Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Brain Imaging Behav ; 6(2): 208-23, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22684770

RESUMO

Traumatic brain injury results in a metabolic cascade of changes that occur at the molecular level, invisible to conventional imaging methods such as computed tomography or magnetic resonance imaging. Non-invasive metabolic imaging tools such as single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance spectroscopy (MRS) are the ideal methods for providing insight to these changes by measuring regional cerebral blood flow, glucose metabolism, and brain metabolite concentrations, respectively, after mild traumatic brain injury (mTBI). The purpose of this review is to provide an overview of the different methodologies and provide an up-to-date summary of recent findings with SPECT, PET, and MRS technologies, specifically after mTBI, as defined by standardized criteria. Given that the different physiological and pathological responses are heterogeneous, efforts will be made to separate studies at different time points after injury (acute, subacute, and chronic stages) as well as to the different types of mTBI such sports-related head injury where repetitive head injuries are much more common and may present a unique signature.


Assuntos
Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/metabolismo , Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neuroimagem Funcional/métodos , Tomografia Computadorizada de Emissão/métodos , Humanos
2.
J Cardiovasc Pharmacol ; 38(6): 909-21, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11707695

RESUMO

Vascular smooth muscle cell (VSMC) migration involves adhesion, locomotion, and invasion regulated by various signaling molecules, among which the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) play a critical role. We have shown that the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands troglitazone and rosiglitazone inhibit VSMC migration downstream of ERK MAPK. The purpose of the current study was to more specifically determine which step(s) in VSMC migration are targeted by inhibition of the ERK MAPK pathway or activation of PPAR-gamma. VSMC adhesion was not affected by the ERK MAPK pathway inhibitor PD98059 or PPAR-gamma ligands. Phosphorylation and activation of myosin light chain kinase (MLCK) play important roles in cell locomotion. Platelet-derived growth factor (PDGF)-induced MLCK phosphorylation (1.7-fold) was completely blocked by PD98059 at 30 microM (p < 0.05), but not by troglitazone or rosiglitazone. PDGF-directed migration (5.8-fold) was inhibited by PD98059 (-88% at 30 microM) and the MLCK inhibitor ML9 (0.1-1 microM, -84% at 1 microM) (all p < 0.05). The transcription factor Ets-1 mediates matrix metalloproteinase induction required for tissue invasion by VSMC. PDGF (20 ng/ml) stimulated an Ets-1 protein expression (14-fold at 60 min) in VSMC, which was inhibited by PD98059 (-72% at 30 microM), troglitazone (-69% at 20 microM), and rosiglitazone (-54% at 10 microM) (all p < 0.05). Immunohistochemistry of rat aortae 2 h after balloon injury showed a dramatic upregulation of Ets-1, which was markedly inhibited in animals that had received troglitazone treatment. In contrast, phosphorylated ERK MAPK was not affected by troglitazone. These data are consistent with PPAR-gamma ligands exerting their anti-migratory effects downstream of ERK MAPK activation by blocking nuclear events, such as Ets-1 expression, required for cell invasion in response to arterial injury.


Assuntos
Movimento Celular , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Células Cultivadas , Cromanos/farmacologia , Citosol/enzimologia , Inibidores Enzimáticos/farmacologia , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/metabolismo , Oclusão de Enxerto Vascular/patologia , Ligantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Tiazóis/farmacologia , Fatores de Transcrição/metabolismo , Ativação Transcricional , Troglitazona
3.
Atherosclerosis ; 159(1): 93-101, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11689211

