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 the systolic blood pressure (SBP) and serum potassium level in spontaneous

Title page DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats This article has not been copyedited and formatted. The final version may differ from this version. This article has not been copyedited and formatted. The final version may differ from this version. Recommended section Cardiovascular This article has not been copyedited and formatted. The final version may differ from this version. Abstract Mineralocorticoid receptor (MR) antagonists such as spironolactone (SPI) and eplerenone (EPL) are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 (MR antagonist with weak CA inhibitory activity) in regard to anti-mineralocorticoid actions by examining relationships between urinary excretion of sodium (index of anti-mineralocorticoid action) in deoxycorticosterone acetate (DOCA)-treated rats, and elevation of serum levels of potassium in potassium-loaded rats, compared with a DSR-71167 derivative without CA inhibition (DSR-30192), SPI and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in DOCA-treated rats without elevating serum levels of potassium in potassium-loaded rats. DSR-30192, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed anti-hypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist with CA inhibitory activity that is expected to become a safer MR antagonist with a low potential risk for hyperkalemia.