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Background/aims: This study was performed to investigate the detailed mechanism underlying the effects of the selective α(1A)-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI)., Methods: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured., Results: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin., Conclusion: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF., (© 2016 S. Karger AG, Basel.)

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background/aims: To evaluate the effects of silodosin (α1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study., Methods: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system., Results: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone., Conclusions: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an α1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an α1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use.

Objective: To compare the effects of four α(1)-adrenoceptor (AR) subtype-selective antagonists on ejaculatory function in rats to investigate whether the differences in their modes of action-based on their selectivities for the α(1A)-AR subtype-would be related to the prevalence of ejaculation disorder (EjD)., Methods: The effects of α(1)-AR antagonists on noradrenaline-induced contractions were studied in rat isolated seminal vesicles, vas deferens, bladder trigone, and prostate. Male rats were given α(1)-AR antagonists orally and, 1 hour after the drug administration they were cohoused in pairs for 1 hour with untreated female rats certified to be in estrus. The number of copulatory plugs (NP) present after mating was measured as a marker of EjD. Drug effects on ejaculatory function (ie, on NP) were compared with those on the prostatic urethra (ie, phenylephrine-induced increase in intraurethral pressure [IUP])., Results: All α(1)-AR antagonists concentration-dependently inhibited noradrenaline-induced contraction in all 4 tissues, and there were no differences in the rank order of potencies (tamsulosin > silodosin > alfuzosin > naftopidil) among the tissues. All α(1)-AR antagonists dose-dependently decreased NP and inhibited the phenylephrine-induced increase in IUP. There was little difference in the dose ratio ID(50) value (dose required to produce 50% inhibition) for NP/ID(50) value for IUP response among the four drugs. Drug potencies associated NP and IUP correlated closely with affinities for the human α(1A)-AR., Conclusion: α(1)-AR antagonists cause EjD as a class effect that depends on affinity for α(1A)-AR. Differences in α(1A)-AR selectivity would be unlikely to be related to the incidence of EjD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Alpha(1)-adrenoceptor antagonists relax the obstructed prostatic urethra and suppress the irritative symptoms frequently observed in patients with benign prostatic hyperplasia. We investigated the effects of 3 alpha(1)-adrenoceptor antagonists on urodynamics in rats with hormone induced benign prostatic hyperplasia to determine which alpha(1)-adrenoceptor subtype selective antagonists would suppress irritative symptoms., Materials and Methods: Rats were treated with testosterone and 17beta-estradiol by weekly intramuscular injections. After 4 weeks a pressure flow study was done and the effects of the alpha(1)-adrenoceptor antagonists KMD-3213 silodosin, tamsulosin and prazosin on urodynamics were compared. We especially investigated the involvement of the bladder and prostatic urethra to clarify the mechanism of detrusor overactivity expression., Results: Hormone treatment induced benign prostatic hyperplasia and resulted in detrusor overactivity, as determined by cystometry. Baseline perfusion urethral pressure and the phenylephrine induced increase in it were significantly higher in rats with vs without benign prostatic hyperplasia. Cystometry in hormone treated female rats did not show detrusor overactivity. KMD-3213 decreased detrusor overactivity, similar to other alpha(1)-adrenoceptor antagonists., Conclusions: These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

We compared the urethral and cardiovascular effects of silodosin (selective alpha(1A)-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective alpha(1A)/alpha(1D)-adrenoceptor antagonist) and naftopidil (selective alpha(1D)-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin>silodosin>naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED(15) value for hypotensive effect/ID(50) value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients.

The duration of action of Silodosin (KMD-3213) against the phenylephrine-induced increase in intraurethral pressure in urethane-anesthetized rats was compared with that of tamsulosin hydrochloride. Silodosin, tamsulosin, or vehicle was orally administered to fasted male rats. Then, under urethane anesthesia, a cannula was inserted into the prostatic urethra. Phenylephrine, at a dose of 30 microg/kg, was infused (infusion rate: 36 ml/h; infusion time: 100 s/kg) via the femoral vein at 12 h, 18 h, or 24 h after administration of the study drug, and the intraurethral pressure in the prostate region was measured. Although the plasma silodosin concentration would have resolved within a few hours, silodosin significantly inhibited the phenylephrine-induced increase in intraurethral pressure (versus the vehicle-treated group) at 12 h, 18 h, and 24 h after its oral administration (at doses of 100 microg/kg and above, 1000 microg/kg and above, and 3000 microg/kg, respectively). On the other hand, tamsulosin hydrochloride showed no inhibitory action at 24 h after its oral administration at doses up to 3000 microg/kg. Thus, silodosin inhibits the phenylephrine-induced increase in intraurethral pressure for a longer time than tamsulosin hydrochloride.

The effects of silodosin, an alpha(1A)-adrenoceptor (AR) antagonist, and of other alpha(1)-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 microg/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 microg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID(50) for IUP and ED(15) for BP were calculated, and uroselectivity was determined as ED(15)/ID(50) 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 (alpha(1A)/alpha(1D)-AR), naftopidil (alpha(1D)-AR), or prazosin (non-selective alpha(1)-AR). These results suggested that an alpha(1A)-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.

The selectivity of silodosin (KMD-3213), an antagonist of alpha(1)-adrenoceptor (AR), to the subtypes (alpha(1A)-, alpha(1B)- and alpha(1D)-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other alpha(1)-AR antagonists. In the receptor-binding study, a replacement experiment using [(3)H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human alpha(1)-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of alpha(1)-AR subtypes (alpha(1A)-AR: rabbit prostate, urethra and bladder trigone; alpha(1B)-AR: rat spleen; alpha(1D)-AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory effect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the alpha(1A)-AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (affinity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strongly antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA(2) or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA(2) values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other alpha(1)-AR antagonists. Our data suggest that silodosin has a high selectivity for the alpha(1A)-AR subtype and for the lower urinary tract.

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.