RESUMO

Migration, proliferation and differentiation of vascular smooth muscle cells (VSMC) and macrophages are important pathological responses that contribute to the development and progression of vascular lesions. Cytokines such as TNFalpha are present at sites of vascular injury and regulate a variety of cellular functions of inflammatory cells and VSMC. Cell migration, proliferation and differentiation require de novo gene transcription resulting from extracellular signals being transduced to the nucleus, where multiple genes are regulated to participate in lesion formation. In VSMC and macrophages, TNFalpha induces activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2), which transmit signals from the cytosol to the nucleus. Potential nuclear targets of TNFalpha-activated ERK 1/2 include the transcription factors Ets-1, Egr-1, and c-fos, which are known to regulate cellular growth, differentiation, and migration. The aim of this study was to investigate the expression of the transcription factors Ets-1, Egr-1 and c-fos in different types of vascular lesions, their regulation by TNFalpha and the role of ERK 1/2 in these signaling events. Atherosclerotic lesions from fructose-fed LDL-receptor deficient mice and neointimal lesions from rat aortae 2 weeks post balloon injury demonstrated the presence and colocalization of TNFalpha, phosphorylated and activated ERK 1/2, and transcription factors Ets-1, Egr-1 and c-fos. Neointimal lesions consisted primarily of VSMC, whereas atherosclerotic lesions predominantly contained macrophages. In cultured rat aortic VSMC, TNFalpha (100 U/ml) stimulated a rapid and transient expression of Ets-1, Egr-1 and c-fos with a maximal induction 1 h after stimulation. In cultured RAW 264.7 mouse macrophages, TNFalpha similarly induced the expression of Ets-1, Egr-1, and c-fos. Induction of these transcription factors was mediated via ERK 1/2 activation, since the ERK 1/2-pathway inhibitor PD98059 (10-30 microM) significantly inhibited their TNFalpha-induced expression. TNFalpha induced ERK 1/2 activation in both cell types. These findings underscore the importance of the ERK 1/2 pathway in the expression of TNFalpha-regulated transcription factors, which may participate in different forms of vascular lesion formation.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Proteínas Imediatamente Precoces , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Músculo Liso Vascular/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Fatores de Transcrição/biossíntese , Fator de Necrose Tumoral alfa/fisiologia , Animais , Arteriosclerose/metabolismo , Western Blotting , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Imuno-Histoquímica , Macrófagos/metabolismo , Masculino , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-ets , Ratos , Ratos Sprague-Dawley
4.
Arterioscler Thromb Vasc Biol ; 21(3): 365-71, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11231915

RESUMO

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor expressed in all of the major cell types found in atherosclerotic lesions: monocytes/macrophages, endothelial cells, and smooth muscle cells. In vitro, PPARgamma ligands inhibit cell proliferation and migration, 2 processes critical for vascular lesion formation. In contrast to these putative antiatherogenic activities, PPARgamma has been shown in vitro to upregulate the CD36 scavenger receptor, which could promote foam cell formation. Thus, it is unclear what impact PPARgamma activation will have on the development and progression of atherosclerosis. This issue is important because thiazolidinediones, which are ligands for PPARgamma, have recently been approved for the treatment of type 2 diabetes, a state of accelerated atherosclerosis. We report herein that the PPARgamma ligand, troglitazone, inhibited lesion formation in male low density lipoprotein receptor-deficient mice fed either a high-fat diet, which also induces type 2 diabetes, or a high-fructose diet. Troglitazone decreased the accumulation of macrophages in intimal xanthomas, consistent with our in vitro observation that troglitazone and another thiazolidinedione, rosiglitazone, inhibited monocyte chemoattractant protein-1-directed transendothelial migration of monocytes. Although troglitazone had some beneficial effects on metabolic risk factors (in particular, a reduction of insulin levels in the diabetic model), none of the systemic cardiovascular risk factors was consistently improved in either model. These observations suggest that the inhibition of early atherosclerotic lesion formation by troglitazone may result, at least in part, from direct effects of PPARgamma activation in the artery wall.


Assuntos
Arteriosclerose/prevenção & controle , Cromanos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Receptores de LDL/deficiência , Tiazóis/farmacologia , Tiazolidinedionas , Vasodilatadores/farmacologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Arteriosclerose/etiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/farmacologia , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Endotélio Vascular/citologia , Flavonoides/farmacologia , Frutose/administração & dosagem , Humanos , Insulina/sangue , Lipídeos/sangue , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/efeitos dos fármacos , Receptores de LDL/genética , Rosiglitazona , Troglitazona , Células Tumorais Cultivadas
5.
Basic Res Cardiol ; 96(1): 42-9, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11215531

