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MP1-15 FUNCTIONAL AND MOLECULAR CHARACTERISTIC OF UNDERACTIVE BLADDER INDUCED BY LUMBAR CANAL STENOSIS IN RATS
THE JOURNAL OF UROLOGYâ
Vol. 191, No. 4S, Supplement, Friday, May 16, 2014
e7
MP1-15
MP1-16
FUNCTIONAL AND MOLECULAR CHARACTERISTIC OF UNDERACTIVE BLADDER INDUCED BY LUMBAR CANAL STENOSIS IN RATS
STRIKING DOSE- AND TIME-DEPENDENCE OF RADIATION CYSTITIS IN THE RAT: WEEKLY CYSTOMETRIC EVALUATION UP TO NINE WEEKS AFTER PELVIC IRRADIATION
Yao-Chi Chuang*, Hung-Jen Wang, Kaohsiung, Taiwan; Naoki Yoshimura, Pittsburgh, PA; Michael Chancellor, Royl Oak, MI
Nicholas J. Kuntz*, Matthew O. Fraser, Danielle J. Degoski, Abhay A. Singh, Paul C. Dolber, Andrew C. Peterson, Durham, NC
INTRODUCTION AND OBJECTIVES: It has been recognized that lumbar canal stenosis (LCS) compromised neurological function is a common problem in elderly patients and may cause underactive bladder (UAB). However, the mechanism and molecular change underlying the UAB is not clear. METHODS: One small hole was drilled at the fifth lumbar vertebral arch (sham), and a rectangular piece of silicone rubber was inserted into the L5¡VL6 epidural space (LCS) of female Sprague-Dawley rats. LCS rats underwent bladder expression twice a day. Before and after surgery, a metabolic cage study was performed. Continuous cystometry (CMG) was performed at day 14, or 28 under urethane anesthesia. The bladder was then harvested for histology, expression of M2 and M3 receptors, NGF, and agrin by western blotting. Some animals received intravesical PGE2 instillation. RESULTS: LCS induced acute urinary retention and progressive increase of bladder weight. The LCS rats showed a significant decrease in voided volume and a significant increase in postvoid residual urine compared with Sham rats. CMG showed that the LCS bladder was no contraction, high compliance and overflow incontinence. Intravesical PGE2 induced decreased bladder compliance, but no recovery of bladder contraction in the LCS rats. In contrast, there was a significant decrease in intercontraction interval (ICI) and increased in contraction amplitude in response to PGE2 in sham rats. LCS rats showed no obvious difference in detrusor morphology (Fig 1), M2, M3 receptor, NGF, and agrin compared with the sham rats. CONCLUSIONS: LCS induced UAB model preserved bladder morphology and functional receptor. It might be a useful model for the mechanism and treatment of neurogenic UAB.
INTRODUCTION AND OBJECTIVES: Radiation therapy (RT) is a common treatment for prostate cancer and other pelvic malignancies. Radiation cystitis (PRC) occurs frequently and is characterized by acute irritative voiding symptoms and chronic hemorrhagic cystitis. We describe the development of a rat model designed to test novel therapeutic strategies for prevention and treatment of PRC. METHODS: Female SD rats (n¼24) received specially fabricated chronic bladder catheters positioned to better maintain the natural position of the bladder for the duration of the experiments (up to 9 weeks) and tunneled subcutaneously to the midscapular region for ready access. One week after catheter implant, the animals received single dose pelvic RT with either 0, 5, 10 or 20 Gy using a small-field biological irradiator (X-RAD 225Cx, Precision X-Ray, Inc.) with a 42 collimator (Exp1) or 0, 20, 30 and 40 Gy with a 2.52 collimator (Exp2). Every week for 4 or 9 weeks thereafter, resp., conscious restrained cystometry was performed with infusion of normal saline, and 300 and 500 mM KCl. The primary outcome measure was bladder capacity (BC) for each infusate at each interval. Data were analyzed using 2-Way RM ANOVA, p<0.05 was considered significant. RESULTS: Statistical analysis revealed a marked and significant inverse relationship between radiation dose and BC for both sets. Exp1 - the 0 and 5 Gy doses had no effect. 10 Gy dose was also without effect until week 4, with w30% drop under saline. The 20 Gy dose resulted in a w50% reduction in BC by Week 1, that evolved to a w60% decrease by Week 4. KCl sensitivity was evident by Week 1 following 20 Gy, and BC was reduced w50% and w75% by 10 and 20 Gy, resp. by Week 4. Exp2 e KCL decreased BC at 3 and 4 weeks for 40 and 30 Gy by 87 and 70%, resp. BC under saline alone was reduced 65% by Week 6 for 40 Gy. CONCLUSIONS: The results clearly support a dose-response relationship between radiation exposure and bladder physiology using serial cystometric evaluation intravesical KCl challenge. Intensity of effect was + and e related to RT intensity and field size, resp. These preliminary results set the stage for the development of therapeutic approaches directed toward the treatment and prevention of radiation cystitis. Source of Funding: Division of Urology, DUMC
