449 SM-368229, A MINERALOCORTICOID RECEPTOR ANTAGONIST WITH MODERATE PARTIAL AGONISTIC ACTIVITY SHOWS ANTI-HYPERTENSIVE EFFICACY WITH MINIMAL EFFECT ON SERUM POTASSIUM LEVEL IN RATS

Objective: Mineralocorticoid receptor (MR) antagonists, such as spironolactone and eplerenone, have a serious side effect, hyperkalemia, which is caused by excess inhibition of MR activity. We hypothesized that MR antagonists having partial agonistic activity for MR can attenuate the risk of hyperkalemia. Methods: We evaluated the effects of MR agonistic activities on the serum potassium elevation in potassium-loaded rats or spontaneously hypertensive rats (SHRs) by using spironolactone, SM-368229, and DSR-14397, which are MR antagonists showing different partial agonistic activities for MR (0%, 12%, and 36%, respectively). Results: Spironolactone (300 mg/kg) produced a significant increase in serum potassium levels in potassium-loaded rats (+1.35 mmol/L), however, SM-368229 (300 mg/kg) and DSR-14397 (300 mg/kg) showed minimal effects on serum potassium levels in these rats (+0.36 and +0.16 mmol/L, respectively). Two-week treatment with spironolactone at 300 mg/kg reduced systolic blood pressure while elevating serum potassium levels in SHRs (+0.49 mmol/L). SM-368229 at 10 mg/kg also showed an anti-hypertensive effect similar to spironolactone in SHRs, but had little effects on serum potassium levels (−0.06 mmol/L). Though DSR-14397 at 30 mg/kg failed to prevent the increase in blood pressure in SHRs, it decreased serum potassium levels significantly (−0.50 mmol/L), probably due to its strong agonistic activity for MR. Conclusion: AnMR antagonist with moderate partial agonistic activity (e.g. SM-368229) exerted an anti-hypertensive effect without serum potassium elevation, suggesting that this concept can be useful for the development of novel MR antagonists reducing hyperkalemia risk.