline), the NO donor DEA-NO (diethylamine NONOate) and CGRP were analysed. NA, NO and CGRP releases were measured. Phospho-nNOS (neuronal NOS) expression was studied. The vasoconstrictor response to EFS was decreased in STPH animals. Phentolamine decreased this vasoconstrictor response more strongly in SO animals. Both L-NAME and CGRP-(8-37) increased vasoconstrictor response to EFS more strongly in PH than SO segments. PH did not modify vasomotor responses to NA, DEA-NO or CGRP, but it decreased NA release while increasing those of NO and CGRP. Phospho-nNOS expression was increased by PH. In LTPH, no differences were observed in vasoconstrictor response to EFS, vasomotor responses or neurotransmitter release when compared with age-matched SO animals. In conclusion, the mesenteric innervation may participate in the development of the characteristic hyperdynamic circulation observed in STPH through the joint action of decreased adrenergic influence, and increased nitrergic and sensory innervations influences. The participation of each innervation normalizes under conditions of LTPH.
Assuntos
Hipertensão Portal/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Células Receptoras Sensoriais/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Peso Corporal/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Estimulação Elétrica , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Fentolamina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Células Receptoras Sensoriais/efeitos dos fármacos , Tetrodotoxina/farmacologia , Fatores de Tempo , Vasodilatadores/farmacologiaRESUMO
INTRODUCTION AND OBJECTIVES: The Paris System (PS) has replaced the classical Papanicolaou System (PapS) in reporting urine cytology, due to its improved sensitivity and negative predictive value (NPV) without loss of specificity. Furthermore, it has enabled the risk of malignancy to be established in each cytological category. The aim of this study is to compare the Paris System with previous results and determine the changes in sensitivity, specificity, positive predictive value, NPV and risk of malignancy in our centre, MATERIALS AND METHODS: Evaluation of the diagnostic power of urine cytology by means of a retrospective cohort study, comparing two series of 400 cytological studies, one using the Papanicolaou System and the other the Paris System. RESULTS: In the detection of high-grade urothelial carcinoma, Paris System has better specificity (93.82% PapS vs 98.64% PS; P=.001) and PPV (39.5% PapS vs 70.6% PS; P=.044) than Papanicolaou System, without changes in sensitivity (53.5% PapS vs 37.5% PS; P=.299) or NPV (96.4% PapS vs 94.8% PS; P=.183). The risk of malignancy for the atypical category increases from low to high levels (1.6% PapS vs 40.0% PS; P=.001); the other categories showed no significant statistical changes. CONCLUSION: The Paris System improves specificity and positive predictive value and establishes a better indication of risk of malignancy for each category, enabling specific clinical management in each case.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Carcinoma de Células de Transição/patologia , Citodiagnóstico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/patologiaRESUMO
INTRODUCTION: In spite of the changes for the treatment of glioblastoma since 2005, we have not seen differences between long-survival patients of more than 10 years showing a value minor than 1%. MATERIAL AND METHOD: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient. RESULTS: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival. CONCLUSIONS: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/patologia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/terapia , Humanos , Proteínas Supressoras de TumorRESUMO
Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE-/- mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE-/- mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.
RESUMO
Our study determines alterations in the vasoconstrictor response elicited by electric field stimulation (EFS) in mesenteric arteries from cirrhotic rats treated with CCl(4), and how calcitonin gene-related peptide (CGRP) participates in this response. Vasoconstriction induced by EFS was analysed in the absence and presence of the CGRP receptor antagonist CGRP(8-37) in arterial segments from control and cirrhotic rats. The vasodilator response to exogenous CGRP was tested in both groups of rats, and the interference of the guanylate cyclase inhibitor ODQ or the K(ATP) channel blocker glibenclamide was analysed only in segments from cirrhotic rats. The vasodilator response to the K(ATP) channel opener pinacidil and to 8-bromo-cyclic GMP was tested. The K(ATP) currents were recorded using the patch-clamp technique. Expression of receptor activity-modifying protein 1 (RAMP1), calcitonin receptor-like receptor, Kir 6.1 and sulfonylurea receptor 2B (SUR2B) was also analysed. Release of CGRP and cGMP was measured. The EFS-elicited vasoconstriction was less in segments from cirrhotic rats. The presence of CGRP(8-37) increased the EFS-induced response only in segments from cirrhotic rats. The CGRP-induced vasodilatation was greater in segments from cirrhotic rats, and was inhibited by ODQ or glibenclamide. Both pinacidil and 8-bromo-cyclic GMP induced a stronger vasodilator response in segments from cirrhotic rats. Pinacidil induced greater K(ATP) currents in cirrhotic myocytes. Expression of RAMP1, calcitonin receptor-like receptor, Kir 6.1 and SUR2B was not modified by liver cirrhosis. Liver cirrhosis increased CGRP release, but did not modify cGMP formation. The decreased vasoconstrictor response to EFS in cirrhosis is mediated by increased vasodilator response to CGRP, as well as increased K(ATP) channel gating. This effect of CGRP may play a role in the splanchnic vasodilatation present in liver cirrhosis.
