Antihypertensive and Cardiorenal Protective Effects of SM-368229, a Novel Mineralocorticoid Receptor Antagonist, in Aldosterone/Salt-Treated Rats

Abstract

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist, on the blood pressure and cardiorenal injury markers in aldosterone/salt-treated hypertensive rats, in comparison to those of spironolactone (SPI). Uninephrectomized rats, given 1% NaCl to drink, were infused with aldosterone (0.75 μg/h, s.c.). In experiment 1, SM-368229 (10, 30 mg/kg) or SPI (100 mg/kg) were administered for 14 days immediately after aldosterone/salt loading. In experiment 2, SM-368229 (10 mg/kg) or SPI (100 mg/kg) were administered for 10 days after 10 days of aldosterone/salt loading. In both experiments, SM-368229 prevented the increase in systolic blood pressure, heart/kidney weights, and urinary protein/N-acetyl-β-D- glucosaminidase excretion caused by aldosterone infusion. In real-time polymerase chain reaction analysis, SM-368229 abolished aldosterone-induced gene expression levels for inflammatory, fibrosis and oxidative stress markers in hearts and kidneys. The antihypertensive effect of SM-368229 (30 mg/kg) was superior to that of SPI, and the antihypertensive and cardiorenal protective effects of SM-368229 (10 mg/kg) were similar to those of SPI (100 mg/kg) in both experiments. These results clearly demonstrated that SM-368229 strongly attenuated the progression of hypertension and exerted cardiorenal protection in aldosterone/salt-treated hypertensive rats.