1605 BISPHENOL-A INDUCES URINARY VOIDING DYSFUNCTION IN ADULT MALE MICE

Vol. 189, No. 4S, Supplement, Tuesday, May 7, 2013

THE JOURNAL OF UROLOGY姞

1603 PERIURETHRAL FIBROSIS SECONDARY TO PROSTATIC INFLAMMATION CAUSING LOWER URINARY TRACT SYMPTOMS: A PROSPECTIVE COHORT STUDY Francesco Cantiello, Antonio Cicione, Catanzaro, Italy; Riccardo Autorino, Cleveland, OH; Andrea Salonia, Milan, Italy; Rocco Damiano*, Catanzaro, Italy INTRODUCTION AND OBJECTIVES: The etiology of lower urinary tract symptoms (LUTS) remains to be fully elucidated and it is widely recognized that BPH is not the exclusive cause of LUTS in the ageing male. The aim of this clinic study was to investigate the role of peri-urethral fibrosis secondary to chronic prostatic inflammation as a potential contributing factor to the etiology of LUTS in male patients. METHODS: Peri-urethral prostate tissue from 30 consecutive patients who underwent retropubic radical prostatectomy (RRP) for prostate cancer was analyzed. We circumferentially performed 16 peri-urethral core bench biopsies on each radical prostatectomy specimen to evaluate the extent of peri-urethral inflammatory infiltrate and collagen and elastin amount. The clinical and urodynamic findings and the collagen and elastin peri-urethral amount in groups of patients with inflammation or not were compared using Mann Whitney U Test and Pearson Chi Square Test. Spearman correlation analysis tested the association between variables. RESULTS: 21/30 patients (70%) presented inflammatory infiltration and 9/30 (30%) no inflammation. A significant difference was found between the two groups in terms of IPSS score (p⫽ 0.03) and urodynamics findings [Schafer class (p⫽0.01) and Abrams Griffiths number (p⫽0.002)]. The histological evaluation showed a higher collagen quantity (p⫽0.04) and lower albeit not statistically significant elastin amount (p⫽0.19) in the inflammation group. A positive association was observed between IPSS score with inflammation grading (r⫽0.507; p⫽ 0.004) and collagen content (r⫽0.649; p⬍0.001) while IPSS score was correlated negatively with elastin content ( r⫽ -0.565; p⫽0.001). CONCLUSIONS: the prostate inflammation may induce fibrotic changes in peri-urethral prostatic tissues, and this may eventually promote urethral stiffness and LUTS. Table. Spearman correlation analysis (Spearman rho coefficient; p- value) Grading IPSS Inflammation Collagen Elastin IPSS 1.000 0.507; 0.004 0.649; 0.001 -0.565; 0.001 Grading Inflammation

1.000

Collagen Elastin

0.508; 0.001

-0.246; 0.190

1.000

-0.495; 0.005 1.000

Source of Funding: None

1604 CONTRACTIONS OF PROSTATES FROM SPONTANEOUSLY HYPERTENSIVE RATS ARE EFFICIENTLY INHIBITED BY SILODOSIN Roberta Buono*, Paolo Dell’Oglio, Giovanni La Croce, Fabio Benigni, Francesco Montorsi, MILAN, Italy; Petter Hedlund, Linkoping, Sweden INTRODUCTION AND OBJECTIVES: Silodosin, a highly selective ␣1A- AR antagonist improves lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). Hypertension is a risk factor for BPH and LUTS. Silodosin reduce bladder dysfunction in spontaneously hypertensive rats (SHR). It is not known if silodosin has similar effect on prostate contractility in individuals with or without hypertension. We therefore compared the effects of silodosin, tamsulosin (moderate ␣1A and ␣1D selective AR antagonist) and Y27632 (Rho-kinase inhibitor) on nerve-induced contractions of prostates from SHR and Wistar-Kyoto (WKY) controls without hypertension. METHODS: After ethical approval, prostate preparations from 4 month old SHR (n⫽10) and WKY (n⫽9) rats were functionally evaluated in organbaths. A Grass Polygraph and a Biopac system recorded