RESUMO

Neointima formation involves tissue expression of matrix proteins and growth factors. The role of alphavbeta3, but not alphavbeta5 integrin in vascular cells has been sufficiently investigated. The aim of the present study was to determine and compare the function of alphavbeta3 and alphavbeta5 integrins in rat aortic (RASMC) and human coronary vascular smooth muscle cells (HCSMC) and to characterize their expression accompanying neointima formation in vivo. RASMC and HCSMC express alphavbeta3 and alphavbeta5 integrin subunits. The alphavbeta5 integrin predominantly mediated adhesion of RASMCs to vitronectin and spreading on vitronectin via RGD-binding sequences. In contrast, the alphavbeta3 integrin did not contribute to the adhesion and spreading on fibronectin, vitronectin, gelatin or collagen I coated layers. PDGF-directed migration through gelatin coated membranes involved both alphavbeta3 and alphavbeta5 integrins. Selective blocking antibodies for alphavbeta3 and alphavbeta5 inhibited migration of RASMC and HCSMC by more than 60 % (p < 0.01). Integrin expression was studied in vivo in thoracic aorta of Sprague Dawley rats before and after balloon injury. In situ hybridization demonstrated low signals for alphav, beta3 and beta5 mRNA in uninjured aorta, which increased significantly at 14 days, localized predominantly in the neointima. Northern analysis of aorta after 14 days of injury also demonstrated an upregulation of alphav, beta3 and beta5 mRNA compared to uninjured aorta. Consistent with the increase in message levels, increased integrin protein expression was seen in the neointima after 7 and 14 days. This study provides evidence that alphavbeta3 and alphavbeta5 are elevated during neointima formation in the rat and indicates a novel role for alphavbeta5 participating in mechanisms regulating smooth muscle cell migration.


Assuntos
Aorta/fisiologia , Músculo Liso Vascular/fisiologia , Receptores de Vitronectina/fisiologia , Animais , Aorta/citologia , Aorta/lesões , Aorta/metabolismo , Cateterismo , Adesão Celular , Movimento Celular/fisiologia , Células Cultivadas , Imuno-Histoquímica , Hibridização In Situ , Músculo Liso Vascular/citologia , Ratos , Ratos Sprague-Dawley , Valores de Referência
6.
J Cardiovasc Pharmacol ; 35(5): 749-57, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10813377

RESUMO

Troglitazone (TRO) is an oral insulin-sensitizer that has direct effects on the vasculature to inhibit cell growth and migration. In vascular smooth muscle cells (VSMCs), insulin transduces a mitogenic signal that is dependent on the ERK1/2 MAP kinases. We examined the effects of TRO on this pathway and found that it inhibits mitogenic signaling. In quiescent VSMCs, insulin (1 microM) induced a 3.2-fold increase in DNA synthesis. TRO (1-20 microM) inhibited insulin-stimulated DNA synthesis by 72.8% at the maximal concentration. TRO at I and 10 microM had no significant effect on insulin-stimulated ERK1/2 activity. At 20 microM, however, TRO modestly enhanced insulin-stimulated ERK1/2 activity by 1.5-fold. ERKs transduce a mitogenic signal by phosphorylating transcription factors such as Elk-1. which regulate critical growth-response genes. We used GAL-Elk-1 expression plasmids to detect ERK-dependent activation of Elk-1. TRO at 1-20 microM potently inhibited insulin-stimulated, ERK1/2-dependent Elk-1 transcription factor activity. Neither early steps in insulin signaling nor the phosphatidylinositol 3-kinase (PI3K) branch of this pathway were affected by TRO, because it had no effect on IRS-1 phosphorylation, PI3K/IRS-1 association, or Akt phosphorylation. Because TRO is a known ligand for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), we tested two other ligands for this receptor, rosiglitazone (RSG) and 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2). Both also inhibited insulin-induced DNA synthesis. In summary, these data show that TRO inhibits mitogenic signaling by insulin at a point distal of ERK1/2 activation, potentially by a PPARgamma-mediated inhibition of ERK-dependent phosphorylation and activation of nuclear transcription factors that regulate cell growth.


Assuntos
Cromanos/farmacologia , Proteínas de Ligação a DNA , Hipoglicemiantes/farmacologia , Antagonistas da Insulina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Tiazolidinedionas , Animais , Células Cultivadas , DNA/biossíntese , DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Troglitazona , Proteínas Elk-1 do Domínio ets
7.
Circulation ; 101(11): 1311-8, 2000 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-10725292

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is activated by fatty acids, eicosanoids, and insulin-sensitizing thiazolidinediones (TZDs). The TZD troglitazone (TRO) inhibits vascular smooth muscle cell (VSMC) proliferation and migration in vitro and in postinjury intimal hyperplasia. METHODS AND RESULTS: Rat and human VSMCs express mRNA and nuclear receptors for PPARgamma1. Three PPARgamma ligands, the TZDs TRO and rosiglitazone and the prostanoid 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), all inhibited VSMC proliferation and migration. PPARgamma is upregulated in rat neointima at 7 days and 14 days after balloon injury and is also present in early human atheroma and precursor lesions. CONCLUSIONS: Pharmacological activation of PPARgamma expressed in VSMCs inhibits their proliferation and migration, potentially limiting restenosis and atherosclerosis. These receptors are upregulated during vascular injury.


