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1.
Nutr Metab Cardiovasc Dis ; 27(1): 32-40, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27612985

RESUMO

Cardiovascular disease (CVD) is one of the main causes of mortality and morbidity worldwide. As an emerging population, South Asians (SAs) bear a disproportionately high burden of CVD relative to underlying classical risk factors, partly attributable to a greater prevalence of insulin resistance and diabetes and distinct genetic and epigenetic influences. While the phenotypic distinctions between SAs and other ethnicities in CVD risk are becoming increasingly clear, the biology of these conditions remains an area of active investigation, with emerging studies involving metabolism, genetic variation and epigenetic modifiers (e.g., extracellular RNA). In this review, we describe the current literature on prevalence, prognosis and CVD risk in SAs, and provide a landscape of translational research in this field toward ameliorating CVD risk in SAs.


Assuntos
Povo Asiático , Doenças Cardiovasculares/etnologia , Síndrome Metabólica/etnologia , Crescimento Demográfico , Ásia/epidemiologia , Povo Asiático/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Emigrantes e Imigrantes , Emigração e Imigração , Epigênese Genética , Predisposição Genética para Doença , Disparidades nos Níveis de Saúde , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/genética , Obesidade/etnologia , Fenótipo , Prevalência , Medição de Risco , Fatores de Risco
2.
J Thromb Haemost ; 13 Suppl 1: S33-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26149043

RESUMO

Our understanding of platelets, anucleate cells with a traditional role in hemostasis and inflammation, has developed greatly over the last decade. Platelets' role in the systemic response of the body to vascular injury, inflammation, and infection has expanded as has our understanding of their importance to the body's regulation of these processes. One recently explored mechanism by which platelets regulate the body's inflammatory and immune response is through its endogenous RNA. Platelets' messenger RNA (mRNAs) and microRNA (miRNAs) profiles have been shown to reflect disease and disease risk factors and have been correlated with select human clinical phenotypes. Developing an understanding of platelet transcripts in the circulation elucidates how platelets function in both their traditional thrombotic role and non-traditional functions and may have widespread implications in several fields including thrombosis, infection, cancer, and systemic inflammation.


Assuntos
Transtornos Plaquetários/genética , Plaquetas/metabolismo , Hemostasia/genética , MicroRNAs/sangue , RNA Mensageiro/sangue , Trombose/genética , Transcriptoma , Animais , Transtornos Plaquetários/sangue , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , MicroRNAs/genética , Fenótipo , RNA Mensageiro/genética , Trombose/sangue , Transcrição Gênica
4.
J Thromb Haemost ; 8(4): 817-27, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20102488

RESUMO

BACKGROUND: Activation of platelets is a critical component of atherothrombosis and plays a central role in the progression of unstable cardiovascular syndromes. Adenosine, acting through adenosine receptors, increases intracellular cAMP levels and inhibits platelet aggregation. The A2a adenosine receptor has already been recognized as a mediator of adenosine-dependent effects on platelet aggregation, and here we present a new role for the A2b adenosine receptor (A2bAR) in this process. METHODS AND RESULTS: As compared with platelets from wild-type controls, platelets derived from A2bAR knockout mice have significantly greater ADP receptor activation-induced aggregation. Although mouse megakaryocytes and platelets express low levels of the A2bAR transcript, this gene is highly upregulated following injury and systemic inflammation in vivo. Under these conditions, A2bAR-mediated inhibition of platelet aggregation significantly increases. Our studies also identify a novel mechanism by which the A2bAR could regulate platelet aggregation; namely, ablation of the A2bAR leads to upregulated expression of the P2Y1 ADP receptor, whereas A2bAR-mediated or direct elevation of cAMP has the opposite effect. Thus, the A2bAR regulates platelet function beyond mediating the immediate effect of adenosine on aggregation. CONCLUSIONS: Taken together, these investigations show for the first time that the platelet A2bAR is upregulated under stress in vivo, plays a significant role in regulating ADP receptor expression, and inhibits agonist-induced platelet aggregation.


