Selective Alpha 1A-adrenoceptor Research Articles

The efficacy and safety of silodosin-a review of literature

Background: Benign prostatic hyperplasia is a compilation of irritative voiding and obstructive symptoms which are consistent with reduced emptying of urine from and defective storage of urine in the bladder. Medications are a common method of treatment to delay complications and reduce symptoms. Silodosin is a highly selective alpha-1A adrenoceptor blocker that has 162 times more affinity for alpha-1a than alpha 1b, thus resulting in high uroselectivity and decreased side effects. Aim: In this review article our aim was to elucidate the clinical effects, safety and tolerability profile of silodosin in the treatment of benign prostatic hyperplasia. Method: Literatures were retrieved by a PubMed search, using different combinations of pertinent keywords (e.g., silodosin, hypotension, benign prostatic hyperplasia), without any limitations in terms of publication date and language. Papers which assessed the therapeutic efficacy and tolerability of silodosin were selected for inclusion according to their relevance for the topic, as judged by the authors. Overv?ew of clinical data: Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia. It has a rapid onset of effect in men with lower urinary tract symptoms and improvements were seen in voiding and storage symptoms, maximum urinary flow rate and health-related quality of life. The efficacy of silodosin was maintained in several controlled studies and also non-interventional real-world setting. Silodosin was generally well tolerated. Conclusion: Silodosin is the most uroselective α-blocker. Silodosin has been emphasized in the 2021 European Association of Urology Conservative treatment of non-neurogenic male LUTS guidelines and it has been reported that the hypotensive effect of silodosin is comparable with placebo and has favorable safety and tolerability profile. Dosing of silodosin does not need to be adjusted according to age, concurrent medication with antihypertensives and phosphodiesterase type 5 inhibitors.

Protective effects of the selective alpha1A-adrenoceptor antagonist silodosin against cyclophosphamide-induced cystitis in rats

We investigated the protective effects of a selective α1A-adrenoceptor antagonist, silodosin (Silod) on urinary bladder function in cyclophosphamide (CYP)-induced cystitis rats, with and without desensitization of the capsaicin (CAP)-sensitive afferent nerve pathway. Male Wistar rats (310–400 g) were pretreated with Silod (0, 100, or 300 μg/kg/day, p.o.) for 1 week before cystometry, and were administered either CYP (150 mg/kg, i.p.) or saline 2 days before the experiment. In another experiment, the rats were treated with CAP (125 mg/kg, s.c.) 4 days before the cystometry. The rat bladders were harvested, weighed, and evaluated histologically. The cystometric evaluation showed significant reductions in the intercontraction interval (ICI), single voided volume (SVV), and bladder compliance in CYP-treated rats compared to those in the vehicle-treated rats. High-dose Silod or CAP treatment significantly increased the ICI and SVV in the CYP rats. However, high-dose Silod treatment did not increase the ICI and SVV in CAP-treated CYP rats. Treatment with Silod did not improve the bladder weight, edema, and leukocyte infiltration resulting from the CYP-induced bladder inflammation. These data suggest that blockade of α1-adrenoceptors by Silod inhibited the CAP-sensitive afferent pathway in rats with cystitis.

Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release.

Pathophysiological mechanisms of chronic visceral pain (CVP) are unknown. This study explores the association between the sympathetic system and bladder nociceptors activity by testing the effect of a prolonged adrenergic stimulation on transient receptor potential vanilloid 1 (TRPV1) activity and on urothelial adenosine triphosphate (ATP) release. Female Wistar rats received saline, phenylephrine (PHE), PHE+silodosin, PHE+naftopidil or PHE+prazosin. TRPV1 knockout and wild-type mice received saline or PHE. Visceral pain behaviour tests were performed before and after treatment. Cystometry was performed, during saline and capsaicin infusion. Fos immunoreactivity was assessed in L6 spinal cord segment. Human urothelial ATP release induced by mechanical and thermal stimulation was evaluated. Subcutaneous, but not intrathecal, PHE administration induced pain, which was reversed by silodosin, a selective alpha 1A adrenoceptor antagonist, but not by naftopidil, a relatively selective antagonist for alpha 1D adrenoceptor. Silodosin also reversed PHE-induced bladder hyperactivity and L6 spinal cord Fos expression. Thus, in subsequent experiments, only silodosin was used. Wild-type, but not TRPV1 knockout, mice exhibited phenylephrine-induced pain. Capsaicin induced a greater increase in voiding contractions in PHE-treated rats than in control animals, and silodosin reversed this effect. When treated with PHE, ATP release from human urothelial cells was enhanced either by mechanical stimulation or by lowering the thermal threshold of urothelial TRPV1, which becomes abnormally responsive at body temperature. This study suggests that the activation of peripheral alpha 1A adrenoceptors induces CVP, probably through its interaction with TRPV1 and ATP release.

