Cardiovascular Effects of the Selective α1A-Adrenoceptor Antagonist Silodosin (KMD-3213), a Drug for the Treatment of Voiding Dysfunction

Abstract

The aim of this study was to assess the cardiovascular effects of silodosin (CAS 160970-54-7, (-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyllamino)propyll-2,3-dihy-dro-1H-indole-7-carboxamide, KMD-3213), a potent selective alpha1A-adrenoceptor (AR) antagonist used for the treatment of dysuria. In conscious dogs, orally administered silodosin, at doses (0.2, 2 and 20 mg/kg) considerably higher than the pharmacologically effective dose, decreased blood pressure. These doses, however, had no effects on heart rate or on the electrocardiogram (PR interval, QRS interval, QT interval or QTc). In addition, the cardiac effects of silodosin were evaluated in an in vitro electrophysiological study. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current, leaving a residual tail current of 45 % control at 10 micromol/L. However, the concentration that inhibited the HERG tail current was considerably higher than its affinity for alphal-ARs. These results suggest that while the alpha1B-AR subtype is mainly involved in the regulation of blood pressure, the alphalA-AR subtype is not. There seems to exist no evidence of a correlation between the function of alphal-AR and ECG changes reflecting inhibition of the HERG current. The cardiovascular profile of silodosin suggests therefore that it is a safe and well-tolerated drug.