Assuntos
Difosfato de Adenosina/sangue , Plaquetas/metabolismo , Agregação Plaquetária , Receptor A2B de Adenosina/sangue , Agonistas do Receptor A2 de Adenosina , Adenosina-5'-(N-etilcarboxamida)/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Células Cultivadas , AMP Cíclico/sangue , Modelos Animais de Doenças , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Genótipo , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/genética , RNA Mensageiro/sangue , Receptor A2B de Adenosina/deficiência , Receptor A2B de Adenosina/genética , Receptores Purinérgicos P2/sangue , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2Y1 , Fatores de Tempo , Regulação para Cima
6.
J Thromb Haemost ; 1(6): 1183-8, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12871317

RESUMO

Nitric oxide (NO) is released by the endothelium preventing platelet adhesion to the vessel wall. When released by platelets, NO inhibits further recruitment of platelets to a growing thrombus. Modulation of endogenous NO release may be a mechanism by which the thrombotic response can be regulated as suggested by several clinical diseases associated with impaired bioactive NO. Diseases including atrial fibrillation and coronary atherothrombotic disease have been associated with impaired NO release or decrease in NO bioavailability.


Assuntos
Óxido Nítrico/fisiologia , Trombose/etiologia , Antioxidantes/fisiologia , Plaquetas/metabolismo , Endotélio Vascular/metabolismo , Hemostasia , Humanos , Espécies Reativas de Oxigênio/metabolismo
7.
J Neurosci ; 21(23): 9092-100, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11717342

RESUMO

We have used single-channel patch-clamp recordings to study opiate receptor effects on freshly dissociated neurons from the rat amygdalohippocampal area (also called the posterior nucleus of the amygdala), an output nucleus of the amygdala implicated in appetitive behaviors. Dissociated cells included a distinct subpopulation that was 30-40 micrometer in diameter, multipolar or pyramidal in shape, and immunoreactive for neuron-specific enolase, mu opioid receptors, and galanin. In whole-cell perforated-patch recordings, these cells responded to low concentrations of mu opioid agonists with a hyperpolarization. In cell-attached single channel recordings, these cells expressed a large variety of K(+)-permeable ion channels, including 20-100 pS inward rectifiers and 150-200 pS apparent Ca(2+)-activated K(+) channels, none of which appeared sensitive to the presence of opioid drugs. In contrast, a 130 pS inwardly rectifying channel was selectively activated by mu opioid receptors in this same subpopulation of cells and was active only in the presence of opioid agonists, and inhibited in the presence of antagonists. Channels identical to the 130 pS channel in conductance and voltage sensitivity were activated in the absence of opioids, when the cells were treated with glucose-free medium or with the metabolic inhibitor rotenone. The sulfonylurea drug tolbutamide inhibited 130 pS channel openings elicited by opioids. Thus, a subpopulation of amygdala projection neurons expresses a metabolically sensitive ion channel that is selectively modulated by opiate receptors. This mechanism may allow opioid neurotransmitters to regulate ingestive behaviors, and thus, opiate drugs to influence reward pathways.


Assuntos
Tonsila do Cerebelo/metabolismo , Ativação do Canal Iônico/fisiologia , Neurônios/metabolismo , Receptores Opioides mu/metabolismo , Somatostatina/análogos & derivados , Tonsila do Cerebelo/citologia , Animais , Separação Celular , Imuno-Histoquímica , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Neurônios/classificação , Neurônios/citologia , Técnicas de Patch-Clamp , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/antagonistas & inibidores , Rotenona/farmacologia , Somatostatina/farmacologia , Compostos de Sulfonilureia/farmacologia , Tolbutamida/farmacologia , Desacopladores/farmacologia
8.
Pharmacol Res ; 44(4): 255-64, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11592859

RESUMO

Advancement in the understanding of the mechanisms of platelet activation, as well as the development of new techniques for studying platelet function, have led to the availability of new classes of platelet inhibiting drugs. Initially, characterization of arachidonic acid metabolism in platelets furthered an understanding of the utility of cyclooxygenase inhibitors, most notably aspirin. The discovery and characterization of platelet receptors such as the adenosine diphosphate (ADP) receptor and glycoprotein IIb/IIIa has been associated with the development of novel classes of anti-platelet drug, such as thienopyridine derivatives and glycoprotein IIb/IIIa receptor antagonists, respectively. Future development in receptor pathway inhibitors also includes glycoprotein Ib/IX as well as the potential use of platelet signaling pathway inhibitors.