Effect of Silodosin, an Alpha1A-Adrenoceptor Antagonist, on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat.

BackgroundA decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow.MethodsTwelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining.ResultsThere was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR.ConclusionsSilodosin can inhibit the progression of prostatic hyperplasia through a recovery of prostatic blood flow.

MP41-06 ADMINISTRATION OF THE SELECTIVE ALPHA 1A ADRENOCEPTOR ANTAGONIST SILODOSIN FACILITATES EXPULSION OF SIZE 5 - 10 MM DISTAL URETERAL STONES, AS COMPARED TO CONTROL.

You have accessJournal of UrologyStone Disease: Medical Therapy1 Apr 2015MP41-06 ADMINISTRATION OF THE SELECTIVE ALPHA 1A ADRENOCEPTOR ANTAGONIST SILODOSIN FACILITATES EXPULSION OF SIZE 5 - 10 MM DISTAL URETERAL STONES, AS COMPARED TO CONTROL. Yasunori Itoh, Atsushi Okada, Kazumi Taguchi, Yasuhiko Hirose, Yasuhiro Fujii, Takahiro Kobayashi, Masayuki Usami, Shuzo Hamamoto, Masahito Hirose, Takahiro Yasui, Keiichi Tozawa, Shoichi Sasaki, Yutaro Hayashi, and Kenjiro Kohri Yasunori ItohYasunori Itoh More articles by this author , Atsushi OkadaAtsushi Okada More articles by this author , Kazumi TaguchiKazumi Taguchi More articles by this author , Yasuhiko HiroseYasuhiko Hirose More articles by this author , Yasuhiro FujiiYasuhiro Fujii More articles by this author , Takahiro KobayashiTakahiro Kobayashi More articles by this author , Masayuki UsamiMasayuki Usami More articles by this author , Shuzo HamamotoShuzo Hamamoto More articles by this author , Masahito HiroseMasahito Hirose More articles by this author , Takahiro YasuiTakahiro Yasui More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , Shoichi SasakiShoichi Sasaki More articles by this author , Yutaro HayashiYutaro Hayashi More articles by this author , and Kenjiro KohriKenjiro Kohri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1634AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently, we reported that alpha 1A adrenoceptor (AR) is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha 1A AR antagonist, as a medical expulsive therapy (MET) for distal ureteral stones. METHODS A total of 112 male patients, who were referred to our department for the management of symptomatic unilateral distal ureteral calculi of less than 10 mm, were randomly divided into two groups: group A (56 patients) who were instructed to drink 2 L of water daily and group B (56 patients) who received the same instruction and were also given silodosin (8 mg/daily) for a maximum of 4 weeks. Expulsion rate, expulsion time and need for analgesics were examined. RESULTS The expulsion rate was 55.3% (56 patients) for group A and 72.7% (55 patients) for group B (P = 0.106). The expulsion rate for < 5 mm was 92.9% (28 patients) for group A and 69.2% (26 patients) for group B (P =0.053). The expulsion rate for > or = 5 mm was 17.9% (28 patients) for group A and 75.9% (29 patients) for group B (P =0.001). The expulsion time was 13.40 ± 5.90 and 9.29 ± 5.91 days, respectively (P = 0.012). Analgesics were required 1.5 ± 3.1 and 0.3 ± 0.9 times, respectively (P = 0.382). Stone size in expulsion cases was 3.64 ± 1.25 and 5.23 ± 2.32 mm, respectively (P = 0.003). In all stone sizes, group B showed high expulsion rate (Fig.). CONCLUSIONS Due to the high likelihood of spontaneous passage of stones up to 5 mm, MET is less likely to increase the stone-free rate. Here, we have shown that MET for distal ureteral stones by silodosin was effective for stones ≥5 mm. Silodosin is used in Japan, the United States, Korea, Germany, Lebanon, Ireland, Spain, France, Portugal, Belgium, Romania, Taiwan, Italy, Greece, Netherland, Russia, Czech, Slovakia, Canada, Bulgaria, Cyprus, Turkey, Poland, Ukraine, Georgia, and China. We believe that silodosin might have potential as a MET for distal ureteral stones. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e502 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yasunori Itoh More articles by this author Atsushi Okada More articles by this author Kazumi Taguchi More articles by this author Yasuhiko Hirose More articles by this author Yasuhiro Fujii More articles by this author Takahiro Kobayashi More articles by this author Masayuki Usami More articles by this author Shuzo Hamamoto More articles by this author Masahito Hirose More articles by this author Takahiro Yasui More articles by this author Keiichi Tozawa More articles by this author Shoichi Sasaki More articles by this author Yutaro Hayashi More articles by this author Kenjiro Kohri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

