Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) are highly prevalent in older men. Medical therapy is the first-line treatment for LUTS associated with BPH. Mainstays in the treatment of male LUTS and clinical BPH are the α1-adrenergic receptor antagonists. Silodosin is a new α1-adrenergic receptor antagonist that is selective for the α1A-adrenergic receptor. By antagonizing α1A-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. Since silodosin has greater affinity for the α1A-adrenergic receptor than for the α1B-adrenergic receptor, it minimizes the propensity for blood pressure-related adverse effects caused by α1B-adrenergic receptor blockade. In the clinical studies, patients receiving silodosin at a total daily dose of 8 mg exhibited significant improvements in the International Prostate Symptom Score and maximum urinary flow rate compared with those receiving placebo. Silodosin showed early onset of efficacy for both voiding and storage symptoms. Furthermore, long-term safety of silodosin was also demonstrated. Retrograde or abnormal ejaculation was the most commonly reported adverse effect. The incidence of orthostatic hypotension was low. In conclusion, silodosin, a novel selective α1A-adrenergic receptor antagonist, was effective in general and without obtrusive side effects. This review provides clear evidence in support of the clinical usefulness of silodosin in the treatment of LUTS associated with BPH.

Abbreviations & Acronyms a1-AR = a1-adrenoceptor a1A-AR = a1A-adrenoceptor AE = adverse effects BOO = bladder outlet obstruction BOOI = bladder outlet obstruction index BPH = benign prostatic hyperplasia CI = confidence interval CP/CPPS = chronic prostatitis/chronic pelvic pain syndrome DE = disorders of ejaculation GRA = global response assessment HR-QOL = health-related quality of life IPSS = International Prostate Symptom Score ITT = intention to treat LOCF = last observation carried forward LUTS = lower urinary tract symptoms LUTS/BPH = lower urinary tract symptoms associated with benign prostatic hyperplasia mRNA = messenger ribonucleic acid NIH-CPSI = National Institutes of Health Chronic Prostatitis Symptom Index Pdet•Qmax = detrusor pressure at maximal flow PI = prostate implantation PP = per protocol PVR = post-void residual urine Qmax = maximal flow rate RE = retrograde ejaculation SF-12 = Medical Outcomes Study Short Form 12 SIL + EjD = silodosin-treated group with ejaculation disorder SIL -EjD = silodosin-treated group without ejaculation disorder TEAE = treatment emergent adverse effects. Abstract: Lower urinary tract symptoms associated with benign prostatic hyperplasia are highly prevalent in older men. Pharmacological treatment is the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia. The first choice in the pharmacological treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia is the a1-adrenoceptor antagonists. Many a1-adrenoceptor antagonists are available in the world. Silodosin is an a1-adrenoceptor antagonist developed by Kissei Pharmaceutical, and has a specific selectivity for the a1A-adrenoceptor subtype. By antagonizing a1A-adrenoceptor in the prostate and urethra, silodosin causes smooth muscle relaxation in the lower urinary tract. As a result of the high affinity for the a1A-adrenoceptor than for the a1B-adrenoceptor, silodosin minimizes the propensity for blood pressure-related adverse effects caused by blockade of a1B-adrenoceptor. The efficacy and safety of silodosin for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia was first reported by Japanese investigators in 2006. At present, silodosin is used in many countries. In the present review, we summarize the new clinical evidence for lower urinary tract symptoms associated with benign prostatic hyperplasia and introduce the data supporting the new clinical indications of silodosin.Key words: a1A adrenergic receptor subtypes, a1-adrenoceptor antagonists, benign prostatic hyperplasia (BPH), lower urinary tract symptoms (LUTS), silodosin.

Objectives: To clarify the contribution of mucosal muscarinic receptors to bladder function, we investigated the effects of various antimuscarinic drugs on stretch‐induced non‐neuronal adenosin triphosphate (ATP) release in human bladder. Methods: Human bladders were obtained from 17 patients. Bladder strips with and without mucosa were suspended in organ baths. A microdialysis probe was inserted into the strip, Ringer's solution was perfused into the probe, and dialysate was collected under tetrodotoxin pretreatment. The amount of ATP released in dialysate was measured by luciferin‐luciferase assay. The effects of various antimuscarinic drugs on non‐neuronal ATP release were evaluated. Results: Non‐neuronal ATP release from bladder strips without mucosa was approximately 10% of that from strips with mucosa. Non‐neuronal ATP release was significantly inhibited by pretreatment with nifedipine or in Ca2+‐free medium. Both methoctramine (M2 receptor selective antagonist) and 4‐diphenyl‐acetoxy‐N‐methylpiperidine methiodide (4‐DAMP [M3 receptor selective antagonist]) significantly inhibited release. However, M1 receptor selective antagonist (pirenzepine) did not have a significant effect on release. Oxybutynin, propiverine, tolterodine and solifenacin caused concentration‐dependent inhibition in non‐neuronal ATP release. The rank order of the maximum inhibition rate was propiverine ≥ solifenacin ≥ tolterodine ≥ oxybutynin. Solifenacin showed an inhibitory effect at a lower concentration compared to other drugs. Conclusion: The data suggest that human bladder mucosa is a main source of stretch‐induced non‐neuronal ATP release, and that stimulation of M2 and M3 receptor subtypes of mucosa partly contributes to non‐neuronal ATP release. Various antimuscarinic drugs used for the treatment of overactive bladder may have different inhibitory effects on non‐neuronal ATP release.

To evaluate the effects of chronic hyperlipidemia on bladder function, we examined the functional and histological changes of the bladder in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits. Two age groups of WHHL-MI rabbits (6-12 months old, young WHHL-MI rabbits; and 20-24 months old, old WHHL-MI rabbits group) and the sex-and age-matched control rabbits were prepared. Bladder functions were evaluated using frequency volume charts and cystometrograms, and functional experiments using isolated bladder specimens. Histological studies of bladder were performed with HE staining and immunohistochemical staining with mouse monoclonal S-100 protein antibodies and sheep polyclonal calcitonin gene-related peptide (CGRP) antibodies. In cystometrograms, it has been demonstrated that WHHL-MI rabbits showed significantly shorter micturition interval, smaller voided volume with non-voiding contractions compared to control. There was no significant difference in voiding pressure between young WHHL-MI and control rabbits. However, old WHHL-MI rabbits showed a lower voiding pressure than control rabbits. The functional experiments revealed that carbachol-and electrical field stimulation (EFS)-induced contractile responses of isolated bladder strips were significantly increased in young WHHL-MI rabbits than in control rabbits. However, in the bladder strips of old WHHL-MI rabbits, decreased responses to carbachol and EFS were observed. In WHHL-MI rabbits, bladder urothelium became thinner, smooth muscle area decreased and connective tissue area increased gradually with aging. A significant decrease in S-100 protein-positive neurons, and an increased number of CGRP-positive neurons were observed in both young and old WHHL-MI rabbits. The data demonstrated that there were differences in bladder dysfunction between young and old WHHL-MI rabbits. Old WHHL-MI rabbits showed detrusor hyperactivity with impaired contraction. This study may demonstrate the developmental mechanism of bladder dysfunction in chronic hyperlipidemia.

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