TY - JOUR T1 - Effect of Fiduxosin, an Antagonist Selective for α<sub>1A</sub>- and α<sub>1D</sub>-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 487 LP - 494 DO - 10.1124/jpet.300.2.487 VL - 300 IS - 2 AU - Michael E. Brune AU - Sweta P. Katwala AU - Ivan Milicic AU - David G. Witte AU - James F. Kerwin, Jr. AU - Michael D. Meyer AU - Arthur A. Hancock AU - Michael Williams Y1 - 2002/02/01 UR - http://jpet.aspetjournals.org/content/300/2/487.abstract N2 - Fiduxosin is an α1-adrenoceptor antagonist with higher affinity for α1A-adrenoceptors and for α1D-adrenoceptors than for α1B-adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs. Phenylephrine (PE)-induced increases in IUP and MAP were determined before and at various time points after an oral dose of each antagonist. Hypotensive potency was also determined. All three antagonists caused dose- and time-dependent blockade of the IUP and MAP pressor effects of PE. The IUP ED50 values of fiduxosin, tamsulosin, and terazosin were 0.24, 0.004, and 0.23 mg/kg p.o., respectively. The corresponding MAP ED50 values were 1.79, 0.006, and 0.09 mg/kg p.o. The rank order of IUP selectivity (ratio) was fiduxosin (7.5-fold), tamsulosin (1.5-fold), and terazosin (0.4 = 2.5-fold MAP-selective). Tamsulosin and terazosin caused dose-dependent hypotension, whereas no change in arterial pressure was seen after fiduxosin. These data, illustrating a superior selectivity profile of fiduxosin, are consistent with our hypothesis. The American Society for Pharmacology and Experimental Therapeutics ER -