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isometric tension. Nerves were transmurally activated by electrical field stimulation (EFS) with a Grass S48 stimulator (20Hz). Concentrationresponse curves (0.1-100␮M) for silodosin, tamsulosin, or Y27632 were determined. The pIC50 values were determined by linear interpolation. An ANOVA was used for statistical comparisons. RESULTS: Resting tensions (RT), responses to 60mM potassium (K), and contractions to EFS were similar for prostate preparations from all rats. For WKY, RT, K and EFS were 1.2⫾0.1, 0.21⫾0.03, and 0.10⫾0.02 mN. Corresponding values were 1.4⫾0.1, 0.22⫾0.03, and 0.12⫾0.02 mN for SHR. All the investigated drugs concentrationdependently inhibited EFS-induced contractions of prostate preparations from WKY and SHR with maximal inhibitory activities (Emax) at 100␮M. For silodosin, Emax was 76⫾8% (p⬍0.05 vs Y27632) and 94⫾8% (p⬍0.05 vs tamsulosin) in prostate preparations from WKY and SHR, respectively. In comparison, Emax for tamsulosin was 44⫾8% in WKY and 42⫾5% in SHR (both p⬍0.05 vs silodosin and Y27632). Y27632 reduced EFS contractions by 90⫾9% (p⬍0.05 vs silodosin and tamsulosin) in WKY and 93⫾5% in SHR (p⬍0.05 vs WKY). The pIC50 values were similar for the three drugs in prostate preparations from WKY. In SHR prostate preparations, the pIC50 were 5.4⫾0.3 (silodosin), 5.3⫾0.2 (Y27632), and ⬎4 (tamsulosin; p⬍0.05). CONCLUSIONS: Silodosin and Y27632 have equal potency and efficacy to inhibit contractions of SHR prostate preparations. Tamsulosin is less active. Considering the uroselectivity of silodosin, the current data may suggest that this ␣1-AR antagonist could be a preferred choice in the treatment of BPH LUTS in patients with hypertension. Source of Funding: the Gester Foundation, the Urological Research Institute

1605 BISPHENOL-A INDUCES URINARY VOIDING DYSFUNCTION IN ADULT MALE MICE Tristan Nicholson*, Madison, WI; Ronald Wood, Rochester, NY; Glen Leverson, Madison, WI; Barry Timms, Vermillion, SD; Frederick vom Saal, Columbia, MO; William Ricke, Madison, WI INTRODUCTION AND OBJECTIVES: Bisphenol-A (BPA) was originally developed as a synthetic estrogen and is now a component of polycarbonate plastics and epoxy resins used to line food and beverage containers. BPA is detectable in the urine of ⬎90% of Americans and has been implicated in a wide range of human health problems. While BPA exposure during development is known to cause male urogenital malformations in animal models, its effects on adult lower urinary tract symptoms (LUTS) have not been explored. We designed a study to elucidate the effects of adult BPA exposure on the urinary voiding behavior of male mice, supplemented with testosterone to mimic the hormonal milieu of older men. METHODS: Adult male C57bl/6 mice underwent subcutaneous implantation with slow release pellets of 25 mg testosterone (T) plus 25 mg BPA or 2.5 mg 17␤-estradiol (E2). Mice treated with T⫹BPA were compared to mice treated with T⫹E2 (positive controls) and to mice that underwent sham surgery but were not implanted with a pellet (UNT). We placed mice in metabolic cages suspended over a precision balance to measure uroflow non-invasively for one month prior to, and for four months after treatment. At necropsy, we evaluated bladders from mice treated with T⫹BPA and compared volume and mass to UNT and positive controls. RESULTS: As expected, relative to UNT mice, T⫹E2-treated positive controls showed bladder hypertrophy and significantly decreased median uroflow (P ⬍ 0.0001) in all months following treatment; an increased proportion of short duration, small volume voids (droplet voiding) was also observed (P ⬍ 0.0001). Mice treated with T⫹BPA had significantly larger bladder volumes (P ⬍ 0.01) and mass (P ⬍ 0.01) than UNT mice, but bladder hypertrophy was less severe that in T⫹E2-treated mice (P ⬍ 0.01). While voiding dysfunction among mice treated with T⫹BPA was not observed in early time points, 80% of mice displayed predominantly droplet voiding after four months of hormone treatment.