Assuntos
Cirrose Hepática/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Proteína Semelhante a Receptor de Calcitonina/sangue , Proteína Semelhante a Receptor de Calcitonina/genética , Tetracloreto de Carbono/farmacologia , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Estimulação Elétrica/métodos , Glibureto/farmacologia , Canais KATP/efeitos dos fármacos , Canais KATP/metabolismo , Canais KATP/fisiologia , Cirrose Hepática/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Oxidiazóis/farmacologia , Fragmentos de Peptídeos/farmacologia , Pinacidil/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/biossíntese , Canais de Potássio Corretores do Fluxo de Internalização/genética , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteína 1 Modificadora da Atividade de Receptores/biossíntese , Proteína 1 Modificadora da Atividade de Receptores/genética , Receptores de Droga/biossíntese , Receptores de Droga/genética , Receptores de Sulfonilureias , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Our present study examines, in mesenteric resistance arteries, possible vasodilation alterations, and the role of NO and COX (cyclo-oxygenase) derivatives, in cirrhosis. The vasodilator response to acetylcholine was analysed in segments from control and cirrhotic rats. The effects of the non-specific COX inhibitor indomethacin, the specific COX-1 inhibitor SC-560 and the specific COX-2 inhibitor NS-398 were analysed in segments from both groups of rats. NO release was measured, and eNOS [endothelial NOS (NO synthase)], phospho-eNOS, iNOS (inducible NOS), COX-1 and COX-2 protein expression was also analysed. The effects of the TP receptor [TXA2 (thromboxane A(2)) receptor] antagonist SQ 29548, the TXA(2) synthesis inhibitor furegrelate, the PGI(2) (prostaglandin I(2)) synthesis inhibitor TCP (tranylcypromine) or TCP+furegrelate were only determined in segments from cirrhotic rats. The vasodilator response to acetylcholine was higher in segments from cirrhotic rats. Indomethacin, SC-560 and NS-398 did not modify the vasodilator response in control rats; however, indomethacin, NS-398 and TCP+furegrelate increased, whereas SC-560 did not modify and SQ 29548, furegrelate or TCP decreased, the vasodilator response to acetylcholine in cirrhotic rats. NO release was higher in cirrhotic rats. Furegrelate decreased, whereas TCP+furegrelate increased, the NO release in segments from cirrhotic rats. eNOS and COX-1 protein expression was not modified, whereas phosho-eNOS, iNOS and COX-2 protein expression was higher in cirrhotic rats. Therefore the increase in iNOS expression and eNOS activity may mediate increases in endothelial NO release. The COX-2 derivatives TXA(2) and PGI(2) may act simultaneously, producing a compensatory effect that reduces NO release and may limit the hyperdynamic circulation.
Assuntos
Cirrose Hepática Experimental/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Prostaglandinas A/fisiologia , Tromboxano A2/fisiologia , Animais , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Proteína C-Reativa/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fígado/patologia , Cirrose Hepática Experimental/fisiopatologia , Masculino , Tamanho do Órgão/fisiologia , Prostaglandinas/metabolismo , Prostaglandinas A/biossíntese , Ratos , Ratos Sprague-Dawley , Baço/patologia , Superóxidos/metabolismo , Tromboxano A2/biossíntese , Vasodilatação/fisiologiaRESUMO
OBJECTIVE: The purpose of this article is to describe the high-resolution CT (HRCT) features of uncommon occupational lung diseases. CONCLUSION: HRCT plays an increasing role in the evaluation of occupational lung diseases. We present several cases of unusual occupational lung diseases and their HRCT findings. The diseases studied were siderosis, talcosis, berylliosis, calcicosis, hypersensitivity pneumonitis (due to wheat flour and isocyanates), and Ardystil syndrome. The characteristic HRCT findings together with clinical features and related occupational history improve the diagnostic accuracy of these diseases.
