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In two clinical trials on the antihypertensive effects of the mineralocorticoid receptor antagonist eplerenone 397 essential hypertensives were dose titrated (50, 100, and 200 mg/d) over successive 4-wk periods until they reached target blood pressure levels. Of the total, 44% reached target on 50 mg/d, 17% on 100 mg/d, and 19% on 200 mg/d, with 20% failing to do so despite stepwise dose increases. At each dose level, those who reached target (responders) were compared with those who did not (nonresponders), with three major findings. First, at each dose level, the blood pressure fall in responders (systolic, 16-20 mm Hg; diastolic, approximately 15 mm Hg) was markedly more than mean values in nonresponders (systolic, 2-5 mm Hg; diastolic, 1-3 mm Hg). Second, sensitivity to eplerenone varied widely across the population studied in terms of blood pressure reduction. Third, there was no difference in plasma [K+] levels between responders and nonresponders at any dose level. We interpret these data as evidence for the major antihypertensive effect of eplerenone being via mechanisms other than those involving epithelial electrolyte and fluid transport. The modest (&lt; or =0.2 mEq/liter at 200 mg/d) mean elevation in plasma [K+] suggests that titration to effect rather than forced titration may minimize the risk of hyperkalemia, even where relatively high (100-200 mg/d) doses of the specific mineralocorticoid receptor antagonist eplerenone may ultimately be required.

Distinguishing the Antihypertensive and Electrolyte Effects of Eplerenone