SM-368229, a Novel Promising Mineralocorticoid Receptor Antagonist, Shows Antihypertensive Efficacy With Minimal Effect on Serum Potassium Level in Rats

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property.