title: Roles of oxidative stress and the mineralocorticoid receptor in cardiac pathology in a rat model of metabolic syndrome.
abstract: Oxidative stress and the mineralocorticoid receptor (MR) are implicated in the pathogenesis of salt-induced left ventricular (LV) diastolic dysfunction associated with metabolic syndrome (MetS). We recently characterized DahlS.Z-Lepr(fa) /Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We investigated the pathophysiological roles of increased oxidative stress and MR activation in cardiac injury with this model. DS/obese rats were treated with the antioxidant tempol (1 mmol/L in drinking water) or the selective MR antagonist eplerenone (15 mg/kg per day, per os) for 5 weeks beginning at 10 weeks of age. The increased systolic blood pressure and LV hypertrophy that develop in untreated DS/obese rats were substantially ameliorated by eplerenone but not by tempol. Eplerenone also attenuated LV fibrosis and diastolic dysfunction more effectively than did tempol in DS/obese rats, whereas cardiac oxidative stress and inflammation were reduced similarly by both drugs. Both the ratio of plasma aldosterone concentration to plasma renin activity and cardiac expression of the MR and serum/glucocorticoid-regulated kinase 1 genes were decreased to a greater extent by eplerenone than by tempol. Our results indicate that both increased oxidative stress and MR activation in the heart may contribute to the development of LV remodeling and diastolic dysfunction in DS/obese rats. The superior cardioprotective action of eplerenone is likely attributable to its greater antihypertensive effect, which is likely related to its greater inhibition of aldosterone-MR activity in the cardiovascular system.
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Keiji
authors: K
authors: Takahashi
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Tamayo
authors: T
authors: Murase
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Miwa
authors: M
authors: Takatsu
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Natsumi
authors: N
authors: Matsuura
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kai
authors: K
authors: Nagasawa
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Takuya
authors: T
authors: Hattori
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Shogo
authors: S
authors: Watanabe
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Toyoaki
authors: T
authors: Murohara
authors: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kohzo
authors: K
authors: Nagata
keywords: cardiac remodeling; metabolic syndrome; mineralocorticoid receptor; oxidative stress; renin-angiotensin-aldosterone system