E80 Administration of the selective alpha 1A adrenoceptor antagonist silodosin facilitates expulsion of size 5–10 mm distal ureteral stones, as compared to control

Objective Recently, we reported that alpha 1A-adrenoceptor (AR) is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha 1A AR antagonist, as a medical expulsive therapy (MET) for distal ureteral stones.

Administration of the selective alpha 1A-adrenoceptor antagonist silodosin facilitates expulsion of size 5–10 mm distal ureteral stones, as compared to control

Recently, we reported that alpha 1A-adrenoceptor (AR) is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha 1A AR antagonist, as a medical expulsive therapy (MET) for distal ureteral stones. A total of 112 male patients, who were referred to our department for the management of symptomatic unilateral distal ureteral calculi of less than 10 mm, were randomly divided into two groups: group A (56 patients) who were instructed to drink 2 L of water daily and group B (56 patients) who received the same instruction and were also given silodosin (8 mg/daily) for a maximum of 4 weeks. Expulsion rate, expulsion time and need for analgesics were examined. The expulsion rate was 55.3 % (56 patients) for group A and 72.7 % (55 patients) for group B (P = 0.106). The expulsion rate for <5 mm was 92.9 % (28 patients) for group A and 69.2 % (26 patients) for group B (P = 0.053). The expulsion rate for ≥ 5 mm was 17.9 % (28 patients) for group A and 75.9 % (29 patients) for group B (P = 0.001). The expulsion time was 13.40 ± 5.90 and 9.29 ± 5.91 days, respectively (P = 0.012). Analgesics were required 1.5 ± 3.1 and 0.3 ± 0.9 times, respectively (P = 0.382). Stone size in expulsion cases was 3.64 ± 1.25 and 5.23 ± 2.32 mm, respectively (P = 0.003). Stone size has been identified as an important predictive factor for stone expulsion. Therefore, it is important that administration of silodosin can facilitate expulsion of 1.5 mm or larger distal ureteral stones, as compared to control. We believe that silodosin might have potential as a MET for distal ureteral stones.

2088 ADMINISTRATION OF THE SELECTIVE ALPHA 1A ADRENOCEPTOR ANTAGONIST SILODOSIN FACILITATES EXPULSION OF 1.5 MM OR LARGER DISTAL URETERAL STONES, AS COMPARED TO CONTROL

