Heart Center, Department of Cardiology and Angiology I, University of Freiburg, 79106 Freiburg, Germany; email:
Annu Rev Pharmacol Toxicol. 2015;55:289-312. doi: 10.1146/annurev-pharmtox-010814-124302. Epub 2014 Sep 10.
The mineralocorticoid aldosterone is a key regulator of water and electrolyte homeostasis. Numerous recent developments have advanced the field of mineralocorticoid pharmacology—namely, clinical trials have shown the beneficial effects of aldosterone antagonists in chronic heart failure and post-myocardial infarction treatment. Experimental studies using cell type-specific gene targeting of the mineralocorticoid receptor (MR) gene in mice have revealed the importance of extrarenal aldosterone signaling in cardiac myocytes, endothelial cells, vascular smooth cells, and macrophages. In addition, several molecular pathways involving signal transduction via the classical MR as well as the G protein-coupled receptor GPER mediate the diverse spectrum of effects of aldosterone on cells. This knowledge has initiated the development of new pharmacological ligands to specifically interfere with targets on different levels of aldosterone signaling. For example, aldosterone synthase inhibitors such as LCI699 and the novel nonsteroidal MR antagonist BAY 94-8862 have been tested in clinical trials. Interference with the interaction between MR and its coregulators seems to be a promising strategy toward the development of selective MR modulators.
醛固酮是一种调节水和电解质平衡的关键激素。最近的许多新进展推动了醛固酮药理学领域的发展，即临床试验表明醛固酮拮抗剂在慢性心力衰竭和心肌梗死后治疗中的有益作用。使用细胞类型特异性基因靶向小鼠的醛固酮受体 (MR) 基因的实验研究表明，肾脏外的醛固酮信号在心肌细胞、内皮细胞、血管平滑肌细胞和巨噬细胞中很重要。此外，涉及通过经典 MR 以及 G 蛋白偶联受体 GPER 进行信号转导的几种分子途径介导了醛固酮对细胞的多种作用。这些知识引发了新的药理学配体的开发，以专门干扰醛固酮信号不同水平上的靶点。例如，醛固酮合酶抑制剂（如 LCI699 和新型非甾体 MR 拮抗剂 BAY 94-8862）已在临床试验中进行了测试。干扰 MR 与其共调节剂之间的相互作用似乎是开发选择性 MR 调节剂的一种很有前途的策略。