Assuntos
Músculo Liso Vascular/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Células 3T3/fisiologia , Animais , Aorta/lesões , Aorta/metabolismo , Cateterismo , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , DNA/biossíntese , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Ligantes , Camundongos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Frações Subcelulares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Túnica Íntima/metabolismo
8.
Brain Res ; 835(2): 104-12, 1999 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-10415365

RESUMO

Mice deficient in monoamine oxidase A (MAO A) have elevated brain levels of 5-HT and manifest enhanced aggression. We used these mice as a model to study the role of 5-HT in aggression. Our results show that ketanserin and tetrabenazine (TBZ) strikingly abolished the aggressive behavior of MAO A-deficient mice. The anti-aggressive effect of ketanserin may be primarily mediated by 5-HT(2A) receptors. Another specific 5-HT(2A) antagonist, [R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methan ol (MDL 100907), also blocks the aggression of mutant mice but was less dramatic. Ketanserin and TBZ are both antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive effect of TBZ and part of the effect of ketanserin may be mediated by the VMAT2. Using radioligand binding and autoradiography, we also showed that the numbers of VMAT2, 5-HT(1A), 5-HT(2A) and 5-HT(2C) sites are decreased in brains of mutant mice, which may reflect down-regulation by excess 5-HT. This study suggests that ketanserin and TBZ may be developed as novel anti-aggressive agents.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Agressão/efeitos dos fármacos , Ketanserina/farmacologia , Monoaminoxidase/deficiência , Antagonistas da Serotonina/farmacologia , Tetrabenazina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fluorbenzenos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Masculino , Camundongos , Camundongos Knockout , Monoaminoxidase/genética , Neurotransmissores/metabolismo , Piperidinas/farmacologia , Ensaio Radioligante
9.
Basic Res Cardiol ; 93(6): 477-86, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9879454

RESUMO

OBJECTIVES: The efficacy of three different echocardiographic techniques to assess cardiac structures and function in the rat heart was studied. BACKGROUND: With increasing costs for large animal studies there is need for improved assessment of ventricular function in small animal models. METHODS: Transthoracic, transesophageal, or intracavitary echocardiography was performed in 138 rats using either a pediatric or an intravascular ultrasound transducer in control, infarcted, and obese rats. Left ventricular dimensions and wall thickness were measured. RESULTS: Transthoracic echocardiography allows qualitative and quantitative estimation of cardiac dimensions and ventricular function. End-diastolic and end-systolic diameters were 0.53 +/- 0.08 and 0.26 +/- 0.05 cm in controls, 0.63 +/- 0.08 and 0.41 +/- 0.07 cm in infarcted (p < 0.001 vs controls), and 0.66 +/- 0.1 and 0.21 +/- 0.07 cm in obese rats (p < 0.01 vs controls). Fractional shortening was 52 +/- 6% in controls, 36 +/- 5% in infarcted (p < 0.001), and 68 +/- 9% in obese rats (p < 0.001). Wall thickness was increased in obese rats. Transesophageal echocardiography allows a qualitative rather than quantitative assessment. Intracavitary ultrasound enabled visualization of the endocardium. Following coronary occlusion, fractional shortening and ejection fraction were decreased (30.8 +/- 4.5 vs 44.4 +/- 4.7%, p < 0.005, and 46.7 +/- 8.5 vs 63.4 +/- 5.4%, p < 0.005, respectively). CONCLUSIONS: Transthoracic echocardiography is a non-invasive technique to sufficiently provide information about cardiac structures and function, while transesophageal echocardiography allows rather a qualitative estimation of the rat heart. Intracavitary ultrasound can be used to assess the endocardium, ventricular function, and dimensions in open-chest studies in rats.


