Selective alpha1A-adrenoceptor Antagonist Research Articles

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.

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.

Long-Term Evaluation of Tamsulosin in Benign Prostatic Hyperplasia: Placebo-Controlled, Double-Blind Extension of Phase III Trial

Objectives. To evaluate the long-term efficacy and safety of once-daily tamsulosin (0.4 and 0.8 mg), a unique selective alpha 1A-adrenoceptor antagonist in patients with benign prostatic hyperplasia (BPH). Methods. This trial extended a 13-week, Phase III multicenter placebo-controlled, double-blind outpatient trial for an additional 40 weeks. Of 618 patients, 418 (68%) continued into the extension phase on the same double-blind medication and dose. The primary efficacy parameters were total American Urological Association (AUA) symptom score and maximum urinary flow (Qmax). Results. The mean changes in AUA symptom score from baseline to end point were statistically significant in all groups ( P <0.001). Significant improvements were observed in Qmax for both tamsulosin groups but not for the placebo group. The statistically significant improvements from baseline in efficacy parameters observed for each tamsulosin group at the end of the 13-week Phase III trial were maintained during the long-term extension phase. Tamsulosin at both dosages was well tolerated as maintenance therapy. Clinically significant orthostatic hypotension was not observed. Vital sign changes in either hypertensive or normotensive patients were not clinically significantly different across the three groups. Conclusions. Tamsulosin once-daily at 0.4 or 0.8 mg was shown to be effective, safe, and well tolerated in the target BPH population during long-term use.

Exacerbation of reperfusion arrhythmias by 1 adrenergic stimulation: a potential role for receptor mediated activation of sarcolemmal sodium-hydrogen exchange

Stimulation of myocardial alpha 1 adrenoceptors causes (1) exacerbation of reperfusion induced arrhythmias, and (2) stimulation of sarcolemmal Na+/H+ exchange. The aims of this study were to identify the alpha 1 adrenoceptor subtype involved in the former effect and to determine whether stimulation of the Na+/H+ exchanger may play a role in this phenomenon. Isolated rat hearts were subjected to independent perfusion of the left and right coronary beds. After 15 min of aerobic perfusion of both beds, the alpha 1 adrenoceptor agonist phenylephrine (0.1, 1, or 10 microM) was infused selectively into the left coronary bed for 2 min. The left coronary bed was then subjected to 7 min of zero flow ischaemia and 5 min of reperfusion. The incidence of reperfusion induced ventricular fibrillation was increased from 0% in controls to 8%, 42%*, and 75%* with 0.1, 1, and 10 microM phenylephrine (*P < 0.05); this dose dependent effect occurred in the absence of significant intergroup differences in vascular resistance or heart rate. Similar infusion of methoxamine at 10 microM also increased the incidence of reperfusion induced ventricular fibrillation from 13% to 88%*. Infusion of 10 microM phenylephrine during reperfusion alone did not affect the incidence of reperfusion induced ventricular fibrillation. Infusion of the selective alpha 1A adrenoceptor antagonist WB4101 at 0.1, 1, or 10 microM for 2 min immediately before ischaemia (concomitantly with 10 microM phenylephrine) reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 75%, 25%*, and 0%*. Similar infusion of the selective alpha 1B adrenoceptor antagonist chloroethylclonidine (0.1 or 1 microM) or the selective beta 1 adrenoceptor antagonist atenolol (0.1 or 1 microM) did not reduce the incidence of reperfusion induced ventricular fibrillation. The novel NHE-1 selective Na+/H+ exchange inhibitor HOE694 (10 microM), when infused into the left coronary bed before ischaemia (concomitantly with 10 microM phenylephrine) and throughout reperfusion, reduced the incidence of reperfusion induced ventricular fibrillation from 83% to 25%*. In hearts that received 10 microM phenylephrine before ischaemia. HOE694 (10 microM) was partially effective when infused during reperfusion alone (ventricular fibrillation incidence reduced from 83% to 42%). (1) the exacerbation of reperfusion induced arrhythmias by alpha 1 adrenergic stimulation during ischaemia is mediated by the alpha 1A adrenoceptor subtype, and (2) increased Na+/H+ exchanger activity during ischaemia and reperfusion may play a causal role in this phenomenon.

