silodosin and Disease-Models--Animal

Benign prostatic hyperplasia (BPH) is an age-related disease, affecting a majority of elderly men worldwide. Medical management of BPH is an alternative to surgical treatment of this disease. Currently, α1-adrenergic receptor (α1-AR) antagonists are among the first line drugs to treat BPH by reducing the tension of urinary track and thus the obstructive symptoms in voiding. In drug development, old male dogs with spontaneous BPH are considered the golden standard of the animal models. However, old dogs (>6 years) are expensive and not all old dogs develop BPH. So it is necessary to develop more accessible animal models for drug efficacy evaluation. Here we describe the development of testosterone-induced BPH models in both rats and young adult dogs and their applications in the in vivo evaluation of α1-AR antagonist. The BPH rats and dogs induced by chronic testosterone treatment have significantly increased micturition frequency and reduced mean voided volume, very similar to the clinical symptoms of BPH patients. Silodosin, an α1-AR antagonist, significantly reduces the urinary frequency and increases the voided volume in BPH model animals in a dose-dependent manner. The results demonstrate that testosterone-induced BPH rat and dog models might provide a more efficient way to evaluate micturition behavior in anti-BPH drug studies.

Topics: Adrenergic alpha-1 Receptor Antagonists; Aged; Animals; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Female; Humans; Indoles; Lower Urinary Tract Symptoms; Male; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Testosterone; Urination; Urological Agents

To investigate single or combined effect of silodosin, an α1A-adrenoceptor antagonist, and imidafenacin, an antimuscarinic agent, on bladder function in a subacute bladder outlet obstruction (BOO) model of male rats.. Partial BOO was created in male Wistar rats by ligating the urethra with a steel rod. On day 10 after surgery, when frequent voiding was most remarkable on voiding behavior measurement in a metabolic cage, cystometric investigations in a conscious restrained condition were conducted with cumulative intravenous administration of silodosin alone (0.1, 1, 10, and 100 µg/kg), imidafenacin alone (1, 3, and 10 µg/kg), or a combination of the two drugs.. When compared with the Sham rats, the BOO rats showed an increase in bladder capacity, residual volume, mean amplitude and the number of non-voiding contractions (NVCs), accompanied with an increase in bladder weight. In the BOO rats, silodosin alone at 100 µg/kg significantly decreased the number of NVCs, whereas imidafenacin alone at 3 and 10 µg/kg significantly decreased both the number and mean amplitude of NVCs. The combination administration with lower doses (silodosin at 10 µg/kg and imidafenacin at 1 µg/kg) significantly suppressed both the number and mean amplitude of NVCs.. The present results indicate a suppressive effect of silodosin or imidafenacin alone and a synergic effect of the combination of these two drugs on NVCs in a subacute BOO model of male rats.

Topics: Acute Disease; Animals; Disease Models, Animal; Drug Combinations; Imidazoles; Indoles; Male; Muscarinic Antagonists; Muscle Contraction; Organ Size; Rats, Wistar; Urinary Bladder; Urinary Bladder Neck Obstruction; Urination; Urological Agents

We investigated the effects of silodosin (selective α. Adult male Sprague-Dawley rats (n = 32) were divided into four groups: (i) sham-operated control; (ii) silodosin-treated (sham) control (0.1 mg/kg/day); (iii) partial bladder outlet obstruction (PBOO); and (iv) silodosin-treated with PBOO. PBOO was induced by ligation of the urethra for 6 weeks. In vivo, erectile responses were monitored by evaluating ratios of intracavernosal pressure (ICP)/mean arterial pressure (MAP). Organ-bath studies were performed on corpus cavernosum (CC) strips. Penises were assessed at baseline for protein expression of neuronal nitric oxide synthase (nNOS) and Rho-associated protein kinase (ROCK2) by Western blot. Immunohistochemistry and Masson trichrome staining were performed for analysis of nNOS protein levels and tissue alterations.. The ratio of ICP/MAP was significantly decreased in obstructed rats (0.26 ± 0.043, P < 0.01) compared to sham-control rats (0.64 ± 0.10), which was restored by the treatment (0.59 ± 0.14, P < 0.01) compared with obstructed rats. Relaxation responses were significantly reduced in strips from the obstructed group. Silodosin restored nitrergic relaxant responses. nNOS expression in the obstructed group decreased, which was improved by treatment. The decreased smooth muscle/collagen ratio in the bladder obstructed group was reversed by the treatment.. Silodosin improves erectile function in obstructed rats. Further clinical trials are needed to explore fully the potential benefits of silodosin in patients with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in association with ED. Neurourol. Urodynam. 36:597-603, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Disease Models, Animal; Erectile Dysfunction; Indoles; Male; Muscle, Smooth; Nitric Oxide Synthase Type I; Penile Erection; Penis; Rats; Rats, Sprague-Dawley; Urinary Bladder Neck Obstruction; Urological Agents