Assuntos
Ecocardiografia , Contração Miocárdica , Função Ventricular , Animais , Ecocardiografia Transesofagiana , Feminino , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Obesidade/fisiopatologia , Ratos , Ratos Sprague-Dawley
10.
Circulation ; 96(9): 3063-71, 1997 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-9386176

RESUMO

BACKGROUND: Osteopontin (OP) has been identified in cultured rat cardiac fibroblasts, where it contributes to angiotensin II (AII)-induced remodeling processes; in cultured cardiomyocytes; and in macrophages in cardiac tissues with inflammation. However, the presence of OP has not been reported in histological sections of myocardial tissue. In the present study, we investigated (1) the regulation of OP mRNA expression in cultured rat cardiomyocytes; (2) the localization of OP mRNA in neonatal and adult normal and hypertrophied rat hearts; and (3) the histology of OP expression in myocardial specimens from humans either with myocyte hypertrophy or with no pathological changes. METHODS AND RESULTS: Cultured neonatal cardiomyocytes expressed OP mRNA and were immunoreactive for OP. Endothelin-1 (ET-1) and norepinephrine (NE) increased both OP and atrial natriuretic peptide (ANP) mRNA levels twofold to threefold (P<.01). OP mRNA was prominent in ventricular tissue from neonatal and adult rats with renovascular hypertension and aortic banding, whereas barely detectable levels were observed in normal adult cardiac tissue. ANP and OP mRNA levels in normal and hypertrophied ventricles correlated (r2=.87, P<.001). OP immunoreactivity and mRNA transcripts were predominantly found in cardiomyocytes not associated with inflammatory cells in sections from neonatal and adult hypertrophied hearts. No staining was detectable in normal adult hearts. Human myocardium with extensive fibrosis and cardiomyocyte hypertrophy obtained from explanted hearts with either idiopathic (n=5) or ischemic cardiomyopathy (n=7) demonstrated substantial myocyte immunoreactivity for both OP and ANP in right and left ventricles that was not associated with leukocyte infiltration. In situ hybridization identified cardiomyocytes as the major source of OP mRNA transcripts in these hearts. In contrast, OP immunoreactivity was not detectable in four of five endomyocardial biopsies with normal histology. CONCLUSIONS: The present study provides the first evidence that cardiomyocytes are a prominent source of OP in vivo and suggests that induction of OP expression is strongly associated with ventricular hypertrophy.


Assuntos
Regulação da Expressão Gênica , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Sialoglicoproteínas/genética , Animais , Células Cultivadas , Endotelina-1/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Osteopontina , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Sialoglicoproteínas/análise
11.
Acta Physiol Scand Suppl ; 640: 26-9, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9401600

RESUMO

James Paget Henry really began his productive research career at the outset of the second world war. His studies of acceleration and the anoxia of high altitude were supported by the development of then new techniques of measuring and recording critical physiologic parameters such as vascular pressures, respiratory functions and haemoglobin saturation. His inquisitive mind made productive use of the instruments that had to be made by skilled instrument makers working in university shops. Much of this instrumentation has now found its way into the clinical arena where it is now the main armamentarium of cardiac diagnostic and respiratory function laboratories. His work in the space program preceeded that of the Russians but did not get recognition until Sputnik awakened the world to the possibilities of space flight. His development of the concept of a cardiovascular basis for fluid volume control and the supportive investigative work undertaken constitute a milestone in the annals of experimental physiology. The chimpanzees used in Project Mercury were found to be hypertensive which was related to the method of capture used by the commercial suppliers. This lead Jim to study the effect of early experience on resting blood pressure, an effort that soon developed into provocative studies of the biological basis of the stress response.


Assuntos
Estresse Fisiológico/história , Estresse Fisiológico/fisiopatologia , Canadá , História do Século XX , Humanos , Fisiologia/história , Pressão/efeitos adversos
12.
J Clin Invest ; 98(10): 2218-27, 1996 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-8941637