Assuntos
Pneumopatias/diagnóstico por imagem , Doenças Profissionais/diagnóstico por imagem , Exposição Ocupacional/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Adipatos/toxicidade , Alveolite Alérgica Extrínseca/diagnóstico por imagem , Beriliose/diagnóstico por imagem , Carbonato de Cálcio/toxicidade , Poeira , Humanos , Pneumopatias/etiologia , Poliaminas/toxicidade , Siderose/diagnóstico por imagem , Síndrome , Talco/toxicidadeRESUMO
The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.
RESUMO
BACKGROUND: Breast cancer is a frequent indication for ovarian cortex cryopreservation due to its high incidence. The main concern of this procedure is the possibility of reintroducing metastatic cells within the implant, an issue that has not been addressed systematically. Thus, a study was designed to analyse the presence of ovarian metastases in breast cancer patients undergoing ovarian tissue cryopreservation. METHODS: Morphological and immunohistochemical studies following the concept of the sentinel lymph node (SLN) were performed on 100 cortical ovarian biopsies obtained from 63 patients and on six frozen-thawed entire cortex from patients with the diagnosis of infiltrating ductal breast carcinoma undergoing ovarian cortex extraction and cryopreservation. The antibody panel included Cytokeratin CAM 5.2, Gross Cystic Disease Fluid Protein-15 (GCDFP15), Wilms' tumour antigen-1 (WT1) and Mammaglobin 1. RESULTS: Employing only morphologic criteria, suspicious neoplastic cells were detected in five biopsies, but in none of the six entire cortex analysed. These five cases were reclassified as hyperplasic surface epithelium-inclusion cysts (CAM 5.2+, WT1+) or apoptotic granulosa cells (CAM 5.2-, GCDFP15+, WT1-). CONCLUSIONS: Using the methodology of the SLN our data suggest the absence of tumour cells in biopsies obtained from patients undergoing ovarian cortex cryopreservation to preserve their fertility potential, although future methods of cancer screening may change our perception of this procedure.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Ovário/patologia , Adulto , Biomarcadores/análise , Biópsia , Proteínas de Transporte/análise , Criopreservação/métodos , Feminino , Glicoproteínas/análise , Humanos , Queratinas/análise , Metástase Linfática/patologia , Mamoglobina A , Proteínas de Membrana Transportadoras , Proteínas de Neoplasias/análise , Estadiamento de Neoplasias , Ovário/química , Ovário/citologia , Ovário/transplante , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/terapia , Biópsia de Linfonodo Sentinela , Transplante Autólogo , Uteroglobina/análise , Proteínas WT1/análiseRESUMO
Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks. Phe-induced vasoconstriction (in the presence/absence of the NO synthase -NOS- inhibitor L-NAME) and vasodilator response to NO donor DEA-NO were analysed. Phe-induced NO release was determined in the presence/absence of either H89 (protein kinase -PK- A inhibitor) or LY 294002 (PI3K inhibitor). PKA and PKG activities, alpha-1 adrenoceptor, endothelial NOS (eNOS), PI3K, AKT and soluble guanylate cyclase (sGC) subunit expressions, as well as eNOS and AKT phosphorylation, were determined. The results show that LC blunted Phe-induced vasoconstriction, and enhanced DEA-NO-induced vasodilation. L-NAME increased the Phe-induced contraction largely in LC animals. The Phe-induced NO release was greater in MRA from LC animals. Both H89 and LY 294002 reduced NO release in LC. Alpha-1 adrenoceptor, eNOS, PI3K and AKT expressions were unchanged, but sGC subunit expression, eNOS and AKT phosphorylation and the activities of PKA and PKG were higher in MRA from LC animals. In summary, these mechanisms may help maintaining splanchnic vasodilation and hypotension observed in decompensated LC.
