Potentiation of 5-hydroxytryptamine (5-HT) responses by a 5-HT uptake inhibitor in pulmonary and systemic vessels: effects of exposing rats to hypoxia

The aim was to determine whether uptake of 5-hydroxytryptamine (5-HT) by the 5-HT transporter (SERT) modulates contractile responses to 5-HT in rat pulmonary arteries and whether this modulation is altered by exposure of rats to chronic hypoxia (10% oxygen; 8 h/day; 5 days). The effects of the SERT inhibitor, citalopram (100 nM), on contractions to 5-HT were determined in isolated ring preparations of pulmonary artery (intralobar and main) and compared with data obtained in systemic arteries. In intralobar pulmonary arteries citalopram produced a potentiation (viz. an increase in potency, pEC(50)) of 5-HT. The potentiation was endothelium-dependent in preparations from normoxic rats but endothelium-independent in preparations from hypoxic rats. In main pulmonary artery endothelium-independent potentiation was seen in preparations from hypoxic rats but no potentiation occurred in preparations from normoxic rats. In systemic arteries, citalopram caused endothelium-independent potentiation in aorta but no potentiation in mesenteric arteries; there were no differences between hypoxic and normoxic rats. It is concluded that SERT can influence the concentration of 5-HT in the vicinity of the vasoconstrictor receptors in pulmonary arteries. The data suggest that in pulmonary arteries from hypoxic rats, unlike normoxic rats, the SERT responsible for this effect is not in the endothelium and, hence, is probably in the smooth muscle. The data are compatible with reports that, in the pulmonary circulation, hypoxia induces/up-regulates SERT, and hence increases 5-HT uptake, in vascular smooth muscle. The findings may have implications in relation to the suggested use of SERT inhibitors in the treatment of pulmonary hypertension.

Alterations in pulmonary vascular function in rats exposed to intermittent hypoxia

Vasoactive agents were examined in arteries from control rats and rats exposed to intermittent hypoxia (10% oxygen; 8 h/day) for 3, 5 or 20 days. Hypoxic rats developed right ventricular hypertrophy after 5 days, but became pulmonary hypertensive (elevated right ventricular systolic pressure; RVSP) only after 20 days. In pulmonary arteries (main and intralobar), responses to acetylcholine and ionomycin (endothelium-dependent vasodilators) were reduced after 20 and 5 days of intermittent hypoxia, whereas contractions to 5-hydroxytryptamine (5-HT) were enhanced (potency increase >10-fold) after 20, 5 and 3 days. Contractions to endothelin-1 and a thromboxane-mimetic, but not Ca-2divided by, were also increased. No changes in vascular function occurred in aorta. Since changes in pulmonary vascular function preceded the increase in RVSP they do not result from, but may contribute to, the development of hypoxia-induced pulmonary hypertension. If similar changes occur in humans, they may be important in conditions characterised by intermittent, as opposed to continuous, hypoxia. (C) 2003 Elsevier B.V. All rights reserved.

S-nitrosocaptopril: acute in-vivo pulmonary vasodepressor effects in pulmonary hypertensive rats

The effects of S-nitrosocaptopril (SNOcap), administered either intravenously or by oral gavage, on pulmonary artery pressure (PAP) were examined in anaesthetised normotensive rats and rats with hypoxic pulmonary hypertension (10% oxygen for 1 week). Mean PAP (MPAP) values in hypoxic and normoxic rats were (mmHg) 26 +/- 1.7 and 15 +/- 1.1, respectively. When given intravenously, 1 mg kg(-1) SNOcap reduced MPAP by 28 and 32% in hypoxic and normoxic rats, respectively. The effects of 2 mg kg(-1) were no greater than those of 1 mg kg(-1). Pulmonary vasoclepressor responses reached equilibrium in 1.7 +/- 0.18 min following intravenous administration. When given orally 30 min before the measurement of PAP, 30 mg kg(-1), but not 10 mg kg(-1), significantly reduced MPAP in hypoxic rats to 17 +/- 1.5 mmHg. These in-vivo data are consistent with previous in-vitro data showing that SNOcap has direct pulmonary vasorelaxant properties in both large and small pulmonary arteries and also show that SNOcap causes pulmonary vasodepression in the setting of pulmonary hypertension. Since SNOcap also inhibits pulmonary vascular angiotensin converting enzyme (ACE) in pulmonary blood vessels (previous study), it would be an interesting drug with which to assess the benefits of direct pulmonary vasodilatation combined with ACE inhibition (which attentuates pulmonary vascular remodelling) in a long-term study in pulmonary hypertension.

