Takahashi Keiji, Murase Tamayo, Takatsu Miwa, Matsuura Natsumi, Nagasawa Kai, Hattori Takuya, Watanabe Shogo, Murohara Toyoaki, Nagata Kohzo
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nagoya J Med Sci. 2015 Feb;77(1-2):275-89.
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.
氧化应激和盐皮质激素受体（MR）与代谢综合征（MetS）相关的盐诱导左心室（LV）舒张功能障碍的发病机制有关。我们最近将源自Dahl盐敏感大鼠和Zucker大鼠杂交的DahlS.Z-Lepr(fa)/Lepr(fa)（DS/肥胖）大鼠鉴定为一种新的MetS动物模型。我们用该模型研究了氧化应激增加和MR激活在心脏损伤中的病理生理作用。DS/肥胖大鼠从10周龄开始，用抗氧化剂tempol（饮用水中1 mmol/L）或选择性MR拮抗剂依普利酮（每天15 mg/kg，口服）治疗5周。依普利酮可显著改善未经治疗的DS/肥胖大鼠出现的收缩压升高和LV肥厚，而tempol则无此作用。在DS/肥胖大鼠中，依普利酮比tempol更有效地减轻LV纤维化和舒张功能障碍，而两种药物对心脏氧化应激和炎症的减轻作用相似。依普利酮比tempol更能降低血浆醛固酮浓度与血浆肾素活性的比值以及心脏MR和血清/糖皮质激素调节激酶1基因的表达。我们的结果表明，心脏中氧化应激增加和MR激活都可能导致DS/肥胖大鼠LV重构和舒张功能障碍的发生。依普利酮优越的心脏保护作用可能归因于其更强的降压作用，这可能与其对心血管系统中醛固酮-MR活性的更强抑制有关。
