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1.
J Am Coll Cardiol ; 40(7): 1356-63, 2002 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-12383586

RESUMO

OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Nitroglicerina/efeitos adversos , Tirosina/análogos & derivados , Tirosina/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Animais , Antioxidantes/metabolismo , Avaliação Pré-Clínica de Medicamentos , Radicais Livres/sangue , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Imuno-Histoquímica , Masculino , Óxido Nítrico/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Espécies Reativas de Oxigênio/sangue , Superóxido Dismutase/sangue , Superóxido Dismutase/efeitos dos fármacos , Tirosina/imunologia , beta Caroteno/sangue
2.
Neurobiol Dis ; 15(1): 160-70, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14751781

RESUMO

We determined systemic oxidative stress in Parkinson's disease (PD) patients, patients with other neurological diseases (OND) and healthy controls by measurement of in vitro lipoprotein oxidation and levels of hydro- and lipophilic antioxidants in plasma and cerebrospinal fluid (CSF). Additionally, we investigated the influence of levodopa (LD) and dopamine agonist therapy (DA) on the oxidative status in PD patients. We found increased oxidative stress, seen as higher levels of lipoprotein oxidation in plasma and CSF, decrease of plasma levels of protein sulfhydryl (SH) groups and lower CSF levels of alpha-tocopherol in PD patients compared to OND patients and controls. Levodopa treatment did not significantly change the plasma lipoprotein oxidation but LD monotherapy tended to result in an increase of autooxidation and in a decrease of plasma antioxidants with significance for ubiquinol-10. DA monotherapy was significantly associated with higher alpha-tocopherol levels. Patients with DA monotherapy or co-medication with DA showed a trend to lower lipoprotein oxidation. These data support the concept of oxidative stress as a factor in the pathogenesis of PD and might be an indicator of a potential prooxidative role of LD and a possible antioxidative effect of DA in PD treatment.


Assuntos
Antiparkinsonianos/farmacologia , Estresse Oxidativo/fisiologia , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Ubiquinona/análogos & derivados , Adulto , Antioxidantes/metabolismo , Ácido Ascórbico/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Feminino , Humanos , Levodopa/farmacologia , Lipoproteínas/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Valores de Referência , Compostos de Sulfidrila/sangue , Ubiquinona/sangue , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , alfa-Tocoferol/líquido cefalorraquidiano
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