RESUMO
1. The present study has evaluated the effect of two phenanthrene alkaloids, uvariopsine and stephenanthrine, on angiotensin II (Ang-II)-induced leukocyte-endothelial cell interactions in vivo and the mechanisms involved in their activity. Intravital microscopy within the rat mesenteric microcirculation was used. 2. A 60 min superfusion with 1 nm Ang-II induced a significant increase in the leukocyte-endothelial cell interactions that were completely inhibited by 1 microm uvariopsine cosuperfusion. A lower dose of 0.1 microm significantly reduced Ang-II-induced leukocyte adhesion by 75%. 3. When Ang-II was cosuperfused with 1 and 0.1 microm stephenanthrine, Ang-II-induced leukocyte responses were significantly diminished. A lower dose of 0.01 microm only affected Ang-II-induced leukocyte adhesion. 4. Both alkaloids inhibited Ang-II-induced endothelial P-selectin upregulation and the generation of reactive oxygen species (ROS) in endothelial cells stimulated with Ang-II, in fMLP-stimulated human neutrophils (PMNs) and in the hypoxanthine-xanthine oxidase system. However, cyclic AMP levels in PMNs stimulated with fMLP were not affected. 5. Uvariopsine and stephenanthrine inhibited PAF-induced elevations in intracellular calcium levels in PMNs (IC50 values: 15.1 and 6.1 microm respectively) and blocked the binding of [3H]PAF to these leukocytes. They also reduced PAF-induced increases in intracellular levels of superoxide anion and hydrogen peroxide. 6. In conclusion, stephenanthrine and uvariopsine are potent inhibitors of Ang-II-induced leukocyte accumulation in vivo. This effect appears to be mediated through ROS scavenging activity and blockade of PAF receptor. Thus, they have potential therapeutic interest for the control of leukocyte recruitment that occurs in cardiovascular disease states in which Ang-II is involved.
Assuntos
Alcaloides/farmacologia , Células Endoteliais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Fenantrenos/farmacologia , Monofosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Colforsina/farmacologia , Relação Dose-Resposta a Droga , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Microscopia de Vídeo , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Extratos Vegetais/química , Fator de Ativação de Plaquetas/metabolismo , Fator de Ativação de Plaquetas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Rolipram/farmacologiaRESUMO
Dennettine, a new 2,6-dimethoxychromone and three known phenanthrene alkaloids (uvariopsine, stephenanthrine and argentinine) in addition to the phenolic and known compound vanillin were isolated from the roots of Dennettia tripetala. Their structures were determined by physical and spectroscopical one dimensional (1D) and 2D-NMR analysis, including heteronuclear multiple bond correlation and nuclear Overhauser enhancement spectroscopy.