There were several reports suggesting α-adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of α-adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved.. We used 130 male Sprague-Dawley rats. After root constriction, rats received three local injections of α-adrenoceptor antagonists around DRG. We administered the non-selective α-adrenoceptor antagonist phentolamine for 3 consecutive days from day 0, 4 or 11 after the surgery, and the α1-adrenoceptor antagonist prazosin, the α1-adrenoceptor antagonist silodosin, the more preferred α1-adrenoceptor than prazosin and the α2-adrenoceptor antagonist yohimbine for 3 consecutive days from day 0 after the surgery.. Phentolamine and yohimbine continually attenuated pain behaviour. Prazosin at high dose attenuated pain behaviour, however, prazosin at low dose did not attenuate pain behaviour every experimental day. Silodosin had no analgesic effect. Phentolamine injections from day 4 after surgery attenuated pain behaviour that had been established on the 3rd experimental day until the 28th post-operative day, although effect of phentolamine wore off. Phentolamine injections from day 11 after surgery temporarily attenuated pain behaviour that had been established on the 3rd, 7th and 10th experimental days.. This study showed α-adrenoceptor antagonists could suppress pain behaviour via α2-adrenoceptor in acute phase and temporary attenuate pain behaviour in chronic phase. These findings presented potentials sympathetic nerve blockade contributed to treat neuropathic pain.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Behavior, Animal; Disease Models, Animal; Ganglia, Spinal; Indoles; Male; Neuralgia; Pain Measurement; Phentolamine; Prazosin; Radiculopathy; Rats; Rats, Sprague-Dawley; Yohimbine

Clinical studies have shown beneficial role of oral alpha-blockers for ureteral stent-related morbidity. However, the in vivo effects of oral alpha-blockers on a stented ureter are unclear. We evaluated the effects of alpha-blockade on ureteral dynamics in a stented porcine ureter.. Twenty-seven female pigs were used in this study. Fourteen pigs received oral alpha-blocker medication (silodosin, 8 mg daily), and 13 pigs received no medication. Under cystoscopic guidance, a 5F ureteral catheter was positioned in the renal pelvis and attached to a pressure monitor. A Foley catheter was placed in the bladder along with a bladder pressure transducer. A lumbotomy was performed, and the ureter was identified. A magnetic sensor was placed on the extraluminal surface of the ureter to monitor ureteral peristalsis. We measured renal pelvic and bladder pressures, urine output, and ureteral peristalsis every hour for 10 minutes for a total of 5 hours. The pigs were then euthanized.. The mean weight was 42.5 kg in the drug group and 45.9 kg in the nondrug group (p = 0.008). Mean hourly urine output was 140 mL in the drug group and 144 mL in the nondrug group (p = 0.76). Mean baseline renal pressure was 13.2 and 13.8 mm Hg (p = 0.69) in the drug and nondrug groups, respectively. Mean peristaltic renal pelvic pressure was 19.1 mm Hg in the drug group and 19.2 mm Hg in the nondrug group (p = 0.97). Mean number of peristalsis was 11/10 and 14/10 minutes (p = 0.03) in the drug and nondrug groups, respectively.. Alpha-blockade in an in vivo stented porcine ureter resulted in no significant effect on renal pelvic pressure but a significant decrease in the number of ureteral peristalsis. Further investigation of the effects of alpha-blocker on ureteral dynamics is required to better understand its effects on stent-related symptoms.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Animals; Disease Models, Animal; Female; Indoles; Kidney Pelvis; Pressure; Stents; Swine; Ureter; Ureteral Calculi; Urinary Bladder; Urinary Catheterization

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adrenergic alpha-1 Receptor Antagonists; Animals; Blood Flow Velocity; Deoxyguanosine; Disease Models, Animal; Female; Immunohistochemistry; In Situ Hybridization; Indoles; Laser-Doppler Flowmetry; Microcirculation; Nerve Growth Factor; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Regional Blood Flow; Time Factors; Ureteral Obstruction; Urinary Bladder; Urinary Bladder Neck Obstruction; Urination; Urodynamics; Urological Agents