You have accessJournal of UrologyStone Disease: Basic Research I1 Apr 20122088 ADMINISTRATION OF THE SELECTIVE ALPHA 1A ADRENOCEPTOR ANTAGONIST SILODOSIN FACILITATES EXPULSION OF 1.5 MM OR LARGER DISTAL URETERAL STONES, AS COMPARED TO CONTROL Yasunori Itoh, Atsushi Okada, Masahito Hirose, Shuzo Hamamoto, Takahiro Kobayashi, Kazuhiro Niimi, Yoshiyuki Kojima, Yasue Kubota, Takahiro Yasui, Keiichi Tozawa, Shoichi Sasaki, and Kenjiro Kohri Yasunori ItohYasunori Itoh Nagoya, Japan More articles by this author , Atsushi OkadaAtsushi Okada Nagoya, Japan More articles by this author , Masahito HiroseMasahito Hirose Nagoya, Japan More articles by this author , Shuzo HamamotoShuzo Hamamoto Nagoya, Japan More articles by this author , Takahiro KobayashiTakahiro Kobayashi Nagoya, Japan More articles by this author , Kazuhiro NiimiKazuhiro Niimi Nagoya, Japan More articles by this author , Yoshiyuki KojimaYoshiyuki Kojima Nagoya, Japan More articles by this author , Yasue KubotaYasue Kubota Nagoya, Japan More articles by this author , Takahiro YasuiTakahiro Yasui Nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa Nagoya, Japan More articles by this author , Shoichi SasakiShoichi Sasaki Nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri Nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2254AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The efficacy of minimally invasive therapies, such as shock wave lithotripsy (SWL), has been proven for ureteral stone expulsion. Nevertheless, SWL is not risk-free and is quite expensive. A watchful waiting approach can be used in a large number of cases. The use of a watchful waiting approach has been extended as a result of advances in pharmacological therapy, which can reduce symptoms and facilitate stone expulsion. Several studies have shown that tamsulosin, an alpha 1A/1D adrenoceptor (AR) antagonist, facilitates ureteral stone expulsion. Recently, we reported that alpha 1A AR is the main participant in phenylephrine-induced human ureteral contraction. We therefore decided to carry out a prospective randomized study to evaluate the effects of silodosin, a selective alpha 1A AR antagonist, as a medical expulsive therapy (MET) for distal ureteral stones. METHODS A total of 112 male patients, who were referred to our department for the management of symptomatic unilateral distal ureteral calculi of less than 10 mm, were randomly divided into two groups: group A (56 patients) who were instructed to drink 2 L of water daily and group B (56 patients) who received the same instruction and were also given silodosin (8 mg/daily) for a maximum of 4 weeks. Expulsion rate, expulsion time and need for analgesics were examined. RESULTS No statistically significant differences were found between the two groups with regard to age, stone size in diameter or stone composition. The expulsion rate was 55.3% (56 patients) for group A and 72.7% (55 patients) for group B (P = 0.106). The expulsion time was 13.40 ± 5.90 and 9.29 ± 5.91 days, respectively (P = 0.012). Analgesics were required 1.5 ± 3.1 and 0.3 ± 0.9 times, respectively (P = 0.382). Stone size in expulsion cases was 3.64 ± 1.25 and 5.23 ± 2.32 mm, respectively (P = 0.003). The percentage of 5 mm or more than in expulsion cases was 16.1% and 55.0%, respectively (P = 0.001). One patient in group B experienced retrograde ejaculation. He was excluded from the present study. Any patients who were not stone-free after 4 weeks of follow up (25 in group A and 15 in group B) were treated with SWL. CONCLUSIONS Stone size has been identified as an important predictive factor for stone expulsion. Therefore, it is important that administration of silodosin can facilitate expulsion of 1.5mm or larger distal ureteral stones, as compared to control. We believe that silodosin might have potential as a MET for distal ureteral stones. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e841 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yasunori Itoh Nagoya, Japan More articles by this author Atsushi Okada Nagoya, Japan More articles by this author Masahito Hirose Nagoya, Japan More articles by this author Shuzo Hamamoto Nagoya, Japan More articles by this author Takahiro Kobayashi Nagoya, Japan More articles by this author Kazuhiro Niimi Nagoya, Japan More articles by this author Yoshiyuki Kojima Nagoya, Japan More articles by this author Yasue Kubota Nagoya, Japan More articles by this author Takahiro Yasui Nagoya, Japan More articles by this author Keiichi Tozawa Nagoya, Japan More articles by this author Shoichi Sasaki Nagoya, Japan More articles by this author Kenjiro Kohri Nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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

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.

E73 Efficacy of a selective alpha 1A adrenoceptor antagonist as a medical expulsive therapy against ureteral stones

E73 Efficacy of a selective alpha 1A adrenoceptor antagonist as a medical expulsive therapy against ureteral stones

Identification of α-1L and α-1A Adrenoceptors in Human Prostate by Tissue Segment Binding