Assuntos
Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Antagonistas do Receptor Purinérgico P2 , Animais , Plaquetas/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Trombose/metabolismo
9.
J Cardiovasc Pharmacol Ther ; 6(2): 163-73, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11509923

RESUMO

Although heparin is a well-known anticoagulant, in some cases it promotes a prothrombotic state and does so through both antibody-dependent and antibody-independent platelet activation. In this study, heparin was found to reverse the antiplatelet effect of an NO donor. S-nitroso-glutathione (SNO-Glu), with an EC(50) of 1.8 U/mL. Ultraviolet/visible spectral analysis and the Griess assay showed that increasing heparin concentrations on a dose-dependent basis eliminated acidified NO(x) species. Since heparin is a heterogeneous mixture of glycosaminoglycans, the effects of six different heparin disaccharides were compared with various substitutions on the hexose rings to determine which functional group(s) of the polysaccharide interact with acidified NO(x). Among the six disaccharides tested, only types I-S and II-S had the effect, suggesting that the sulfamino-group at the C2 position of the glucosamine moiety was critical for the elimination of acidified NO(x) species. Mass spectrometry experiments gave results consistent with these observations, indicating that only the I-S and II-S heparin disaccharides were modified upon treatment with NaNO(2)/HCl. Negative-ion electro-spray ionization MS and tandem MS analyses of the native compounds and their deuterium-labeled analogs confirmed that the reaction products from nitrosation of these N-sulfated disaccharides had eliminated the C2-sulfamino-moiety and replaced it with methoxide derived from the solvent. Participation of the 6-sulfato-substituent appears to facilitate the elimination reaction. These data show that heparin can impair the antiplatelet properties of nitric oxide by interacting with the nitrosating species, and suggest that heparin-like glycosamino-glycans may interact with endothelium-derived nitric oxide in vivo to regulate the bioactivity of this important antiplatelet and vasorelaxant substance.


Assuntos
Anticoagulantes/metabolismo , Heparina/metabolismo , Óxido Nítrico/metabolismo , Anticoagulantes/farmacologia , Dissacarídeos/farmacologia , Interações Medicamentosas , Heparina/química , Heparina/farmacologia , Humanos , Técnicas In Vitro , Espectrometria de Massas , Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Nitritos/metabolismo , Agregação Plaquetária/efeitos dos fármacos
10.
Atherosclerosis ; 156(2): 417-24, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11395039

RESUMO

Leukocyte adhesion and transendothelial migration, prerequisites in the development of atherosclerosis, are largely mediated by adhesion molecules. In addition, unstable coronary syndromes usually involve platelet activation and thrombus formation at the site of atherosclerotic plaque. Therefore, we compared plasma levels of soluble P-selectin, a measurement of platelet activation, as well as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with atherosclerosis undergoing coronary angiography (n=76). Soluble P-selectin levels, as measured by ELISA, were significantly elevated in patients with unstable (n=44) vs stable (n=32) atherosclerotic disease (73.0 +/- 2.5 ng/ml vs 52.3 +/- 3.0 ng/ml, respectively, P<0.01). By logistic regression analysis, plasma level of soluble P-selectin was an independent predictor of an unstable coronary syndrome (OR 4.2, CI 1.4-12.9, P<0.01). Soluble E-selectin level, a marker of endothelial activation, was associated with extent of atherosclerosis but did not correlate with disease stability. Interestingly, soluble P-selectin was inversely correlated with plasma levels of the antioxidant alpha-tocopherol (R=-0.443, P<0.001), a known inhibitor of platelet function. In summary, amongst the soluble adhesion molecules, only P-selectin is significantly increased in patients with unstable coronary syndromes. This study suggests that platelet activation persists in patients with unstable coronary syndromes despite concurrent aspirin therapy. In addition, the beneficial effects of alpha-tocopherol in patients with cardiovascular disease may be related to inhibition of platelet function.


