eplerenone and Hyperlipidemias

Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed.. Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells.. In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone.. By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats.

Topics: Animals; Apoptosis; Cardiomegaly; Cell Line; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diastole; Disease Models, Animal; Eplerenone; Fatty Acids; Fibrosis; Glucose; Hyperlipidemias; Lipid Metabolism; Male; Mineralocorticoid Receptor Antagonists; Mitochondria, Heart; Myocardium; Myocytes, Cardiac; Rats; Rats, Zucker; Spironolactone; Time Factors; Ventricular Dysfunction; Ventricular Function; Ventricular Remodeling

Dynamic mechanical disturbances in the aortic wall may lead to progressive aortic dilation and possibly aneurysmal formation. Here, we investigated the previously unexplored effects of aldosterone inhibition on aortic wall viscoelastic properties in hyperlipidemic rabbits. Thirty-six New Zealand male rabbits, fed a standard diet for four weeks, were separated into three groups: control (C; n = 10), standard diet; eplerenone (A; n = 12), hyperlipidemic diet plus 100 mg/kg/d eplerenone (last 4 weeks); and vehicle (V; n = 14), hyperlipidemic diet (no eplerenone). After eight weeks, animals were sacrificed and rectangular strips from the aortic wall, cut in radial and axial orientations, were prepared. Fresh, saline-wetted strips at 37 degrees C were subjected to cyclic sinusoidal elongation from zero to 20% of the resting length at a frequency of 1 Hz. The dynamic biomechanical viscoelastic characteristics, 'elastin phase' low modulus (E(L)), 'collagen phase' high modulus (E(H)) and dissipated-energy index, were determined. Aortic tissue preparations were also examined histologically. Eplerenone increased aldosterone concentrations but did not affect blood pressure, cholesterol or potassium concentrations. There was a significant reduction of E(H) (from 3.40 to 1.80 MPa; P < 0.01) and E(L) (from 0.46 to 0.27 MPa; P < 0.05) in group A in the radial direction compared with group C. In the axial direction E(L) significantly increased in group A compared with group V (from 0.42 to 1.11 MPa; P < 0.01). Energy dissipation was not significantly different among groups, although there was a trend toward higher values in group A for both directions. Histological assessments revealed no significant differences in collagen or elastic fibers among groups. In conclusion, aldosterone receptor inhibition altered the viscoelastic properties of the aortic wall in hyperlipidemic rabbits without detectable microscopic changes in elastic or collagen fibers, an effect that progressively might predispose to dilation and/or aneurysmal formation.

Topics: Aldosterone; Animals; Aorta; Biomechanical Phenomena; Blood Pressure; Disease Progression; Elasticity; Eplerenone; Hyperlipidemias; Male; Mineralocorticoid Receptor Antagonists; Rabbits; Spironolactone; Viscosity