Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women

Objective: To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor. Design: This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n = 16), HMR 3339 2.5 mg (n = 20), HMR 3339 10 mg (n = 19), HMR 3339 50 mg (n = 20), or raloxifene 60 mg (n = 19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography. Results: HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P < 0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% Cl, -14.2% to 0.2%] for ADMA and -16.2% [95% Cl, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P = 0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment. Conclusions: The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.