RESUMO

Angiotensin II (AII) is a critical factor in cardiac remodeling which involves hypertrophy, fibroblast proliferation, and extracellular matrix production. However, little is known about the mechanism by which AII accelerates these responses. Osteopontin is an acidic phosphoprotein with RGD (arginine-glycine-aspartate) sequences that are involved in the vascular smooth muscle cell remodeling process. We identified the presence of osteopontin mRNA and protein in cultured rat cardiac fibroblasts and its prominent regulation by AII (10(-11) M). Osteopontin message levels were increased fourfold (P < 0.01) and protein fivefold (P < 0.05) at 24 h after addition of AII (10(-7) M). This response was inhibited by the AT1 receptor blocker, losartan. Osteopontin mRNA levels were increased in hypertrophied ventricles from animals with renovascular hypertension (1.6-fold, P < 0.05) and aortic banding (2.9-fold, P < 0.05). To examine the function of osteopontin, we determined its effects on (a) the ability of cardiac fibroblasts to contract three-dimensional collagen gels and (b) cardiac fibroblast growth. A monoclonal antibody against osteopontin partially blocked AII-induced three-dimensional collagen gel contraction by cardiac fibroblasts (64+/-4 vs. 86+/-5% in the presence of antibody, P < 0.05), while osteopontin itself promoted contraction of the gels by fibroblasts (71+/-5%, P < 0.05 compared with control). Either a monoclonal antibody against beta3 integrin which is a ligand for osteopontin or the RGD peptide blocked both AII and osteopontin-induced collagen gel contraction. Thus, the osteopontin RGD sequence binds to beta3 integrins on the fibroblast to promote fibroblast binding to collagen. All induced a threefold increase in DNA synthesis of cardiac fibroblasts, which was completely blocked by antibodies against osteopontin and beta3 integrin, or by RGD peptide, but not by controls. Thus, All-induced growth of cardiac fibroblasts also requires osteopontin engagement of the beta3 integrin. Taken together, these results provide the first evidence that osteopontin is a potentially important mediator of AII regulation of cardiac fibroblast behavior in the cardiac remodeling process.


Assuntos
Angiotensina II/metabolismo , Angiotensina II/fisiologia , Colágeno/metabolismo , DNA/biossíntese , Fibroblastos/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Sialoglicoproteínas/biossíntese , Sialoglicoproteínas/fisiologia , Cicatrização , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais/imunologia , Compostos de Bifenilo/farmacologia , Northern Blotting , Células Cultivadas , Hipertensão Renovascular/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Imidazóis/farmacologia , Imuno-Histoquímica , Integrinas/imunologia , Losartan , Oligopeptídeos/farmacologia , Osteopontina , Proteínas/análise , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Sialoglicoproteínas/imunologia , Tetrazóis/farmacologia
13.
J Clin Invest ; 98(8): 1897-905, 1996 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-8878442

RESUMO

Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis.


Assuntos
Cromanos/farmacologia , Hipoglicemiantes/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Tiazóis/farmacologia , Tiazolidinedionas , Animais , Arteriosclerose/prevenção & controle , Proteínas Quinases Dependentes de Cálcio-Calmodulina/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , DNA/biossíntese , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Genes fos/efeitos dos fármacos , Hiperplasia , Masculino , Músculo Liso Vascular/patologia , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Troglitazona
14.
Physiol Behav ; 58(1): 81-8, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7667431

RESUMO

Male Long-Evans rats were implanted with blood pressure transmitters and introduced as intruders for 60 min into the home cage of a reproductively active resident male rat. Physical interaction ended after 3-5 min when the intruder displayed clear submissive behaviors. A protective wire cage was placed over the intruder until the animal was returned to its home cage. Systolic (+29.3 +/- 3.6 mmHg) and diastolic (+25.7 +/- 3.7 mmHg) blood pressures, pulse pressure (+7.3 +/- 2.0 mmHg), and heart rate (+129.0 +/- 12.6 BPM) peaked in the intruder rats during the defeat and did not fully return to control levels until return to the home cage. These acute changes as well as the heart rate and blood pressure baselines did not change when the confrontations were repeated on alternating days for a maximum of three trials per week. Pretreatment with clonidine (0.01, 0.03, 0.06, and 0.1 mg/kg) led to a dose-dependent decrease in the heart rate response but blood pressure was reduced similarly for all doses. We conclude that acute "defeat" can lead to an abrupt, large increase in blood pressure and heart rate in normotensive, Long-Evans rats that is sustained even in the absence of physical contact with the threatening resident. This response is diminished but not prevented by administration of clonidine.