Assuntos
Angina Instável/sangue , Selectina E/sangue , Molécula 1 de Adesão Intercelular/sangue , Selectina-P/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Idoso , Angina Instável/diagnóstico , Biomarcadores/análise , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Probabilidade , Radioimunoensaio , Sensibilidade e Especificidade
11.
Circulation ; 103(23): 2792-8, 2001 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-11401934

RESUMO

BACKGROUND: Moderate red wine consumption is inversely associated with coronary ischemia, and both red wine and purple grape juice (PGJ) contain flavonoids with antioxidant and antiplatelet properties believed to be protective against cardiovascular events. Acute cardiac events are also associated with decreased platelet-derived nitric oxide (NO) release. In this study, the effects of PGJ and PGJ-derived flavonoids on platelet function and platelet NO production were determined. METHODS AND RESULTS: Incubation of platelets with dilute PGJ led to inhibition of aggregation, enhanced release of platelet-derived NO, and decreased superoxide production. To confirm the in vivo relevance of these findings, 20 healthy subjects consumed 7 mL. kg(-1). d(-1) of PGJ for 14 days. Platelet aggregation was inhibited after PGJ supplementation, platelet-derived NO production increased from 3.5+/-1.2 to 6.0+/-1.5 pmol/10(8) platelets, and superoxide release decreased from 29.5+/-5.0 to 19.2+/-3.1 arbitrary units (P<0.007 and P<0.05, respectively). alpha-Tocopherol levels increased significantly after PGJ consumption (from 15.6+/-0.7 to 17.6+/-0.9 micromol/L; P<0.009), and the plasma protein-independent antioxidant activity increased by 50.0% (P<0.05). Last, incubation of platelets with select flavonoid fractions isolated from PGJ consistently attenuated superoxide levels but had variable effects on whole-blood aggregation, platelet aggregation, and NO release. CONCLUSIONS: Both in vitro incubation and oral supplementation with PGJ decrease platelet aggregation, increase platelet-derived NO release, and decrease superoxide production. These findings may be a result of antioxidant-sparing and/or direct effects of select flavonoids found in PGJ. The suppression of platelet-mediated thrombosis represents a potential mechanism for the beneficial effects of purple grape products, independent of alcohol consumption, in cardiovascular disease.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Flavonoides/farmacologia , Óxido Nítrico/metabolismo , Rosales , Adulto , Antioxidantes/metabolismo , Linhagem Celular , Separação Celular , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Flavonoides/química , Frutas/química , Humanos , Masculino , Megacariócitos/efeitos dos fármacos , Megacariócitos/enzimologia , Pessoa de Meia-Idade , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Agregação Plaquetária/efeitos dos fármacos , Testes de Função Plaquetária , Proteína Quinase C/metabolismo , Superóxidos/metabolismo , Vitamina E/sangue
13.
Eur J Pharmacol ; 415(1): R1-3, 2001 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-11245859

RESUMO

In cell-attached patch-clamp recordings from freshly dissociated neurons of the rat amygdalohippocampal area, clonidine principally activated a 95-pS (picosiemens) inwardly rectifying K+-permeable channel, whereas morphine acting at mu-opioid receptors activated a different 130-pS channel. Clonidine's effects were largely antagonized by the alpha(2)-adrenoceptor antagonist idazoxan, but were poorly mimicked by agmatine. These results partially contradict the prevailing hypothesis that alpha(2) and opioid receptors act through the same ion channel transduction pathways.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Analgésicos/farmacologia , Clonidina/farmacologia , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Idazoxano/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Ratos
14.
J Nutr ; 131(2): 374S-7S, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11160564

RESUMO

Vitamin E is the principal lipid-soluble antioxidant in human plasma, and some studies indicate that it may provide cardiovascular protection. To investigate putative mechanisms for vitamin E in this regard, the effect of vitamin E on vascular function and platelet aggregation was examined. In animal models of endothelial dysfunction, vitamin E improved the activity of endothelium-derived nitric oxide, and this effect was not dependent upon the antioxidant protection of LDL. In fact, vitamin E improved endothelial function in part due to the inhibition of protein kinase C (PKC) stimulation. This activity of vitamin E was examined in platelets, and vitamin E inhibited platelet aggregation in part through a mechanism that involves PKC. Moreover, the platelet inhibitory activity of vitamin E was independent of its antioxidant action because platelet inhibition was still observed with isoforms of vitamin E that were devoid of antioxidant activity.