Assuntos
Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Cirrose Hepática/tratamento farmacológico , Artérias Mesentéricas/efeitos dos fármacos , Fenilefrina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Insuficiência Hepática Crônica Agudizada/genética , Insuficiência Hepática Crônica Agudizada/metabolismo , Insuficiência Hepática Crônica Agudizada/patologia , Animais , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/antagonistas & inibidores , Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Hipertensão Portal/metabolismo , Hipertensão Portal/patologia , Isoquinolinas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Sulfonamidas/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
Peritoneal carcinomatosis (PC) is a malignant entity with a high rate of morbimortality. It is considered an end-stage common to several abdominal and pelvic malignant tumours, such as epithelial ovarian, fallopian tubal and peritoneal cancer. Although many of these tumors have a good response to chemotherapy, prognosis is poor due to the high rate of recurrence. Surgeons, gynecologists and oncologists are increasingly concerned with improving the survival. The surgical technique described by Sugarbaker in the eighties is a plausible option. It aims for a complete resection of macroscopic carcinomatosis (cytoreductive surgery) followed by intraoperative or perioperative intraperitoneal chemotherapy. This therapeutic option necessarily involves specific multidisciplinary units; histopathology of specimens from this surgical technique is now more frequent in our department. We describe our initial experience with PC originating from epithelial ovarian, tubal and peritoneal cancer treated with the modified Sugarbaker surgery employed in our hospital. We outline our protocol designed to achieve uniformity in procedure, and summarize the initial results.
Assuntos
Carcinoma/secundário , Procedimentos Cirúrgicos de Citorredução , Neoplasias das Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Patologia Cirúrgica/métodos , Neoplasias Peritoneais/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Carcinoma/cirurgia , Protocolos Clínicos , Colo/patologia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/cirurgia , Feminino , Humanos , Infusões Parenterais , Fígado/patologia , Linfonodos/patologia , Pessoa de Meia-Idade , Omento/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Peritônio/patologia , Estudos Retrospectivos , Manejo de Espécimes , Estômago/patologiaRESUMO
INTRODUCTION: We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated. MATERIALS AND METHODS: In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4. Superoxide anion (O2-), peroxynitrite (ONOO-) and superoxide dismutase (SOD) activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg) I and II were analysed. RESULTS: EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups. CONCLUSIONS: Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Estimulação Elétrica , Masculino , Artérias Mesentéricas/metabolismo , Ácido Peroxinitroso/metabolismo , Ratos , Estreptozocina , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Fatores de TempoRESUMO
We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non-specific nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments. Vasomotor responses to noradrenaline (NA) or CGRP were greater in LC segments, while NO analogue DEA-NO induced a similar vasodilation in both experimental groups. The release of NA was not modified, while those of ATP, nitrite and CGRP were increased in segments from LC. Alpha 1 adrenoceptor, Rho kinase (ROCK) 1 and 2 and total myosin phosphatase (MYPT) expressions were not modified, while alpha 2B adrenoceptor, nNOS expression and nNOS and MYPT phosphorylation were increased by LC. Together, these alterations might counteract the increased splanchnic vasodilation observed in the last phases of decompensated liver cirrhosis.
Assuntos
Cirrose Hepática/fisiopatologia , Artéria Mesentérica Superior/fisiopatologia , Animais , Cirrose Hepática/patologia , Masculino , Artéria Mesentérica Superior/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Norepinefrina/farmacologia , Proteína Fosfatase 1/metabolismo , Ratos , Ratos Wistar , Suramina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Ischemic changes in 31 samples of lateral retinacula excised at surgical realignment in patients with isolated symptomatic patellofemoral malalignment resistant to conservative treatment were evaluated with conventional histology, electron microscopy, immunohistochemistry, and molecular biology. Morphologic and ultrastructural changes associated with ischemia including hypervascularization and increased vascular endothelial growth factor release were identified in painful patellofemoral malalignment. It is hypothesized that periodic short episodes of ischemia could be implicated in the pathogenesis of anterior knee pain in most cases of isolated symptomatic patellofemoral malalignment in active young patients by triggering neural proliferation.
