RESUMO
ABSTRACT: The aim of the present work was to examine whether metabolic syndrome-like conditions in rats with fructose (F) overload modify the cardiotoxic effects induced by doxorubicin (DOX) and whether the treatment altered the expression of P-gp, breast cancer resistance protein, and organic cation/carnitine transporters in the heart. Male Sprague-Dawley rats received either tap water (control group [C]; n = 16) or water with F 10% wt/vol (n = 16) during 8 weeks. Three days before being killed, the animals received a single dose of DOX (6 mg/kg, ip, md) (C-DOX and F-DOX groups) or vehicle (VEH; ISS 1 mL/kg BW; ip) (C-VEH and F-VEH groups) (n = 8 per group). F overload enhanced thiobarbituric acid-reactive substance levels in the left ventricle, and DOX injection further increased those values. DOX did not alter thiobarbituric acid-reactive substance production in C animals. DOX caused a decrease of 30% in the ejection fraction and a nearly 40% reduction in the fractional shortening in F animals, but not in C rats. Cardiac tissue levels of P-gp decreased by about 30% in F rats compared with the C groups. DOX did not modify cardiac P-gp expression. Breast cancer resistance protein and organic cation/carnitine transporter (OCTN 1/2/3) protein levels did not change with either F or DOX. It is suggested that DOX could cause greater cardiotoxicity in rats receiving F, probably due to enhanced cardiac lipid peroxidation and lower expression of cardiac P-gp. These results support the hypothesis that the cardiotoxicity of DOX could be increased under metabolic syndrome-like conditions or in other health disorders that involve cardiovascular risk factors.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos , Doxorrubicina , Cardiopatias/induzido quimicamente , Síndrome Metabólica/complicações , Miocárdio/metabolismo , Estresse Oxidativo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Cardiotoxicidade , Modelos Animais de Doenças , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Peroxidação de Lipídeos , Masculino , Síndrome Metabólica/metabolismo , Miocárdio/patologia , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Erythropoietin (EPO) has been linked to cardioprotective effects. However, its effects during the aging process are little known. We investigated the effect of EPO administration on hemodynamic parameters, cardiac function, oxidative damage, and erythropoietin receptor (EPOR) expression pattern in the hypovolemic state. EPO was administered (1000 IU/kg/3 days) and then acute hemorrhage (20% blood loss) was induced in young and adult rats. There was no difference in plasmatic EPO in either age group. The hemodynamic basal condition was similar, without alterations in renal function and hematocrit, in both age groups. After bleeding, both EPO-treated age groups had increased blood pressure at the end of the experimental protocol, being greater in adult animals. EPO attenuated the tachycardic effect. Ejection fraction and fractional shortening were higher in adult EPO-treated rats subjected to hemorrhage. In the left ventricle, young and adult EPO-treated rats subjected to bleeding showed an increased EPOR expression. A different EPOR expression pattern was observed in the adult right atrial tissue, compared with young animals. EPO treatment decreased oxidative damage to lipids in both age groups. EPO treatment before acute hemorrhage improves cardiovascular function during the aging process, which is mediated by different EPOR pattern expression in the heart tissue.