Ejaculation dysfunction is one of the most common male sexual disorders. Despite its prevalence and adverse impact on patients, little attention has been given to investigating ejaculation dysfunction.. We introduce a new method for evaluating ejaculation dysfunction in rats with a telemetric device.. A pressure transducer was surgically implanted in the seminal vesicles of 7-week-old male Sprague-Dawley rats. One week later, the rats were subcutaneously administered tamsulosin 3 μg/kg, and intra-seminal vesicle pressure (ISVP) was recorded in freely moving rats after an injection of apomorphine (80 μg/kg). Same rats repeated experiment with tamsulosin 10 μg/kg, silodosin 1 mg/kg, and normal saline with 3-day intervals.. Sexual events were visually identified and recorded. Ejaculation was confirmed by visualization of a copulatory plug in the tip of the penis. We compared the maximal ISVP and area under the curve (AUC) of the ISVP.. Adequate ISVP data were easily recorded and available in 66.6% rats (10/15) over a 6-week telemetric recording period (12 recordings). The mean number of ejaculations during an inspection time of 30 minutes was 1.5 ± 0.1. The maximal ISVP values in rats receiving 3 μg/kg (30.0 ± 5.2 mm Hg) and 10 μg/kg tamsulosin (15.1 ± 1.6 mm Hg) and 1 mg/kg silodosin (12.9 ± 2.2 mm Hg) were significantly lower than that in control rats (61.4 ± 13.4 mm Hg, P < 0.05). The AUC values in rats receiving 3 μg/kg (72.7 ± 18.9 mm Hg × s) and 10 μg/kg tamsulosin (23.5 ± 6.1 mm Hg) and 1 mg/kg silodosin (23.9 ± 8.0 mm Hg) were also lower than that of control rats (162.6 ± 34.3 mm Hg, P < 0.05).. Telemetric ISVP assessment is reliable and feasible for investigating apomorphine-induced ejaculation in rats. Tamsulosin (3 μg/kg and 10 μg/kg) and silodosin 1 mg/kg decreased the ISVP during ejaculation.

Topics: Animals; Apomorphine; Disease Models, Animal; Ejaculation; Indoles; Male; Penis; Pressure; Rats; Rats, Sprague-Dawley; Seminal Vesicles; Sexual Behavior; Sulfonamides; Tamsulosin; Telemetry; Urological Agents

We investigated the effects of the selective α1A-adrenoceptor antagonist silodosin on bladder blood flow and bladder function in a rat model of atherosclerosis induced chronic bladder ischemia without bladder outlet obstruction.. The chronic bladder ischemia model was prepared by creating balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, chronic bladder ischemia rats received silodosin subcutaneously at a rate of 0.1 or 0.3 mg/kg per day, or vehicle for 8 weeks. All groups received a 2% cholesterol diet throughout the experiment. For each α1-adrenoceptor subtype mRNA expression in bladder microvessels was examined by in situ hybridization. Bladder blood flow was measured using a laser speckle blood flow imager. Malondialdehyde in bladder tissue and 8-hydroxy-2'-deoxyguanosine in urine were measured as markers of oxidative stress. A metabolic cage study and cystometry were performed in conscious rats.. The expression of all α1-adrenoceptor subtype mRNA was observed in rat bladder microvessels. Silodosin abrogated the decreased bladder blood flow in the empty bladder and during bladder distention that were evident in rats with chronic bladder ischemia. Levels of oxidative stress markers in these rats were significantly decreased by silodosin administration. Silodosin ameliorated bladder dysfunction in rats with chronic bladder ischemia in the metabolic cage study and on cystometry.. Results suggest that in ischemic conditions α1-adrenoceptor antagonists such as silodosin may improve bladder function by restoring bladder blood flow.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Atherosclerosis; Blood Flow Velocity; Disease Models, Animal; Glomerular Filtration Rate; Immunohistochemistry; In Situ Hybridization; Indoles; Ischemia; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Urinary Bladder; Urinary Bladder Neck Obstruction

Using a rat BOO model, we determined whether α1-adrenoceptor (AR) antagonists (silodosin, prazosin) improve the bladder storage function by reducing afferent input from the lower urinary tract.. Male rats received partial bladder outlet obstruction or sham surgery were used. Four weeks following surgery, their voiding behavior was measured in a metabolic cage. BOO-rats were administered silodosin, prazosin or vehicle for 2 weeks subcutaneously using osmotic pump. At the post-drug condition, voiding behavior was measured again. The L6 spinal cord was removed and immunostained using anti c-Fos antibody. The rats were also performed continuous cystometry with saline without anesthesia or restraint at the pre- and post-drug conditions.. Metabolic cage study showed the voiding behavior of BOO-rats was characterized by increase in frequency of urination and decrease in volume voided. Cystometric evaluation also showed the significant increase both in the number of successive voiding contraction and in contraction pressure. The administration of silodosin or prazosin significantly decreased urinary frequency and the number of micturition reflex but affected neither bladder contraction pressure nor residual volume. The number of c-Fos-positive cell significantly increased in BOO-rats, while significantly decreased in those receiving αl-AR antagonists.. The present study demonstrates that α1-AR antagonists silodosin and prazosin have an inhibitory effect on afferent input from the lower urinary tract independently of reducing urethral resistance, and thereby reduce the storage dysfunction secondary to BOO. This result suggests that αl-AR, particularly αlA-AR, may play an important role in the activation of the afferent pathway.

Topics: Adrenergic alpha-1 Receptor Antagonists; Afferent Pathways; Analysis of Variance; Animals; Disease Models, Animal; Indoles; Infusions, Subcutaneous; Lumbosacral Region; Male; Prazosin; Pressure; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Reflex; Spinal Cord; Time Factors; Urinary Bladder; Urinary Bladder Neck Obstruction; Urination; Urodynamics

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.. 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.. 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.. 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.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Disease Models, Animal; Female; Indoles; Male; Prazosin; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Sulfonamides; Tamsulosin; Urinary Incontinence