Silodosin (KMD-3213 or [(-)-1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide]) (Kissei Pharmaceutical Co., Ltd., Matsumoto, Japan) is a selective antagonist for alpha-1A and alpha-1L adrenoceptors. Using this tritiated ligand the 2 alpha-1 adrenoceptors were examined in binding studies with intact tissue segments and membrane preparations of human prostate, and compared with functionally identified alpha-1 adrenoceptor. Binding assays with tissue segments and membrane preparations of human prostate samples were performed using [3H]-silodosin and binding affinities for various drugs were estimated. In functional experiments antagonist affinities were evaluated from the inhibitory potency against the contractile response to noradrenaline. [3H]-silodosin bound to intact segments and membrane preparations of human prostate with subnanomolar affinity. [3H]-silodosin binding sites in intact segments were divided into 2 distinct components with different affinities for prazosin and RS-17053 (N-[2(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl1H-indole-3-ethanamine hydrochloride) (Research Biochemicals International, Natick, Massachusetts), while binding in membrane preparations showed single high affinity for these drugs. [3H]-silodosin binding sites also showed high affinity for silodosin and tamsulosin but low sensitivity to BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)decane-7,9-dione) (Research Biochemicals International) in intact segments and in membrane preparations. In functional experiments silodosin and tamsulosin potently inhibited the contractile response to noradrenaline but prazosin, RS-17053 and BMY 7378 showed low antagonistic affinity. The current binding studies in human prostate samples clearly show that alpha-1L and alpha-1A adrenoceptors coexist as pharmacologically distinct entities in intact tissues but not in crude membrane preparations. Also, alpha-1 adrenoceptors involved in the contractile response to noradrenaline are the alpha-1L subtype.

INCREASED CONTRACTILE RESPONSE TO PHENYLEPHRINE IN DETRUSOR OF PATIENTS WITH BLADDER OUTLET OBSTRUCTION: EFFECT OF THE α1A AND α1D-ADRENERGIC RECEPTOR ANTAGONIST TAMSULOSIN

Alpha1-adrenergic receptor (alpha1-AR) antagonists are effective for treating patients with lower urinary tract symptoms associated with bladder outlet obstruction (BOO). In humans up-regulation of alpha1-AR function in the detrusor in patients with BOO has been suggested but to our knowledge it is not yet confirmed. We investigated the effect of phenylephrine, an alpha1-AR agonist, on isometric tension in small detrusor muscle biopsies from patients with lower urinary tract symptoms and BOO compared with controls. Detrusor biopsies were obtained from 7 men with BOO undergoing prostatectomy and 7 undergoing cystectomy for bladder cancer (controls). Patients were characterized by symptom score and urodynamics. Isometric tension was measured in detrusor biopsies with an especially built mini myograph. Mean International Prostate Symptom Score +/- SEM in patients with BOO and controls were 22.3 +/- 2.3 and 4.0 +/- 0.8, respectively. Phenylephrine (10(-6) to 10(-3) M) induced a significant contractile response increase in detrusor biopsies from patients with BOO compared with controls at all concentrations. Tamsulosin (0.1 to 3.0 nM) inhibited phenylephrine induced contraction in a dose dependent manner. To our knowledge this functional study shows for the first time a highly significant increase in contractile force to phenylephrine in patients with BOO compared with controls. These results suggest up-regulation of alpha1-AR function in BOO since contractile responses were potently inhibited by the alpha1A/D-AR antagonist tamsulosin.

Long-term Safety and Efficacy of Tamsulosin for the Treatment of Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia

We evaluated the long-term (up to 6 years) safety and efficacy of the selective alpha 1A-adrenoceptor antagonist tamsulosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. A total of 609 patients were enrolled in a 4-year multicenter open label extension study. Subjects entered the study after completion of a 1-year open label trial that included patients who previously completed up to 57 weeks of double-blind, placebo controlled studies. Maintenance doses (0.4 or 2 x 0.4 mg daily) established in the 1-year study were continued. Efficacy and safety were assessed every 3 months. Primary efficacy evaluations were changes from baseline maximum urine flow rate and total American Urological Association symptom index, and the responder rates for those 2 end points. Secondary end points were changes in American Urological Association subset scores, Boyarsky symptom scores, average urine flow rate, post-void residual urine volume, quality of life index and investigator global assessment. Of the 609 patients who entered the 4-year extension study 159 had a 2-year or greater prior experience with tamsulosin, yielding a potential 6-year experience on the medication. Of this 159 patient subset 109 completed the whole 6 years. Initial rapid improvements from baseline in primary and secondary end points were maintained each year throughout the duration of the study. Tamsulosin was well tolerated, confirming the safety profile demonstrated in earlier studies. Orthostatic hypotension was observed in 1.3% of the patients. This study demonstrates the sustained efficacy, safety and excellent long-term tolerability of tamsulosin for up to 6 years in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia.

