Finerenone, a Novel Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Protects From Rat Cardiorenal Injury
Finerenone, a Novel Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Protects From Rat Cardiorenal Injury
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DOI：
10.1097/fjc.0000000000000091
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发表时间：
2014-07-01
影响因子：
3
通讯作者：
Schaefer, Stefan
中科院分区：
文献类型：
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作者：
Kolkhof, Peter;Delbeck, Martina;Schaefer, Stefan
药物阻断矿皮质激素受体（MR）改善慢性心力衰竭终末器官损伤。然而，由于伴随高钾血症，特别是在肾功能减退的患者中，可用的类固醇MR拮抗剂的临床使用受到限制。我们最近发现了一种新的非甾体MR拮抗剂，finerenone，它独特地结合了MR的效力和选择性。在这里，我们研究了在2种不同的临床前大鼠疾病模型中，与甾体MR拮抗剂eplerenone相比，finerenone的组织分布和慢性心肾终末器官保护。定量全身放射自显像显示[C-14]标记的细烯酮均匀分布于大鼠心脏和肾脏组织。在不降低全身血压的剂量下，芬纳酮治疗可防止醋酸脱氧皮质酮/盐刺激大鼠的功能性和结构性心脏和肾脏损伤。当比较等尿剂量时，芬烯酮比依普利酮更有效地减少心肌肥厚、血浆脑钠肽原激素和蛋白尿。在冠状动脉结扎后发生慢性心力衰竭的大鼠中，细芬烯酮（1 mg.kg(-1)）。D(-1))，但eperenone （100 mg.kg(-1)）没有。D(-1))改善左心室收缩和舒张功能，降低血浆脑利钠肽原激素水平。我们得出结论，芬烯酮可以提供终端器官保护，降低电解质紊乱的风险。
Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C-14]labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg.kg(-1).d(-1)), but not eplerenone (100 mg.kg(-1).d(-1)) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.