Assuntos
Nível de Alerta/efeitos dos fármacos , Monitores de Pressão Arterial , Clonidina/farmacologia , Processamento de Sinais Assistido por Computador/instrumentação , Meio Social , Telemetria/instrumentação , Agressão/efeitos dos fármacos , Comportamento Agonístico/efeitos dos fármacos , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Dominação-Subordinação , Relação Dose-Resposta a Droga , Habituação Psicofisiológica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microcomputadores , Ratos
15.
J Clin Invest ; 96(1): 354-60, 1995 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7615805

RESUMO

To examine potential mechanisms for the blood pressure-lowering action of the thiazolidinedione compound, pioglitazone (PIO), we studied the effects of the drug on blood pressure and insulin action in vivo and on vascular tissue in vitro. In vivo, PIO lowered blood pressure in fructose-fed and chow-fed rats to an extent that could not be explained by alterations in fasting plasma insulin or free magnesium concentrations or by alterations in whole-body insulin sensitivity. In vitro, PIO caused significant blunting of the contractile responses of aortic rings to NE, arginine vasopressin (AVP), and potassium chloride; the blunting of responses to NE was maintained after removal of the endothelium. To assess the potential importance of extracellular calcium to the vasodepressor effect of PIO, we measured contractile responses to NE in the absence of calcium, and then after acute restoration of calcium in the presence of NE. PIO had no effect on the contractile response in the absence of calcium. By contrast, PIO blunted by 42% the contractile response that occurred when the extracellular calcium supply was acutely restored in the presence of NE, suggesting that the blunting was mediated by blockade of calcium uptake by vascular smooth muscle. Such an effect was confirmed in cultured a7r5 vascular smooth muscle cells, which exhibited a brisk increase in intracellular calcium in response to AVP that was blocked by PIO in a dose-dependent fashion. Our data indicate that PIO has a direct vascular effect that appears to be mediated at least in part by inhibition of agonist-mediated calcium uptake by vascular smooth muscle. The direct vascular effect may contribute to the blood pressure-lowering actions of PIO in vivo, because that effect could not be explained by alterations in whole-body insulin sensitivity.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Tiazóis/farmacologia , Tiazolidinedionas , Animais , Aorta/efeitos dos fármacos , Técnicas In Vitro , Insulina/farmacologia , Magnésio/sangue , Masculino , Pioglitazona , Ratos , Ratos Sprague-Dawley
16.
Diabetes Educ ; 21(2): 113-6, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7698063

RESUMO

The medical records of 173 consecutive patients with diabetes who were newly enrolled in our facility in 1990 were analyzed for blood glucose at 1 year. A total of 81 females and 72 males with non-insulin-dependent diabetes were studied. With regard to overall compliance in keeping clinic appointments, 56 (36.6%) patients were still coming in for follow-up 1 year after the diagnosis of diabetes versus 97 (63.4%) patients who had stopped coming in. Overall, 70 (45.8%) patients had a plasma glucose > 180 mg/dL and had not achieved metabolic control, and 83 (54.2%) patients had a plasma glucose < or = 180 mg/dL and had achieved good metabolic control at their last visit. Most patients with good control (58/153, 69.9%) had stopped coming in by the end of 1 year. Only 25 patients with plasma glucose < or = 180 mg/dL were still coming in for follow-up visits, representing the smallest percentage (16.3%) of the total population studied. At 1 year there also was a correlation between increased body weight and improved glycemic control.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Hospitais Urbanos , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
17.
Pancreas ; 10(1): 66-70, 1995 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7899462

RESUMO

Male athymic "nude" mice (ANM) of the USC colony manifest spontaneous fasting hyperglycemia and reduced glucose tolerance; it has been proposed that they may represent a model of nonobese non-insulin-dependent diabetes. Following the recent demonstration that insulin secretion from the isolated, perfused pancreas of the male ANM appears to be hypersensitive to glucose, the function of individual pancreatic islet beta cells was investigated by measuring the membrane potential electrical activity. Initial studies demonstrated that the cyclic pattern of electrical activity in isolated female ANM islets is indistinguishable from that in control mouse islets. In contrast to control and female ANM beta cells, in which 11.1 mM glucose evoked approximately 50% maximal electrical activity, this concentration evoked almost 80% maximal activity in male ANM beta cells (p < 0.01). Investigating electrical responses at different glucose concentrations demonstrated that this increased sensitivity to glucose extends across the concentration range 2.8 to 22 mM. Assuming that in these islets, as in normal islets, electrical activity is associated with insulin release, these data indicate that the glucose-versus-insulin secretion dose-response is shifted to lower glucose concentrations at the level of the individual beta cell. Although this study demonstrates that altered beta-cell function occurs in the isolated islet of the male ANM, further investigation is under way to determine how the observed beta-cell glucose hypersensitivity is related to the hyperglycemia and impaired glucose tolerance that develop in these animals in vivo.