Assuntos
Plaquetas/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , Proteína Quinase C/antagonistas & inibidores , Vitamina E/uso terapêutico , Antioxidantes/farmacologia , Plaquetas/fisiologia , Relação Dose-Resposta a Droga , Humanos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Trombose/prevenção & controle , Vitamina E/administração & dosagem , Vitamina E/farmacologia
16.
Proc Natl Acad Sci U S A ; 97(26): 14692-6, 2000 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-11121070

RESUMO

The molecular mechanism of tolerance to opiate drugs is poorly understood. We have used single-channel patch-clamp recordings to study opiate receptor effects on dissociated neurons from rat amygdala, a limbic region implicated in addiction processes. A 130-pS inwardly rectifying K(+)-preferring cation channel was activated by mu opioid receptors in a membrane-delimited manner. After chronic treatment of the rats with morphine, channel gating changed markedly, with an approximately 100-fold decrease in open probability at a given morphine concentration. The change in channel gating correlated both in time course and in dose of morphine treatment with the development of functional opiate dependence and appeared to arise at a step after G-protein activation and before channel permeation by K(+). This decreased receptor-channel coupling appears to be large enough to account quantitatively for opiate tolerance and may represent one of the mechanisms through which tolerance occurs.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Ativação do Canal Iônico/fisiologia , Dependência de Morfina/fisiopatologia , Morfina/metabolismo , Neurônios/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/fisiologia , Receptores Opioides mu/metabolismo , Tonsila do Cerebelo/citologia , Analgésicos Opioides/farmacologia , Animais , Células Cultivadas , Eletrofisiologia , Morfina/farmacologia , Dependência de Morfina/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos
17.
FASEB J ; 14(15): 2377-9, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11024007

RESUMO

Platelet activation is tightly regulated by products of the endothelium and platelets including nitric oxide (NO). Excess vascular oxidative stress has been associated with impaired NO release, and antioxidant status has been shown to alter endothelium-derived NO bioactivity. Although physiological levels of a-tocopherol are known to inhibit platelet function, the effect of a-tocopherol on platelet NO release is unknown. Loading platelets with physiologic levels of a-tocopherol increased platelet NO production approximately 1.5-fold (Pa-tocopherol, platelet NO release increased 50% (Pa-Tocopherol-loaded platelets also produced 74% less superoxide as compared with control (Pa-tocopherol inhibited PKC-dependent eNOS phosphorylation as determined by immunoprecipitation. Lastly, platelets isolated from NOS3-deficient mice released 80% less superoxide as compared with control animals (P=0.011), and incubation of NOS III-deficient platelets with 500 mM a-tocopherol only caused a modest additional decrease in platelet superoxide release (NS). Thus, a-tocopherol appears to enhance platelet NO release both in vitro and in vivo through antioxidant- and PKC-dependent mechanisms.


Assuntos
Óxido Nítrico/metabolismo , Ativação Plaquetária/fisiologia , Proteína Quinase C/antagonistas & inibidores , Vitamina E/farmacologia , Alcaloides , Animais , Antioxidantes/farmacologia , Benzofenantridinas , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Mutantes , Modelos Biológicos , Óxido Nítrico Sintase/deficiência , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Fenantridinas/farmacologia , Fosforilação , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Superóxidos/metabolismo
18.
Circ Res ; 84(12): 1416-21, 1999 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-10381894

RESUMO

Endothelial nitric oxide synthase (eNOS) has been identified in human platelets. Although platelet-derived nitric oxide (NO) has been shown to inhibit platelet recruitment in vitro, its role in the regulation of the hemostatic response in vivo has not been characterized. To define the role of platelet-derived NO in vivo, we studied mice that lacked a functional eNOS gene (NOSIII). Surface P-selectin expression in platelets from eNOS-deficient mice was not significantly altered; however, bleeding times were markedly decreased in eNOS-deficient versus wild-type mice (77.2+/-3 versus 133.4+/-3 seconds, P<0.00005). To determine the contribution of endothelium- versus platelet-derived NO to the bleeding time, isolated platelets from either eNOS-deficient or wild-type mice were transfused into a thrombocytopenic eNOS-deficient mouse and the bleeding time was measured. The bleeding times in mice transfused with eNOS-deficient platelets were significantly decreased compared with mice transfused with wild-type platelets (Deltableeding time, -24.6+/-9.1 and -3.4+/-5.3 seconds, respectively; P<0.04). Platelet recruitment was studied by measuring serotonin release from a second recruitable population of platelets that were added to stimulated platelets at the peak of NO production. There was 40.3+/-3.7% and 52. 0+/-2.1% serotonin release for platelets added to wild-type or eNOS-deficient platelets, respectively (P<0.05). In summary, mice that lacked eNOS had markedly decreased bleeding times even after endothelial NO production was controlled. These data suggest that the lack of platelet-derived NO alters in vivo hemostatic response by increasing platelet recruitment. Thus, these data support a role for platelet-derived NO production in the regulation of hemostasis.