Alpha 1b-adrenoceptors mediate renal tubular sodium and water reabsorption in the rat.

1. It is known that activation of alpha 1-adrenoceptors causes renal vasoconstriction and increased tubular Na+ and water reabsorption, with the alpha 1a-subtype mediating the constrictor effect. 2. This study examines which subtype of alpha 1-adrenoceptors mediates tubular Na+ and water reabsorption in pentobarbitone-anaesthetized rats. In order to avoid systemic effects, phenylephrine (0.3 to 30 micrograms kg-1), methoxamine (0.1-10 micrograms kg-1) and vehicle were infused into the right renal artery (via the suprarenal artery) of three groups of rats. Two other groups of rats were continuously infused with the irreversible selective alpha 1b-adrenoceptor antagonist, chloroethylclonidine (3 mg kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine or methoxamine. Another group was continuously infused with the irreversible selective alpha 1a-adrenoceptor antagonist, SZL-49 (10 micrograms kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine. Mean arterial pressure (MAP), heart rate (HR), urine flow, Na+ and K+ excretion, and urine osmolality were monitored. 3. Phenylephrine and methoxamine did not affect MAP or HR but dose-dependently and significantly decreased urine flow, urine osmolality as well as Na+ excretion and, slightly increased K+ excretion, although this was significant only for phenylephrine. 4. The antidiuretic, antinatriuretic and kaliuretic effects of phenylephrine were abolished by pretreatment with chloroethylclonidine, but were not inhibited by SZL-49. The inhibitory effects of methoxamine on urine flow and Na+ excretion were also almost totally abolished by chloroethylclonidine. 5. Our results show that alpha 1b-adrenoceptors mediate renal tubular Na+ and water reabsorption.

Alpha 1-adrenoceptor-mediated Ca(2+)-entry from the extracellular fluid and Ca(2+)-release from intracellular stores: no role for alpha 1A,B-adrenoceptor subtypes in the pithed rat.

1. In the present study, we tested the hypothesis that in the pithed rat preparation two subtypes of the alpha 1-adrenoceptor are linked to two different signal transduction mechanisms, both of which contribute to vasoconstriction, one facilitating Ca(2+)-entry from the extracellular fluid (alpha 1A) and one promoting the release of Ca2+ from intracellular sources (alpha 1B). 2. The selective alpha 1A-adrenoceptor antagonist, 5-methyl-urapidil, and the selective alpha 1B-adrenoceptor antagonist, chloroethylclonidine, were unable to discriminate between alpha 1-adrenoceptor-mediated pressor responses, which relied on an entry of extracellular Ca2+ sensitive to nifedipine and an intracellular release of Ca2+ insensitive to nifedipine, respectively. 3. Chloroethylclonidine, 12.5 and 25 mg kg-1 i.v., were equieffective, and had only minor effects on alpha 1-adrenoceptor-mediated increases in diastolic blood pressure. This could be associated with a small decrease in the receptor-reserve of the pithed rat preparation due to irreversible receptor blockade by this antagonist. These data indicate that chloroethylclonidine-sensitive alpha 1-adrenoceptors constitute only a minor fraction of the total alpha 1-adrenoceptor population on rat arterial resistance vessels. 4. Chloroethylclonidine behaved as a partial agonist eliciting a small increase in baseline diastolic blood pressure which could be inhibited by Ca(2+)-entry blockade with nifedipine. 5. Chloroethylclonidine potentiated the pressor responses elicited by the alpha 2-adrenoceptor agonists UK-14,304 and azepexole (B-HT 933). 6. No evidence was found in the pithed rat that alpha 1-adrenoceptor-mediated Ca(2+)-entry from the extracellular fluid and Ca(2+)-release from intracellular stores are mediated by alpha 1A and alpha 1B-adrenoceptors, respectively.