Early pregnancy factor suppresses the infiltration of lymphocytes and macrophages in the spinal cord of rats during experimental autoimmune encephalomyelitis but has no effect on apoptosis

Early pregnancy factor (EPF) is a secreted protein with immunosuppressive and growth factor properties that has been shown to suppress acute experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP) in Lewis rats. EAE is associated with infiltration of the central nervous system (CNS) with inflammatory cells. Spontaneous recovery involves the loss of T lymphocytes from the CNS and the selective apoptosis of Vbeta8.2(+) cells. In the present study, T cell, macrophage (CD11b/c(+)) and B cell (CD45RA(+)) populations in spinal cord and popliteal lymph nodes (LN) of Lewis rats with EAE were quantitated and apoptosis was studied. Rats were treated with EPF or vehicle. Following treatment on day 14 after inoculation with MBP, neither 1 x 100 mug nor 2 x 100 mug doses of EPF affected the total number of cells infiltrating the spinal cord on day 15, although the higher dose caused a decrease in the number of CD5(+) and CD11b/c(+) cells. Treatment with 2 x 100 mug/day from days 10 to 14 decreased the total number of infiltrating cells, and the numbers of CD5(+), CD11b/c(+) and CD45RA(+) cells. Apoptosis was unaffected. No alteration on the number or type of inflammatory cells in the popliteal LN was observed after treatment on days 10-14. However, treatment with EPF from days 0 to 11 increased the total number of T and B cells and CD5(+) T cells found on day 12 in the LN. Similarly, there was an increase in the frequency of MBP-reactive cells in the LN as determined by limiting dilution analysis. These results suggest that EPF treatment reduces the numbers of lymphocytes and macrophages in the CNS, possibly through an effect on cell trafficking. (C) 2003 Elsevier B.V. All rights reserved.

Dietary interactions influence the effects of bovine folate-binding protein on the bioavailability of tetrahydrofolates in rats

The newborns of mammals have a high folate demand, yet obtain adequate folate nutrition solely from their mothers' milk despite its low folate content. Milk folate is entirely bound by an excess of folate-binding protein (FBP), prompting speculation that FBP may affect the bioavailability of the limited folate supply. Previous research has shown that FBP-bound folic acid is more gradually absorbed, thereby reducing the peak plasma folate concentration and preventing loss into the urine. Natural folates are reduced derivatives of folic acid, with milk predominantly containing 5-methyltetrahydrofolate, yet little research has been carried out to determine the role of FBP in the bioavailability of reduced folates. We studied the effect of FBP on folate nutrition of rats in both single-dose and 4-wk feeding experiments. The effect of FBP was influenced by the presence of other milk components. FBP increased bioavailability of dietary folate when it was consumed with other whey proteins or with soluble casein. However, in the presence of acid-precipitated casein or a whey preparation enriched in lipids, bioavailability was decreased. These results highlight the difficulties of extrapolating from experimental results obtained using purified diets alone and of studying interactions among dietary components. They suggest that the addition of FBP-rich foods to folate-rich foods could enhance the bioavailability of natural folates, but that the outcome of such a combination would depend on interactions with other components of the diet.

Intramolecular electron transfer in a bacterial sulfite dehydrogenase

Sulfite dehydrogenase (SDH) from Starkeya novella, a sulfite-oxidizing molybdenum-containing enzyme, has a novel tightly bound αβ-heterodimeric structure in which the Mo cofactor and the c-type heme are located on different subunits. Flash photolysis studies of intramolecular electron transfer (IET) in SDH show that the process is first-order, independent of solution viscosity, and not inhibited by sulfate, which strongly indicates that IET in SDH proceeds directly through the protein medium and does not involve substantial movement of the two subunits relative to each other. The IET results for SDH contrast with those for chicken and human sulfite oxidase (SO) in which the molybdenum domain is linked to a b-type heme domain through a flexible loop, and IET shows a remarkable dependence on sulfate concentration and viscosity that has been ascribed to interdomain docking. The results for SDH provide additional support for the interdomain docking hypothesis in animal SO and clearly demonstrate that dependence of IET on viscosity and sulfate is not an inherent property of all sulfite-oxidizing molybdenum enzymes.