Assuntos
Plaquetas/enzimologia , Hemostasia/fisiologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Animais , Tempo de Sangramento , Plaquetas/química , Células da Medula Óssea/enzimologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/análise , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Agregação Plaquetária/fisiologia , Selectinas/metabolismo , Tromboxano B2/análise , Tromboxano B2/metabolismo
19.
FASEB J ; 13(9): 965-75, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10336880

RESUMO

Considerable epidemiologic data suggest that dietary consumption of vitamin E reduces the incidence of cardiovascular disease. The precise mechanisms are not clear, but emerging data indicate that vitamin E has numerous activities that may, in part, explain its effect on vascular disease. In particular, vitamin E enhances the bioactivity of nitric oxide, inhibits smooth muscle proliferation, and limits platelet aggregation. One common mechanism to account for these effects of vitamin E is the inhibition of protein kinase C stimulation. In the setting of atherosclerosis, inhibition of protein kinase C by vitamin E would be expected to maintain normal vascular homeostasis and thus reduce the clinical incidence of cardiovascular disease.


Assuntos
Antioxidantes/metabolismo , Arteriosclerose/etiologia , Vasos Sanguíneos/fisiologia , Modelos Biológicos , Vitamina E/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Arteriosclerose/tratamento farmacológico , Células Sanguíneas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Homeostase , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Proteína Quinase C/antagonistas & inibidores , Vitamina E/farmacologia , Vitamina E/uso terapêutico
20.
J Pharmacol Exp Ther ; 288(3): 1278-87, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10027869

RESUMO

The hemodynamic effects of a 20% exchange-transfusion with different solutions of highly purified human hemoglobin A-zero (A0) were evaluated. We compared unmodified hemoglobin with hemoglobin cross-linked with O-raffinose. Unmodified hemoglobin increased systemic vascular resistance and mean arterial pressure more than the O-raffinose cross-linked hemoglobin solution (by approximately 45% and approximately 14%, respectively). Unmodified hemoglobin markedly reduced cardiac output (CO) by approximately 21%, whereas CO was unaffected by the O-raffinose cross-linked hemoglobin solution. Unmodified and O-raffinose cross-linked hemoglobin solutions increased mean arterial pressure to comparable extents ( approximately 14% and approximately 9%, respectively). Unmodified hemoglobin increased renal vascular resistance 2-fold and reduced the glomerular filtration rate by 58%. In marked contrast, the O-raffinose cross-linked hemoglobin had no deleterious effect on the glomerular filtration rate, renal blood flow, or renal vascular resistance. The extents to which unmodified and O-raffinose cross-linked hemoglobin solutions inactivated nitric oxide also were compared using three separate in vitro assays: platelet nitric oxide release, nitric oxide-stimulated platelet cGMP production, and endothelium-derived relaxing factor-mediated inhibition of platelet aggregation. Unmodified hemoglobin inactivated or oxidized nitric oxide to a greater extent than the O-raffinose cross-linked hemoglobin solutions in all three assays. In summary, O-raffinose cross-linking substantially reduced the systemic vasoconstriction and the decrease in CO induced by unmodified hemoglobin and eliminated the deleterious effects of unmodified hemoglobin on renal hemodynamics and function. We hypothesize that O-raffinose cross-linking reduces the degree of oxidation of nitric oxide and that this contributes to the reduced vasoactivity of this modified hemoglobin.


Assuntos
Hemodinâmica/efeitos dos fármacos , Hemoglobinas/farmacologia , Rim/efeitos dos fármacos , Rafinose/análogos & derivados , Animais , Eletrólitos/urina , Transfusão Total , Hematócrito , Hemoglobinas/análise , Humanos , Rim/irrigação sanguínea , Masculino , Óxido Nítrico/metabolismo , Rafinose/análise , Rafinose/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos
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