Role Of Supraspinal α1-Adrenoceptors For Voiding In Conscious Rats With And Without Bladder Outlet Obstruction

Previous studies have shown that spinal alpha1-adrenoceptors can influence voiding in normal rats and in rats with outlet obstruction. Also, at the supraspinal level such receptors may be involved in voiding control. Therefore, we studied in rats the effects on cystometrography of intracerebroventricular administered alpha1-adrenoceptor antagonists. Continuous cystometry was performed in conscious, freely moving rats with and without bladder outlet obstruction. Cystometric parameters were evaluated before and after intracerebroventricular drug administration. In normal rats intracerebroventricular administration of 8 nmol. kg.-1 prazosin (Pfizer Central Research, Sandwich, United Kingdom) or terazosin (Abbott Laboratories, Abbott Park, Illinois) (nonsubtype selective) caused no change in cystometric parameters. At 24 or 80 nmol. kg.-1 the 2 drugs significantly decreased voiding pressure and increased bladder capacity, voided volume and post-void residual urine volume. Administering vehicle had no effect. In rats with outlet obstruction the drug effects were significantly more pronounced than in normal animals (p <0.05), and urinary retention was produced in 50% of rats receiving prazosin. In normal rats the selective alpha1A-adrenoceptor antagonists KMD 3213 (0.8, 8 and 24 nmol. kg.-1) dose dependently depressed voiding pressure, and increased bladder capacity and voided volume, whereas BMY 7378 (selective for alpha1D-adrenoceptors) and A322312 (selective for alpha1B-adrenoceptors) at doses up to 80 nmol. kg.-1 had no effect. The results suggest that in normal rats and in rats with outflow obstruction volume induced bladder activity involves supraspinal alpha1-adrenoceptors. Bladder outlet obstruction seems to enhance the importance of these receptors. At least in normal rats the alpha1A-adrenoceptor subtype seems to mediate the effect.

Alpha1-adrenoceptor subtypes on rat afferent arterioles assessed by radioligand binding and RT-PCR.

We utilized [3H]prazosin saturation and competition radioligand binding studies to characterize the expression of alpha1-adrenoceptors in preglomerular vessels. mRNA for adrenoceptor subtypes was assayed using RT-PCR. The vessels were isolated using an iron oxide-sieving method. [3H]prazosin bound to a single class of binding sites (Kd 0.087 +/- 0.012 nM, Bmax 326 +/- 56 fmol/mg protein). Phentolamine displaced [3H]prazosin (0.2 nM) with a pK(i) of 8.37 +/- 0.09. Competition with the selective alpha1A-adrenoceptor antagonist 5-methylurapidil fit a two-site model (pK(i) 9.38 +/- 0.21 and 7.04 +/- 0.15); 59 +/- 3% of the sites were high-affinity, and 41 +/- 3% were low-affinity binding sites. Competition with the alpha1D-adrenoceptor antagonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY-7378) fit a one-site model with low affinity (pK(i) 6.83 +/- 0.03). The relative contents of alpha1A-, alpha1B-, and alpha1D-adrenoceptor mRNAs were 64 +/- 5, 25 +/- 5, and 11 +/- 1%, respectively. Thus there was a very good correlation between mRNA and receptor binding for the subtypes. These data indicate a predominance of the alpha1A-adrenoceptor subtype in rat renal resistance vessels, with smaller densities of alpha1B- and alpha1D-adrenoceptors.

Contractile properties of urethral smooth muscles of young and aged female dogs: morphological and pharmacological aspects.

