A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice

• Published in: Journal of Atherosclerosis and Thrombosis 2022, pp.63382
• Main Authors: Munkhjargal, Uugantsetseg, Fukuda, Daiju, Ganbaatar, Byambasuren, Suto, Kumiko, Matsuura, Tomomi, Ise, Takayuki, Kusunose, Kenya, Yamaguchi, Koji, Yagi, Shusuke, Yamada, Hirotsugu, Soeki, Takeshi, Wakatsuki, Tetsuzo, Sata, Masataka
• Format: Article
• Language: English
• Subjects: Aldosterone; Aldosterone - metabolism; Aldosterone - pharmacology; Aldosterone - therapeutic use; Animals; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Endothelial Cells - metabolism; Endothelial dysfunction; Endothelium, Vascular - metabolism; Esaxerenone; Humans; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid receptor; Original; Receptors, Mineralocorticoid - metabolism; Receptors, Mineralocorticoid - therapeutic use
• ISSN: 1340-3478; 1880-3873
• DOI: 10.5551/jat.63382

Aims: Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction. Methods: Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study. Results: Induction of diabetes elevated plasma aldosterone level (P＜0.05) and impaired endothelium-dependent vascular relaxation (P＜0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P＜0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOSSer1177 phosphorylation in the aorta obtained from diabetic mice (P＜0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOSSer1177 phosphorylation and increased eNOSThr495 phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P＜0.001). Conclusion: Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes.