Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain.
Exp Physiol. 2012 Jun;97(6):710-8. doi: 10.1113/expphysiol.2011.063230. Epub 2012 Feb 10.
Persistent β-adrenergic receptor stimulation with isoproterenol is associated with cardiac hypertrophy as well as cardiac synthesis of angiotensin II. Serum- and glucocorticoid-regulated kinase type 1 (SGK-1) is a key mediator in structural, functional and molecular cardiac effects of aldosterone in rats. This study was designed to investigate the cardiac effects of the mineralocorticoid receptor antagonist spironolactone on the response to isoproterenol treatment in rats, as well as the involvement of the main mediator of cellular aldosterone action, SGK-1, in the heart. Male Wistar rats received isoproterenol (3 mg kg(-1) day(-1)) or vehicle for 15 days. Half of the animals in each group were simultaneously treated with spironolactone (200 mg kg(-1) day(-1)). Systolic and diastolic blood pressures were not significantly different among groups. Treatment with spironolactone normalized the increased left ventricular end-diastolic pressure observed in isoproterenol-treated rats. Isoproterenol treatment induced cardiac hypertrophy and increased collagen content, both of which were normalized by spironolactone treatment. The mRNA levels of transforming growth factor β, connective tissue growth factor, matrix metalloprotease 2, matrix metalloprotease inhibitor 2, tumour necrosis factor α, interleukin 1β, p22phox and xanthine dehydrogenase were increased (P < 0.05) in isoproterenol-treated rats, and this effect was prevented by spironolactone (P < 0.05). Spironolactone also reduced the elevated SGK-1 expression in isoproterenol-treated rats. The observed reduction of the principal mediator of aldosterone cellular actions, SGK-1, by spironolactone in hearts from isoproterenol-treated rats suggests a role of mineralocorticoids in the cardiac hypertrophy, fibrosis, inflammation, oxidation and diastolic dysfunction induced by isoproterenol treatment in rats.
异丙肾上腺素持续刺激β肾上腺素受体与心脏肥大以及血管紧张素 II 的心脏合成有关。血清和糖皮质激素调节激酶 1（SGK-1）是大鼠醛固酮结构、功能和分子心脏效应的关键介质。本研究旨在探讨盐皮质激素受体拮抗剂螺内酯对异丙肾上腺素治疗大鼠反应的心脏效应，以及细胞醛固酮作用的主要介质 SGK-1 在心脏中的作用。雄性 Wistar 大鼠接受异丙肾上腺素（3mgkg(-1)day(-1)）或载体 15 天。每组中的一半动物同时接受螺内酯（200mgkg(-1)day(-1)）治疗。各组间的收缩压和舒张压无显著差异。螺内酯治疗可使异丙肾上腺素治疗大鼠观察到的左心室舒张末期压升高恢复正常。异丙肾上腺素治疗诱导心脏肥大和胶原含量增加，螺内酯治疗可使这些变化恢复正常。转化生长因子 β、结缔组织生长因子、基质金属蛋白酶 2、基质金属蛋白酶抑制剂 2、肿瘤坏死因子 α、白细胞介素 1β、p22phox 和黄嘌呤脱氢酶的 mRNA 水平在异丙肾上腺素治疗大鼠中升高（P<0.05），螺内酯治疗可预防这种升高（P<0.05）。螺内酯还降低了异丙肾上腺素治疗大鼠中升高的 SGK-1 表达。螺内酯在异丙肾上腺素治疗大鼠心脏中减少醛固酮细胞作用的主要介质 SGK-1 的观察结果表明，在大鼠中，盐皮质激素在异丙肾上腺素治疗引起的心脏肥大、纤维化、炎症、氧化和舒张功能障碍中起作用。
