Abstract
Background: Mineralocorticoid receptor (MR) antagonists, such as spironolactone and eplerenone, are useful for the treatment of hypertension and heart failure. However, these antagonists should be used carefully not to cause hyperkalemia as they can interfere with sodium/potassium exchange and reduce urinary potassium excretion. We hypothesized that increase in urinary potassium excretion can reduce elevated plasma potassium level, and accordingly identified DSR-85955 as a safe and orally effective MR antagonist with low hyperkalemia risk. We present the unique in vitro / in vivo profile of DSR-85955. Methods and Results: Using reporter gene assay, we first determined DSR-85955 selectivity for MR and compared it to that for androgen, progesterone, and glucocorticoid steroid receptors. DSR-85955 exhibited high selectivity for MR with an IC50 value of 0.39±0.1 uM (11±2.3 uM for the androgen / progesterone receptor, and 36±4.7 uM for the glucocorticoid receptor). To clarify DSR-85955 low risk for hyperkalemia, we focused on the hypokalemic side effect of other classes of diuretics. We found that DSR-85955, but not spironolactone or eplerenone, inhibits carbonic anhydrase involved in carbon dioxide transport. Next, we compared the effects of DSR-85955, spironolactone, and eplerenone on sodium excretion in deoxycorticosterone acetate-treated rats and plasma potassium levels in potassium-loaded rats. DSR-85955 (30 - 300 mg/kg) reversed sodium excretion without increasing plasma potassium level. Spironolactone and eplerenone, on the other hand, reversed sodium excretion at doses that increased plasma potassium level. In another experiment, 2-week-treatment with DSR-85955 (10 - 100 mg/kg) reduced systolic blood pressure in both uninephrectomized rats treated with aldosterone/salt (UN-Ald/Salt) and spontaneous hypertensive rats. DSR-85955 also decreased urinary albumin excretion in UN-Ald/Salt rats and heart weight in spontaneous hypertensive rats. The anti-hypertensive and organ protective effects of DSR-85955 were 2 to 3 times stronger than those of eplerenone. Conclusion: We have identified DSR-85955, a selective MR antagonist with CA inhibitory activity, as a hopeful antihypertensive candidate with low hyperkalemia risk.
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