Neurourology and Urodynamics Characterization of Silodosin and Naftopidil in the Treatment of Bladder Dysfunction in the Spontaneously Hypertensive Rat Motoaki Saito,* Shogo Shimizu, Fumiya Ohmasa, Ryo Oikawa, Panagiota Tsounapi, Fotios Dimitriadis, Yukako Kinoshita, and Keisuke Satoh Division of Molecular Pharmacology, Tottori University School of Medicine, Yonago, Japan Purpose: As increasing evidence suggest that a 1 -blockers prevent benign prostatic hyperplasia related overactive bladder and nocturia in the human, we investigated the effects of silodosin and naftopidil on hypertension-related bladder dysfunction in the spontaneously hypertensive rat (SHR) model. Materials and Methods: Twelve-week-old male SHRs received no treatment or treatment with silodosin (100 mg/kg, p.o.) or naftopidil (10 or 30 mg/kg, p.o.) once daily for 6 weeks. Wistar rats were used as normotensive controls. After 6-week treatment, voiding functions were estimated by metabolic cages (dark- and light-cycle separately) and cystometric studies. Furthermore, the bladder blood flow (BBF) was measured employing the hydrogen clearance method. Results: SHRs showed significant increases in micturition frequency, and decreases in BBF and single voided volume in both metabolic cages and cysto- metrograms compared to the Wistar group. Treatment with silodosin normalized the decreased BBF, and treatment with naftopidil increased the BBF in a dose-dependent manner in the SHR group. Although treatment with silodosin and the high dose of naftopidil significantly inhibited micturition frequency in one day, only treatment with the high dose of naftopidil significantly inhibited micturition frequency and urine production in the light-cycle compared to the non-treated SHRs. Although treatment with silodosin and the high dose of naftopidil significantly increased single voided volume, only treatment with silodosin significantly inhibited non-voiding contractions in the cystometrgrams. Conclusion: Our data suggest that both silodosin and naftopidil improve hypertension-related bladder dysfunction in the SHR, and naftopidil but not silodosin improves urinary frequency in the light-cycle due to inhibition of urine production. Neurourol. Urodynam. ß 2012 Wiley Periodicals, Inc. Key words: bladder blood flow; bladder dysfunction; naftopidil; SHR; silodosin INTRODUCTION Lower urinary tract symptoms (LUTS) are common disease in elderly men, having such as urinary frequency, weak stream, and urgency. The a 1 -blockers are the most frequently prescribed therapeutic agents for patients with LUTS sugges- tive of benign prostatic hyperplasia (BPH). 1 Overactive bladder (OAB) represents a recently defined constellation of LUTS that includes urinary urgency, frequency, and nocturia, with or without urge incontinence. 2 Medical therapy using a 1 -blocker against BPH-related various symptoms was first reported by Caine et al. 3 using a non-selective a-blocker, phenoxybenz- amine. Since then, many reports suggest that medical treat- ment with a 1 -blocker is the first line therapy against BPH related LUTS. Naftopidil and silodosin are now both widely used in Japan for treating LUTS associated with BPH. 4,5 Nafto- pidil is a relatively selective a 1D -adrenoceptor antagonist, whereas silodosin is a highly selective a 1A -adrenoceptor an- tagonist. 6,7 Takahashi et al. 4 reported that naftopidil improves not only voiding symptoms but also storage symptoms, and is effective for nocturia in patients with BPH regardless of the existence of nocturnal polyuria. Moreover, Yokoyama et al. 8 reported that naftopidil improved nocturnal polyuria regard- less of the presence of sleep disturbance, meaning that it might directly reduce nocturnal urine production. Recently, Chapple et al. 1 reported that silodosin is an effective and well- tolerated treatment for the relief of both voiding and storage symptoms in patients with LUTS suggestive of bladder outlet obstruction (BOO) thought to be associated with BPH and that silodosin showed a significant effect on nocturia over placebo. Taken together, these two a 1 -blockers should be effective for not only voiding symptoms but also storage symptoms in patients with LUTS associated with BPH. Pinggera et al. 9 reported that LUTS are associated with chronic ischemia of the prostate and bladder, and that a 1 -blockers improve chronic is- chemia of the lower urinary tract in patients with LUTS. Okutsu et al. 10 reported that a 1 -blocker, tamsulosin improved detrusor overactivity (DO) via improvement of bladder blood flow in the rat with bladder outlet obstruction. These reports indicated that one of the main mechanisms of a 1 -blockers to ameliorate LUTS is to improve chronic ischemia in the bladder and prostate. Spontaneously hypertensive rats (SHRs) develop bladder hy- peractivity, and the SHR is considered a valuable tool for ex- ploring the pathogenesis of hypertension-related bladder dysfunction. 11 Previously, the SHR has shown to be a signifi- cant decrease in bladder blood flow (BBF) and an increase in voiding frequency compared to the non-hypertensive Wistar rat. 12,13 It is reported that daily treatment with six-weeks of silodosin significantly improves BBF and voiding frequency in the SHR. 14 Silodosin treatment improves hypertension-related Conflict of interest: MS: Speakers and research grants from Asahi-Kasei Pharma and Daiichi-Sankyo. Grant sponsor: Ministry of Education, Science, and Culture of Japan; Grant num- bers: 20591880, 24592431. *Correspondence to: Motoaki Saito, MD, PhD, Division of Molecular Pharmacology, Tottori University School of Medicine, 86 Nishimachi, Yonago 683-8503, Japan. E-mail: saitomo@med.tottori-u.ac.jp Received 30 May 2012; Accepted 10 July 2012 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22297 ß 2012 Wiley Periodicals, Inc.