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THE JOURNAL OF UROLOGY姞

CONCLUSIONS: BPA is ubiquitous in the environment and exposure occurs throughout the lifespan. To our knowledge, this is the first demonstration that exposure of adult mice to BPA leads to male urinary voiding dysfunction, similar to the effects observed with estrogen treatment. This finding is consistent with the known weakly estrogenic effects of BPA and implicates this endocrine disruptor as a potential contributor to male LUTS. Source of Funding: R01DK093690, R01CA123199, RC2ESO18764, R01DK075036, T32GM07356 and F30DK093173

1606 FUNCTIONAL PLASTICITY OF AUTONOMIC PELVIC GANGLIA IN RAT MODELS OF OVERACTIVE BLADDER Hyunchul Chung*, Seong Woo Jeong, Jae Mamm Song, Choong Ku Lee, Wonju, Korea, Republic of INTRODUCTION AND OBJECTIVES: Bladder outlet obstruction (BOO) in benign prostatic hyperplasia (BPH), a common problem affecting elderly men, caused urinary symptoms such as urgency, frequency, incomplete bladder emptying, and weak urine flow. Overactive bladder (OAB) is a syndrome characterized by urinary urgency with frequency and nocturia. Peripheral autonomic major pelvic ganglion (MPG) neurons are essential for the generation of storage and voiding reflexes. Under certain pathophysiological conditions such as spinal cord injury and chronic cystitis, plastic alterations in MPG neurons may cause abnormal functions of the bladder. But neurogenic mechanisms underlying OAB remain poorly understood. The hypothesis of the present study is that OAB is associated with changes in functions of MPG and dorsal roots ganglion (DRG) neurons in bladder outlet obstruction (BOO) rat models. METHODS: We were examined whether partial BOO alters expression and activity of nicotinic acetylcholine receptors (nAChRs) involved in synaptic transmission within MPG, and excitability of MPG and DRG neurons innervating the urinary bladder. Toward this end, rat models of partial urethral obstruction (PUO) and BPH were produced by partial urethra ligation and sc injection of testosterone/17-ƒò-estradiol, respectively. Cystometry were performed, indicating development of OAB. Real-time PCR analysis showed that the nAChRs ƒÑ3 and £4 subunits were up-regulated in MPG neurons of BOO rats. Then, nAChR currents were measured in DiI-labeled sympathetic and parasympathetic MPG neurons innervating the bladder detrusor muscles. RESULTS: nAChR current densities were significantly increased in parasympathetic MPG neurons, but not in sympathetic PG neurons. Under the current-clamp mode of the patch-clamp technique, action potentials were recorded in DRG and MPG neurons of control and BOO rats. BOO produced hyperexcitability of the bladder DRG and MPG neurons via reducing rheobase and AHP duration. One of the ionic mechanisms underlying the hyperexcitability is up-regulation of T-type Ca2⫹ channels expressed in DRG and sympathetic MPG neurons. The decreased AHP duration also suggest that expression of Ca2⫹-activated Cl- and/or K⫹ (i.e., SK channels) might be altered in the bladder DRG and MPG neurons of BOO rats. CONCLUSIONS: BOO-induced OAB might be associated with enhanced ganglionic transmission and/or hyperexcitability of peripheral autonomic motor and sensory neurons innervating the bladder. Clinically, use of T-type Ca2⫹ channel blockers might be a potential option of pharmacologic management of OAB. Source of Funding: None

1607 VALIDATION OF THE UWIN SCORE WITH THE AUA SYMPTOM SCORE IN 397 PATIENTS Khadijah Eid*, Kevin Krughoff, Jason Phillips, Colin O’Donnell, Mayer Salfiti, Al Barqawi, Denver, CO INTRODUCTION AND OBJECTIVES: The American Urological Association Symptoms Score (AUA⫺SS) is complex for many

