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Circulation ; 110(7): 796-802, 2004 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-15302788

RESUMO

BACKGROUND: We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction. METHODS AND RESULTS: Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia. CONCLUSIONS: Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.


Assuntos
Angiopoietina-1/análogos & derivados , Bradicardia/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Clonidina/análogos & derivados , Clonidina/uso terapêutico , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Angiopoietina-1/sangue , Angiopoietina-2/sangue , Animais , Bradicardia/induzido quimicamente , Fármacos Cardiovasculares/farmacologia , Clonidina/farmacologia , Vasos Coronários , Avaliação Pré-Clínica de Medicamentos , Proteínas da Matriz Extracelular/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/fisiopatologia , Ligadura , Masculino , Modelos Animais , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Ultrassonografia , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
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