Rates of electronic energy transfer in conformationally flexible bichromophoric macrocyclic complexes: a combined experimental and molecular modeling study

Electronic energy transfer (EET) rate constants between a naphthalene donor and anthracene acceptor in [ZnL4a](ClO4)(2) and [ZnL4b](ClO4)(2) were determined by time-resolved fluorescence where L-4a and L-4b are the trans and cis isomers of 6-((anthracen-9-yl-methyl)amino)-6,13-dimethyl-13-((naphthalen-1-yl-methyl)amino)-1,4,8,11-tetraazacyclotetradecane, respectively. These isomers differ in the relative disposition of the appended chromophores with respect to the macrocyclic plane. The trans isomer has an energy transfer rate constant (k(EET)) of 8.7 x 10(8) s(-1), whereas that of the cis isomer is significantly faster (2.3 x 10(9) s(-1)). Molecular modeling was used to determine the likely distribution of conformations in CH3CN solution for these complexes in an attempt to identify any distance or orientation dependency that may account for the differing rate constants observed. The calculated conformational distributions together with analysis by H-1 NMR for the [ZnL4a](2+) trans complex in the common trans-III N-based isomer gave a calculated Forster rate constant close to that observed experimentally. For the [ZnL4b](2+) cis complex, the experimentally determined rate constant may be attributed to a combination of trans-Ill and trans-I N-based isomeric forms of the complex in solution.

A protective effect of early pregnancy factor on experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

Experimental antoimmune encephalomyelitis (EAE) is an organ-specific autoimmune disease characterised by inflammation and demyelination of the central nervous system and is the best available animal model of multiple sclerosis (MS). Since previous studies have shown that EAE is less severe or is delayed in onset during pregnancy and that administration of the pregnancy hormone early pregnancy factor (EPF) down-regulates EAE, experiments in the present study were designed to explore further the role of EPF in EAE. By using the rosette inhibition test, the standard bioassay for EPF and, by semi-quantitative RT-PCR techniques, we have now shown that inflammatory cells from the spinal cord of rats with EAE can produce and secrete EPF, with production being greatest during recovery from disease. Administration of EPF to rats with EAE resulted in a significant increase in the expression of IL-4 and IL-10 mRNA and a significant decrease in IFN-gamma mRNA expression in spinal cord inflammatory cells. Encephalitogenic MBP-specific T cell lines were prepared from popliteal lymph nodes of rats with EAE. Proliferation assays using these cells demonstrated the ability of exogenous EPF to down-regulate the responses of T lymphocytes to MBP. (C) 2003 Elsevier B.V. All rights reserved.

Electrochemistry of P450cin: new insights into P450 electron transfer

Electrochemistry of bacterial cytochrome P450cin (CYP176A) reveals that, unusually, substrate binding does not affect the heme redox potential, although a marked pH dependence is consistent with a coupled single electron/single proton transfer reaction in the range 6 < pH < 10.

Boletim eletr??nico de bibliografias especializadas: pol??tica de transfer??ncia condicionada de renda

As pol??ticas de Transfer??ncia Condicionada de Renda (TCR) s??o consideradas a mais nova gera????o de pol??ticas sociais. O fato tem chamado a aten????o de profissionais do setor p??blico e de acad??micos de diferentes ??reas. Nos ??ltimos anos, diversas experi??ncias, sobretudo na Am??rica Latina, t??m-se destacado pelo impacto positivo sobre os indicadores sociais da popula????o, entre elas: o Programa Bolsa Fam??lia, no Brasil; o Programa de Desarrollo Humano Oportunidades, no M??xico; e o Sistema Chile Solid??rio, no Chile. O Programa Bolsa Fam??lia, criado em 2003, constitui a maior pol??tica p??blica de TCR da Am??rica Latina, tanto em or??amento quanto em cobertura. Atualmente, atende cerca de 13.800.000 fam??lias, em todos os munic??pios do Pa??s. O Programa tem servido de modelo para a difus??o desse tipo de pol??tica no mundo. O tema envolve v??rias dimens??es da ??rea social, por se tratar de uma pol??tica essencialmente intersetorial. O Bolsa Fam??lia vem se destacando nos debates da administra????o p??blica, devido ?? sua forte capacidade de melhoria das condi????es das fam??lias benefici??rias. Diante disso, a 5a edi????o do Boletim Eletr??nico de Bibliografias Especializadas apresenta uma reuni??o de publica????es do acervo da Biblioteca Graciliano Ramos que abordam os seguintes temas: transfer??ncia condicionada de renda, programas sociais, desigualdade social, combate da pobreza e pol??ticas p??blicas. O objetivo ?? divulgar obras que auxiliem servidores p??blicos na reflex??o e compreens??o desses assuntos