Vol. 189, No. 4S, Supplement, Tuesday, May 7, 2013

patients and can be misunderstood. The UWIN (urgency, weak stream, incomplete emptying and nocturia) questionnaire was developed to serve as a simpler and shorter version of the AUA⫺SS, with the intent of improving accuracy and minimizing error in assessing lower urinary tract symptoms. Both the AUA⫺SS and the UWIN share the final quality of life question. However, the UWIN consists of four questions scored 0 to 3 to give a maximum score of 12 as compared to the AUA⫺SS which consists of 7 questions scored 0⫺5 to give a maximum score of 35. We present the first validation of the UWIN questionnaire with the AUA⫺SS in the clinical setting to assess lower urinary tract symptoms (LUTS) and quality of life score. METHODS: Data was collected prospectively from September 2011 to January 2012 on 397 patients who filled out the UWIN and AUA⫺SS during the same visit at our BPH clinic. Data was collected and analyzed using Spearman correlation coefficients. RESULTS: Spearman correlation coefficients were calculated between the corresponding AUA⫺SS and UWIN items on 397 matched surveys, demonstrating a statistically significant (⬍.01) strong correlation coefficient of 0.81 or greater with for all items. The correlation coefficient between the total scores of the AUA and UWIN was 0.88. When comparing the quality of life question the correlation coefficient was 0.86. The correlation coefficients between the two tests were 0.82 for urgency, 0.88 for weak urinary stream, 0.86 for incomplete emptying, and 0.82 for nocturia. CONCLUSIONS: Based on these results, the UWIN appears to provide statistically significant comparable results to the AUA⫺SS while using a simpler format and taking less time to complete. Further evaluation with larger samples is needed to further validate the strength of these findings. A subset of patients will be evaluated with urodynamic workup to support the present findings. Source of Funding: None

1608 SPONTANEOUS CONTRACTIONS IN THE TRANSITION ZONE OF PROSTATES FROM MEN WITH BENIGN PROSTATIC HYPERPLASIA OR ENLARGEMENT ARE NOT BLOCKED BY TAMSULOSIN Betty Exintaris*, Basu Chakrabarty, Mark Frydenberg, Nathan Lawrentschuk, Gail Risbridger, Melbourne, Australia INTRODUCTION AND OBJECTIVES: Lack of fundamental understanding of the basic biology of the prostate gland remains a significant barrier to developing new and more effective treatments for benign prostatic hyperplasia (BPH). Our overall hypothesis is that age-related changes in the mechanisms regulating spontaneous activity of the prostate gland, significantly contribute to the pathogenesis of BPH. In this study, we characterized the spontaneous contractile activity of the transition zone in fresh specimens from 20 men (⬍65yo) and showed no significant reduction in activity by the clinically used alpha 1 antagonist tamsulosin. METHODS: Transition zone tissue (10 mm ⫻ 15 mm) from the prostate gland was obtained from consenting patients undergoing transurethral resection of prostate or radical prostatectomy. Transition zone tissue was placed into ice-cold RPMI medium supplemented with 5% fetal calf serum and antibiotics (penicillin at 300 units/ml, streptomycin at 300 ␮g/ml and amphotericin at 1 ␮g/ml). Contractile recordings were made from prostatic preparations (5 mm ⫻ 10 mm) using standard tension recording techniques as we have previously described. RESULTS: All specimens contracted spontaneously at a frequency of 1.9 ⫹/⫺ 0.3 contractions per minute; the duration of each contraction was ⬎15 seconds. The basal tension was 4.9 ⫹/⫺ 0.3 mN and the amplitude was 0.3 ⫹/⫺ 0.1N/g. Spontaneous contractions were abolished in 71% of preparations by the clinically used, L-type Ca2⫹ channel blocker, 1␮M nifedipine (n⫽7). Current pharmacotherapy for this condition aims to reduce the size, or to reduce the smooth muscle tone of the prostate. Although alpha 1 antagonists are currently used to reduce the elevated smooth muscle tone, tamsulosin (0.1-