Assuntos
Isquemia/patologia , Síndrome da Dor Patelofemoral/patologia , Adolescente , Adulto , Vasos Sanguíneos/patologia , Feminino , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Isquemia/metabolismo , Masculino , Síndrome da Dor Patelofemoral/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
INTRODUCTION: We investigated whether high-fat diet (HFD)-induced obesity was associated with modifications in mesenteric innervation function, the mechanisms involved, and the possible effects of aerobic exercise training on these changes. MATERIALS AND METHODS: Male Wistar rats were divided into three groups: rats fed a standard diet (control group); rats fed a HFD (35% fat) for 8 weeks; and HFD rats submitted to aerobic exercise training (8 weeks, 5 times per week for 50 âmin). Segments of isolated mesenteric arteries were exposed to electric field stimulation (EFS) with or without phentolamine, suramin, or Nω nitro-L-arginine methyl ester. Noradrenaline, ATP, and nitric oxide release, and total and phosphorylated neuronal nitric oxide synthase (nNOS, P-nNOS) expression were also measured. RESULTS: EFS contraction was greater in sedentary HFD than in control rats. Phentolamine reduced EFS contractions more markedly in HFD rats. Suramin decreased EFS contractions only in control rats. Phentolamine + suramin practically abolished EFS-induced contraction in control rats, whereas it did not modify it in the HFD rats. Noradrenaline release was greater and ATP was lower in HFD rats. Nω nitro-L-arginine methyl ester increased contractions to EFS only in segments from control rats. Nitric oxide release and nNOS and P-nNOS expressions were lower in arterial segments from HFD rats than from control rats. None of these changes in sedentary HFD rats was present in the trained HFD rats. CONCLUSIONS: Enhanced sympathetic and diminished nitrergic components contributed to increased vasoconstrictor responses to EFS in sedentary HFD rats. All these changes were avoided by aerobic exercise training, suggesting that aerobic exercise could reduce peripheral vascular resistance in obesity.
Assuntos
Artérias Mesentéricas/fisiopatologia , Neurônios Nitrérgicos/fisiologia , Obesidade/fisiopatologia , Condicionamento Físico Animal/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Trifosfato de Adenosina/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Dieta Hiperlipídica , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/inervação , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Norepinefrina/metabolismo , Fentolamina/farmacologia , Ratos , Ratos Wistar , Suramina/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: We investigated whether pregnancy was associated with changed function in components of perivascular mesenteric innervation and the mechanism/s involved. EXPERIMENTAL APPROACH: We used superior mesenteric arteries from female Sprague-Dawley rats divided into two groups: control rats (in oestrous phase) and pregnant rats (20 days of pregnancy). Modifications in the vasoconstrictor response to electrical field stimulation (EFS) were analysed in the presence/absence of phentolamine (alpha-adrenoceptor antagonist) or L-NAME (nitric oxide synthase-NOS- non-specific inhibitor). Vasomotor responses to noradrenaline (NA), and to NO donor DEA-NO were studied, NA and NO release measured and neuronal NOS (nNOS) expression/activation analysed. KEY RESULTS: EFS induced a lower frequency-dependent contraction in pregnant than in control rats. Phentolamine decreased EFS-induced vasoconstriction in segments from both experimental groups, but to a greater extent in control rats. EFS-induced vasoconstriction was increased by L-NAME in arteries from both experimental groups. This increase was greater in segments from pregnant rats. Pregnancy decreased NA release while increasing NO release. nNOS expression was not modified but nNOS activation was increased by pregnancy. Pregnancy decreased NA-induced vasoconstriction response and did not modify DEA-NO-induced vasodilation response. CONCLUSIONS AND IMPLICATIONS: Neural control of mesenteric vasomotor tone was altered by pregnancy. Diminished sympathetic and enhanced nitrergic components both contributed to the decreased vasoconstriction response to EFS during pregnancy. All these changes indicate the selective participation of sympathetic and nitrergic innervations in vascular adaptations produced during pregnancy.
Assuntos
Artérias Mesentéricas/inervação , Artérias Mesentéricas/fisiologia , Sistema Vasomotor/fisiologia , Acetilcolina/metabolismo , Animais , Feminino , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Cloreto de Potássio/metabolismo , Gravidez , Ratos Sprague-Dawley , Vasoconstrição , VasodilataçãoRESUMO
BACKGROUND AND PURPOSE: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). EXPERIMENTAL APPROACH: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. KEY RESULTS: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. CONCLUSIONS AND IMPLICATIONS: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels.