Sistema de Gest??o de Conv??nios e Contratos de Repasse (Siconv). Um novo paradigma nas transfer??ncias volunt??rias da Uni??o

O Sistema de Gest??o de Conv??nios e Contratos de Repasse (Siconv) ?? a iniciativa do Governo Federal respons??vel por todo o ciclo de vida dos conv??nios, contratos de repasse e termos de parceria, no qual s??o registrados os atos, desde a formaliza????o da proposta at?? a presta????o de contas final. O Siconv inova no modelo de gest??o, proporciona celeridade aos procedimentos e desburocratiza as atividades fins, com foco na substitui????o do processo f??sico pelo eletr??nico e no registro de todos os procedimentos, o que permite maior transpar??ncia na execu????o das transfer??ncias volunt??rias da Uni??o. Destaca- se ainda que a disponibiliza????o do sistema aos usu??rios e tamb??m para a sociedade por meio do endere??o eletr??nico www.convenios.gov.br deve ser considerada como grande fator de inova????o, uma vez que, mesmo indiretamente, se apresenta como mais uma ferramenta de controle social.

Programa de apoio ao desenvolvimento de novas empresas de base tecnol??gica agropecu??ria e ?? transfer??ncia de tecnologia (Proeta)

Em dezembro de 2001, o Proeta foi criado pela Empresa Brasileira de Pesquisa Agropecu??ria (Embrapa) com apoio financeiro do Fundo Multilateral de Investimentos do Banco Interamericano de Desenvolvimento (Fumin/BID), por meio de um acordo de coopera????o t??cnica n??o-reembols??vel. O programa tem o objetivo de contribuir para a transfer??ncia de tecnologias e conhecimentos gerados pela Embrapa para empreendimentos de base tecnol??gica, mediante a utiliza????o do processo de incuba????o de empresas. Para concretizar a iniciativa, foram estabelecidas experi??ncias-piloto em cinco unidades de pesquisa da Embrapa, estrategicamente situadas nas regi??es Nordeste, Centro-Oeste e Sudeste. Entre os resultados e avan??os obtidos merecem destaque 21 tecnologias disponibilizadas, 14 conv??nios firmados com incubadoras, 16 propostas de neg??cios apresentadas, 14 empresas pr??-selecionadas e incubadas, e uma empresa graduada. A consolida????o das alian??as e parcerias no processo de incuba????o resultou em um sistema de inova????o que auxilia o desenvolvimento sustent??vel da cadeia produtiva do agroneg??cio, gerando benef??cios para a sociedade em geral

STNet: transfer??ncias para estados e munic??pios

O projeto trata da moderniza????o da sistem??tica de disponibiliza????o de informa????es referentes aos repasses das principais transfer??ncias constitucionais da Uni??o para Estados e Munic??pios, atrav??s da utiliza????o de v??rios canais de comunica????o, dentre as quais destaca-se a Internet. Com a implanta????o de novas tecnologias v??m-se atingindo os objetivos desejados propiciando de maneira transparente para a sociedade, atrav??s dos diversos mecanismos, a a????o do Governo Federal no cumprimento do dever constitucional de repassar os recursos federais arrecadados aos estados e munic??pios

M??dulo 1 - contexto normativo e institucional: curso mecanismos OGU PAC (transfer??ncias obrigat??rias)

Esse documento trata de a????es de Saneamento no ??mbito do Programa de Acelera????o do Crescimento; a????es do PAC; Saneamento no ??mbito do Or??amento da Uni??o