The Role of Cytochrome P-450 mediated metabolites of arachidonic acid in diabetic cardiovascular dysfunction in rats -

Abstract

Background: Cardiovascular complications of diabetes mellitus are major causes of the increased mortality and morbidity associated with the disease. Among the manifestations of cardiovascular dysfunction are impaired endothelial mediated vasodilation and vascular responses to vasoactive agents as well as cardiac remodeling with fibrotic changes. Oxidative stress is a major contributor to diabetes induced cardiovascular dysfunction. Recent studies demonstrated significant cardiovascular effects for cytochrome P-450 (CYP-450) mediated arachidonic acid (AA) metabolites, 20-HETE (20- hydroxyeicosatetraenoic acid ) a potent vasoconstrictor, and EET (epoxyeicosatrienoic acid) a vasodilator and potentially cardioprotective eicosanoid. The role of these products in diabetes induced cardiovascular dysfunction, however, is still controversial.Aims: The following study aimed to investigate if blocking 20-HETE production through the treatment with 10 mg-kg-day HET0016 (N-hydroxy-N_-(4-butyl-2 methylphenyl) formamidine), a selective CYP4A isoforms inhibitor, or inducing EETs synthesis by 35 mg-kg-day BNF (β- naphthoflavone), a selective CYP2C11 inducer, in vivo, may decrease diabetes induced cardiovascular dysfunction. CYP-450 has been considered an important source of ROS (reactive oxygen species), so we further investigated the effect of HET0016 and BNF treatment on oxidative stress in diabetes. Our hypothesis was that 20-HETE played a detrimental role while EET’s protected against diabetes induced cardiovascular complications.Methods: Male Sprague- Dawley were divided into four study groups. A dose of 65 mg-kg body weight of streptozotocin (STZ) was used to induce diabetes in three groups. Control (CV) rats were administered the vehicle of STZ (normal saline solution). Two days after STZ, control and diabetic rats (DV) started receiving daily i.p. injections of 5percent DMSO in normal saline, while the remaining two groups received daily i.p. injections of either HET0016 (DH group) or BNF (DF group), dissolved in