Effects of Silodosin (KMD-3213) on Phenylephrine-induced Increase in Intraurethral Pressure and Blood Pressure in Rats—Study of the Selectivity for Lower Urinary Tract

The effects of silodosin, an α1A-adrenoceptor (AR) antagonist, and of other α1-AR antagonists on the phenylephrine (PE)-induced increase in intraurethral pressure (IUP) and on blood pressure (BP) were studied in anesthetized rats. The drugs were administered intravenously (i.v. study) or intraduodenally (i.d. study). IUP and BP were measured via catheters inserted into the prostatic urethra and common carotid artery, respectively. In the i.v. study, drugs were administered every 30 min for effects on BP, and 5 min before each PE-injection (30 μg/kg, every 60 min) with stepwise increases in dose for effects on IUP. In the i.d. study, one dose of drug was administered per rat, then IUP and BP were observed for 4 h [IUP being measured time-dependently following PE-injection (30 μg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID50 for IUP and ED15 for BP were calculated, and uroselectivity was determined as ED15/ID50 for each drug. All drugs both inhibited the IUP increase and lowered BP, each effect being dose-dependent. The order of uroselectivities was silodosin (11.7)>tamuslosin (2.24)>naftopidil (0.133) in the i.v. study, and silodosin (26.0)>tamuslosin (3.82)>naftopidil (1.39) in the i.d. study. Selectivity for the lower urinary tract (LUT) was higher for silodosin than for tamsulosin (α1A/α1D-AR), naftopidil (α1D-AR), or prazosin (non-selective α1-AR). These results suggested that an α1A-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.