Alpha1-adrenoceptors are highly concentrated in the urethral smooth muscles and may play an important role in the contraction of this area. However, detailed examinations of age-related changes of the properties of urethral smooth muscle have rarely been undertaken. The contractile properties of urethras from young non-parous and old parous female beagles were determined with a urethral function study, macroscopic autoradiography for urethras using [3H]-labeled tamsulosin and morphometry of the urethral muscles. The antagonistic effect (pA2) of prazosin for norepinephrine was 7.76+/-0.13 in young dogs and 7.62+/-0.06 in aged dogs. The specific binding of [3H]-tamsulosin (a relatively selective alpha1A-adrenoceptor antagonist) was recognized diffusely in proximal urethras with in vitro autoradiography. The density of binding in smooth muscles was approximately 60 and 40% in circular longitudinal layers, respectively, for both dogs. The female canine urethra had alpha1A, and alpha1L-adrenoceptors. No age-related changes were seen in the function of the proximal urethra, distribution of alpha1-adrenoceptor binding sites and smooth muscle densities.

Contractile responses to alpha1-adrenoceptor agonists in isolated human male and female urethra.

To investigate the contractile responses mediated through alpha1-adrenoceptors in human urethra and to evaluate the effectiveness of NS-49 [(R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulphonanilide++ + hydrochloride], a novel alpha1-adrenoceptor agonist, against contraction of the human urethra. The contractile responses were assessed in 10 male prostatic urethrae and six female urethrae. Antagonism was evaluated in the urethra using phenylephrine, a nonselective alpha1-adrenoceptor agonist, cumulatively applied > 20 min after applying 0.1 micromol/L prazosin or 0.1 micromol/L 5-methylurapidil, a selective alpha1A-adrenoceptor antagonist. Agonism was determined in both male and female urethrae to obtain the concentration-response curve for the agonist. Phenylephrine caused both male and female urethrae to contract, and showed high potency and efficacy. Prazosin antagonized these contractions with low affinity (apparent pKB of 8.30 in male urethrae). 5-Methylurapidil, also antagonized the contractions with low affinity (apparent pKB of 7.88 in male urethrae). Noradrenaline and phenylephrine caused both male and female urethrae to contract, with high potency and efficacy. A novel and selective alpha1A-and alpha1L-adrenoceptor agonist, NS-49, induced contractile responses with high potency and moderate efficacy, whereas methoxamine induced contractions with low potency and moderate efficacy. Norephedrine was a very weak contractile agonist. In the human urethra, phenylephrine-induced contractions were mediated through alpha1L-adrenoceptors and not through alpha1A-adrenoceptors. Contractions of the human urethra induced by NS-49 were also mediated mainly through alpha1L-adrenoceptors, with high potency and moderate efficacy. NS-49 may therefore be useful for the treatment of urinary stress incontinence, with minimal side-effects because it has subtype selectivity.

Analysis of alpha 1L-adrenoceptor pharmacology in rat small mesenteric artery.

1. To illuminate the controversy on alpha 1A- or alpha 1L-adrenoceptor involvement in noradrenaline-mediated contractions of rat small mesenteric artery (SMA), we have studied the effects of subtype-selective alpha 1-adrenoceptor agonists and antagonists under different experimental conditions. 2. The agonist potency order in rat SMA was: A61603 >> SKF89748-A > cirazoline > noradrenaline > ST-587 > methoxamine. Prazosin antagonized all agonists with a low potency (pA2: 8.29-8.80) indicating the involvement of alpha 1L-rather than alpha 1A-adrenoceptors. 3. The putative alpha 1L-adrenoceptor antagonist JTH-601, but not the alpha 1B-adrenoceptor antagonist chloroethylclonidine (10 microM) antagonized noradrenaline-induced contractions of SMA. The potency of the selective alpha 1D-adrenoceptor antagonist BMY 7378 against noradrenaline (pA2 = 6.16 +/- 0.13) and of the selective alpha 1A-adrenoceptor antagonist RS-17053 against noradrenaline (pKB = 8.35 +/- 0.10) and against the selective alpha 1A-adrenoceptor agonist A-61603 (pKB = 8.40 +/- 0.09) were too low to account for alpha 1D- and alpha 1A-adrenoceptor involvement. 4. The potency of RS-17053 (pKB/pA2's = 7.72-8.46) was not affected by lowering temperature, changing experimental protocol or inducing myogenic tone via KCl or U46619. 5. Selective protection of a putative alpha 1A-adrenoceptor population against the irreversible action of phenoxybenzamine also failed to increase the potency of RS-17053 (pA2 = 8.25 +/- 0.06 against A61603). 6. Combined concentration-ratio analysis demonstrated that tamsulosin, which does not discriminate between alpha 1A- and alpha 1L-adrenoceptors, and RS-17053 competed for binding at the same site in the SMA. 7. In summary, data obtained in our experiments in rat SMA indicate that the alpha 1-adrenoceptor mediating noradrenaline-induced contraction displays a distinct alpha 1L-adrenoceptor pharmacology. This study does not provide evidence for the hypothesis that alpha 1L-adrenoceptors represent an affinity state of the alpha 1A-adrenoceptor in functional assays. Furthermore, there is no co-existing alpha 1A-adrenoceptor in the SMA.