Assuntos
Acetilcolina/farmacologia , Fatores Biológicos/fisiologia , Artérias Mesentéricas/efeitos dos fármacos , Vasodilatadores/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Benzimidazóis/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Hidrazinas/farmacologia , Indometacina/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Artérias Mesentéricas/patologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxidos/metabolismoRESUMO
OBJECTIVES: We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries. METHODS: Electrical field stimulation (EFS)-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L), and 3-hour tranilast incubated (0.1 mmol/L). To assess the possible participation of nitrergic or sympathetic innervation, EFS contraction was analyzed in the presence of non-selective nitric oxide synthase (NOS) inhibitor L-NAME (0.1 mmol/L), α-adrenergic receptor antagonist phentolamine (0.1 µmol/L), or the neurotoxin 6-hydroxydopamine (6-OHDA, 1.46 mmol/L). Nitric oxide (NO) and superoxide anion (O2.(-) levels were measured, as were vasomotor responses to noradrenaline (NA) and to NO donor DEA-NO, in the presence and absence of 0.1 mmol/L tempol. Phosphorylated neuronal NOS (P-nNOS) expression was also analyzed. RESULTS: EFS-induced contraction was increased by ketotifen and decreased by tranilast. L-NAME increased the vasoconstrictor response to EFS only in control segments. The vasodilator response to DEA-NO was higher in ketotifen- and tranilast-incubated segments, while tempol increased vasodilator response to DEA-NO only in control segments. Both NO and O2(-) release, and P-nNOS expression were diminished by ketotifen and by tranilast treatment. The decrease in EFS-induced contraction produced by phentolamine was lower in tranilast-incubated segments. NA vasomotor response was decreased only by tranilast. The remnant vasoconstriction observed in control and ketotifen-incubated segments was abolished by 6-OHDA. CONCLUSION: While both ketotifen and tranilast diminish nitrergic innervation function, only tranilast diminishes sympathetic innnervation function, thus they alter the vasoconstrictor response to EFS in opposing manners.
Assuntos
Cetotifeno/farmacologia , Mastócitos/fisiologia , Artérias Mesentéricas/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , ortoaminobenzoatos/farmacologia , Acetilcolina/farmacologia , Animais , Estimulação Elétrica , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Liberação de Histamina/efeitos dos fármacos , Técnicas In Vitro , Masculino , Mastócitos/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios Nitrérgicos/efeitos dos fármacos , Neurônios Nitrérgicos/fisiologia , Cloreto de Potássio/farmacologia , Ratos Wistar , Coloração e Rotulagem , Superóxidos/metabolismo , Cloreto de Tolônio/metabolismo , Vasodilatadores/farmacologia , Sistema Vasomotor/efeitos dos fármacosRESUMO
OBJECTIVES: The aim of this study was to investigate in rat mesenteric artery whether breast feeding (BF) affects the vasomotor response induced by electrical field stimulation (EFS), participation by different innervations in the EFS-induced response and the mechanism/s underlying these possible modifications. METHODS: Experiments were performed in female Sprague-Dawley rats (3 months old), divided into three groups: Control (in oestrous phase), mothers after 21 days of BF, and mothers that had recovered their oestral cycle (After BF, in oestrous phase). Vasomotor response to EFS, noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied. Neuronal NO synthase (nNOS) and phosphorylated nNOS (P-nNOS) protein expression were analysed and NO, superoxide anion (O(2)(.-)), NA and ATP releases were also determined. RESULTS: EFS-induced contraction was higher in the BF group, and was recovered after BF. 1 µmol/L phentolamine decreased the response to EFS similarly in control and BF rats. NA vasoconstriction and release were similar in both experimental groups. ATP release was higher in segments from BF rats. 0.1 mmol/L L-NAME increased the response to EFS in both control and BF rats, but more so in control animals. BF decreased NO release and did not modify O(2)(.-) production. Vasodilator response to DEA-NO was similar in both groups, while nNOS and P-nNOS expressions were decreased in segments from BF animals. CONCLUSION: Breast feeding increases EFS-induced contraction in mesenteric arteries, mainly through the decrease of neuronal NO release mediated by decreased nNOS and P-nNOS expression. Sympathetic function is increased through the increased ATP release in BF rats.