Assuntos
Glucose/farmacologia , Hiperglicemia/fisiopatologia , Ilhotas Pancreáticas/metabolismo , Animais , Feminino , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
18.
Hypertension ; 23(6 Pt 2): 1012-7, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8206584

RESUMO

To examine the relative contribution of dietary glucose and infused insulin on blood pressure, we administered a 4% glucose supplement (in drinking water) with and without insulin infusion (15.8 nmol [2.2 U]/d via osmotic minipump) to male Sprague-Dawley rats (n = 6). We also tested the effect of the sympatholytic agent clonidine on rats receiving glucose and insulin. Blood pressure and heart rate were recorded via a novel radio telemetry system. Experiments were performed using a crossover design with three animals receiving treatment and three receiving vehicle for 10 days. After a 10-day washout period, the groups were reversed, and the experiment was repeated. Blood samples for insulin and glucose were drawn throughout the study. Systolic and diastolic blood pressures increased (by 6.0 +/- 1.2 and 2.2 +/- 1.3 mm Hg, respectively) in the animals given glucose alone in association with an increase in plasma insulin. However, blood pressure increased more rapidly and to a greater extent, systolic by 8.6 +/- 0.7 mm Hg and diastolic by 2.9 +/- 1.1 mm Hg, during the insulin treatment that raised plasma insulin above the levels observed during glucose feeding alone. Heart rate increased equally during both treatments. The average change in blood pressure and average plasma insulin during the infusion were correlated (r = .72, P = .009). Blood pressure dropped during the week following discontinuation of the insulin infusion. On rechallenge with insulin and glucose, blood pressure again rose and then decreased after termination of the insulin and glucose administration. Clonidine prevented the rise in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Insulina/farmacologia , Animais , Glicemia/metabolismo , Clonidina/farmacologia , Hemodinâmica/efeitos dos fármacos , Bombas de Infusão , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
Hypertension ; 23(6 Pt 2): 1036-9, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8206589

RESUMO

Increased dietary fructose may produce insulin insensitivity and elevate blood pressure in rats. It is possible that the reduced magnesium content of the high-fructose commercial diet used in some studies may play a role in these abnormalities because it is known that magnesium deficiency can produce insulin insensitivity and increased angiotensin II action in humans. To study this, we maintained rats for 9 weeks on either a normal control diet, a standard high-fructose diet, or the same high-fructose diet supplemented with magnesium. Glucose uptake was assessed using a perfused rat hindquarter preparation sequentially with 0, 900, and 120,000 pmol/L of added insulin. Basal serum glucose, plasma insulin, and basal glucose uptake in the absence of insulin were similar among all three groups. However, insulin sensitivity, defined as glucose uptake in the presence of 900 pmol/L insulin minus basal, was depressed in the high-fructose compared with the control group (1.02 +/- 0.38 to 1.77 +/- 0.57 mumol/g per hour, P < .05). In contrast, the high-fructose group supplemented with normal magnesium had similar insulin sensitivity as the control group (2.09 +/- 0.69 mumol/g per hour). Total serum magnesium was reduced in the high-fructose group compared with control or high-fructose plus magnesium-supplemented groups. Blood pressure and fasting insulin levels were also lower in the magnesium-supplemented group. These results suggest that magnesium deficiency and not fructose ingestion per se leads to insulin insensitivity in skeletal muscle and changes in blood pressure.


Assuntos
Frutose/farmacologia , Resistência à Insulina , Magnésio/administração & dosagem , Animais , Sangue/metabolismo , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Dieta , Glucose/farmacocinética , Insulina/sangue , Magnésio/farmacologia , Masculino , Músculos/metabolismo , Músculos/fisiologia , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Urina/química
20.
Przegl Lek ; 51(3): 135-48, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8058982

RESUMO

It has been postulated that insulin resistance and the concomitant compensatory hyperinsulinemia contribute to the pathogenesis of hypertension; possible by stimulating the sympathetic nervous system, promoting renal sodium reabsorption, modulating cation transport, and/or stimulating vascular smooth muscle hypertrophy. The purpose of this article is to present a comprehensive up-to-date review of the literature and critically examine the insulin resistance-hyperinsulinemia-hypertension hypothesis.


Assuntos
Hiperinsulinismo/complicações , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Animais , Intolerância à Glucose/complicações , Humanos , Obesidade/complicações
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...