Selective blockade by nicergoline of vascular responses elicited by stimulation of alpha 1A-adrenoceptor subtype in the rat.

The alpha 1-adrenergic blocking activity of nicergoline was re-examined in rats, with a particular emphasis on alpha 1-adrenoceptor subtypes. In pithed rats, nicergoline and prazosin infused at a single small dose (0.5 microgram/kg/min i.v.) produced a substantial and identical shift to the right of the control dose pressor response curve to the specific alpha 1-agonist cirazoline (ED50 = 4.0 +/- 0.1, 4.0 +/- 0.1 and 0.9 +/- 0.01 microgram/kg i.v. for nicergoline, prazosin and vehicle respectively). In the isolated perfused mesenteric vascular bed, nicergoline strongly inhibited the pressor responses elicited by cirazoline, with approximately 40-fold higher potency (pA2 = 11.1 +/- 0.3) than prazosin (pA2 = 9.5 +/- 0.3). Conversely, nicergoline was 20-fold less potent than prazosin to antagonize the contractile effects of cirazoline in isolated endothelium-denuded aorta (pA2 = 8.6 +/- 0.2 and 9.9 +/- 0.2 for nicergoline and prazosin respectively). Pretreatment of mesenteric vascular beds with chloroethylclonidine did not significantly modify nicergoline antagonistic potency (pA2 = 10.6 +/- 0.2). Nicergoline displaced [3H]-prazosin bound to rat forebrain membranes pretreated with chloroethylclonidine (pKi = 9.9 +/- 0.2) at concentrations 60-fold lower than in rat liver membranes (pKi = 8.1 +/- 0.2). Finally, of the nicergoline metabolites studied, lumilysergol acted as a modest alpha 1 antagonist (bromonicotinic acid was devoid of alpha 1 antagonist activity). In conclusion, nicergoline is a potent and selective alpha 1A-adrenoceptor subtype antagonist, an alpha 1-adrenoceptor subtype which is mainly represented in resistance arteries.

Functional assessment of alpha 1-adrenoceptor subtypes in porcine coronary artery.

1. alpha 1-Adrenoceptors are known to play an important role in vasoconstriction in response to adrenergic stimulation. However, the functional importance of alpha 1-adrenoceptor subtypes at the epicardial coronary artery remains unclear. We examined alpha 1-adrenoceptor subtypes by comparing functional affinities for alpha-adrenoceptor antagonists on noradrenaline (NA)-induced vasoconstriction in porcine denuded right coronary arteries. 2. Noradrenaline induced a dose-dependent vasoconstriction in incubated vessel rings. Prazosin and phentolamine were potent and competitive antagonists for NA-induced contraction (pA2 10.27 and 9.03, respectively). In contrast, the selective alpha 2-adrenoceptor antagonist yohimbine had a low affinity (pA2 6.13). Two selective alpha 1A-adrenoceptor antagonists, WB 4101 and 5-methyl urapidil, were potent and competitive antagonists of alpha 1-adrenoceptor-induced contraction (pA2 10.67 and 8.90, respectively) and the selective alpha 1D-adrenoceptor antagonist BMY 7378 had a low affinity (pA2 6.06). Noradrenaline-induced contraction was insensitive to the alkylating effects of chlorethylclonidine. These observations indicate that the vasoconstriction is predominantly mediated by the alpha 1A-adrenoceptor subtype. This was also supported by a good correlation between pA2 values from the present study and reported binding affinities (pKi) of various alpha-adrenoceptor antagonists with cloned human alpha 1A-adrenoceptors (r = 0.98), but not for alpha 1B- or alpha 1D-adrenoceptor subtypes (r = 0.77 and 0.41, respectively). 3. Our results indicate that the alpha 1A-adrenoceptor is the main functional receptor subtype in porcine denuded coronary arteries.