Department of Internal Medicine, University of Missouri, Columbia, 65212, USA.
Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1484-91. doi: 10.1152/ajpheart.01000.2010. Epub 2011 Jan 14.
There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (∼1 mg·kg(-1)·day(-1)) or a vasodilatory, conventional dose (∼30 mg·kg(-1)·day(-1)) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure.
有新的证据表明，醛固酮可促进舒张功能障碍和心肌纤维化，而不依赖于血压的影响，这可能是通过增加氧化应激和炎症实现的。因此，本研究旨在确定醛固酮受体阻断是否通过心肌氧化应激和纤维化的作用，独立于血压变化改善舒张功能障碍。我们使用了组织血管紧张素 II 和循环醛固酮都增加的年轻转基因（mRen2）27 [TG(mRen2)27]大鼠，这些大鼠表现出与年龄相关的高血压和心功能障碍。雄性 TG(mRen2)27 和年龄匹配的 Sprague-Dawley 大鼠分别用低剂量（约 1mg·kg(-1)·day(-1))或血管扩张常规剂量（约 30mg·kg(-1)·day(-1))的螺内酯或安慰剂治疗 3 周。TG(mRen2)27 大鼠的收缩压和血浆醛固酮水平升高，左心室舒张松弛受损，而心脏磁共振电影（cine MRI）显示收缩功能没有变化。TG(mRen2)27 心脏也表现出肥大（左心室重量、心肌细胞肥大和室间隔壁厚度）和纤维化（间质和血管周围）。TG(mRen2)27 心脏的氧化应激增加，表现为 NADPH 氧化酶活性和亚基以及 ROS 形成增加。低剂量螺内酯对收缩压没有影响，但改善舒张功能与常规剂量相当。螺内酯的两种剂量均可导致 ROS/3-硝基酪氨酸免疫染色以及血管周围和间质纤维化的类似减少。这些数据支持这样的观点，即醛固酮受体阻断通过改善氧化应激和纤维化，独立于收缩压的变化来改善舒张功能障碍。