MP1-17 THERAPEUTIC EFFECTS OF INTRAVESICAL APPLICATION OF LIPOSOME CONJUGATED WITH ANTISENSE OLIGONUCLEOTIDE TARGETING NERVE GROWTH FACTOR ON NEUROGENIC DETRUSOR OVERACTIVITY IN RATS WITH SPINAL CORD INJURY Tsuyoshi Yoshizawa*, Pradeep Tyagi, Pittsburgh, PA; Michael B. Chancellor, Royal Oak, MI; Satoru Takahashi, Tokyo, Japan; Naoki Yoshimura, Pittsburgh, PA
Source of Funding: National Science Council, Taiwan
INTRODUCTION AND OBJECTIVES: We recently reported that instillation of liposome conjugated with antisense oligonucleotide (OND) targeting nerve growth factor (NGF) into the bladder suppressed bladder overactivity in a rat model of acute cystitis (Kashyap et al., J Urol, 2013). Therefore, this study investigated whether instillation of liposome with NGF-targeting antisense OND into the bladder can suppress neurogenic detrusor overactivity shown by non-voiding contractions (NVCs) during the storage phase in rats with spinal cord injury (SCI). METHODS: Adult female Sprague-Dawley rats were used. SCI was produced by complete transection of the Th8-9 spinal cord. After 3 weeks, SCI rats were divided into three groups; (a) Control group (no treatment), (b) Liposome without antisense OND group, (c) Liposome
Vol. 191, No. 4S, Supplement, Friday, May 16, 2014
e7
MP1-15
MP1-16
FUNCTIONAL AND MOLECULAR CHARACTERISTIC OF UNDERACTIVE BLADDER INDUCED BY LUMBAR CANAL STENOSIS IN RATS
STRIKING DOSE- AND TIME-DEPENDENCE OF RADIATION CYSTITIS IN THE RAT: WEEKLY CYSTOMETRIC EVALUATION UP TO NINE WEEKS AFTER PELVIC IRRADIATION
Yao-Chi Chuang*, Hung-Jen Wang, Kaohsiung, Taiwan; Naoki Yoshimura, Pittsburgh, PA; Michael Chancellor, Royl Oak, MI
Nicholas J. Kuntz*, Matthew O. Fraser, Danielle J. Degoski, Abhay A. Singh, Paul C. Dolber, Andrew C. Peterson, Durham, NC
INTRODUCTION AND OBJECTIVES: It has been recognized that lumbar canal stenosis (LCS) compromised neurological function is a common problem in elderly patients and may cause underactive bladder (UAB). However, the mechanism and molecular change underlying the UAB is not clear. METHODS: One small hole was drilled at the fifth lumbar vertebral arch (sham), and a rectangular piece of silicone rubber was inserted into the L5¡VL6 epidural space (LCS) of female Sprague-Dawley rats. LCS rats underwent bladder expression twice a day. Before and after surgery, a metabolic cage study was performed. Continuous cystometry (CMG) was performed at day 14, or 28 under urethane anesthesia. The bladder was then harvested for histology, expression of M2 and M3 receptors, NGF, and agrin by western blotting. Some animals received intravesical PGE2 instillation. RESULTS: LCS induced acute urinary retention and progressive increase of bladder weight. The LCS rats showed a significant decrease in voided volume and a significant increase in postvoid residual urine compared with Sham rats. CMG showed that the LCS bladder was no contraction, high compliance and overflow incontinence. Intravesical PGE2 induced decreased bladder compliance, but no recovery of bladder contraction in the LCS rats. In contrast, there was a significant decrease in intercontraction interval (ICI) and increased in contraction amplitude in response to PGE2 in sham rats. LCS rats showed no obvious difference in detrusor morphology (Fig 1), M2, M3 receptor, NGF, and agrin compared with the sham rats. CONCLUSIONS: LCS induced UAB model preserved bladder morphology and functional receptor. It might be a useful model for the mechanism and treatment of neurogenic UAB.
INTRODUCTION AND OBJECTIVES: Radiation therapy (RT) is a common treatment for prostate cancer and other pelvic malignancies. Radiation cystitis (PRC) occurs frequently and is characterized by acute irritative voiding symptoms and chronic hemorrhagic cystitis. We describe the development of a rat model designed to test novel therapeutic strategies for prevention and treatment of PRC. METHODS: Female SD rats (n¼24) received specially fabricated chronic bladder catheters positioned to better maintain the natural position of the bladder for the duration of the experiments (up to 9 weeks) and tunneled subcutaneously to the midscapular region for ready access. One week after catheter implant, the animals received single dose pelvic RT with either 0, 5, 10 or 20 Gy using a small-field biological irradiator (X-RAD 225Cx, Precision X-Ray, Inc.) with a 42 collimator (Exp1) or 0, 20, 30 and 40 Gy with a 2.52 collimator (Exp2). Every week for 4 or 9 weeks thereafter, resp., conscious restrained cystometry was performed with infusion of normal saline, and 300 and 500 mM KCl. The primary outcome measure was bladder capacity (BC) for each infusate at each interval. Data were analyzed using 2-Way RM ANOVA, p<0.05 was considered significant. RESULTS: Statistical analysis revealed a marked and significant inverse relationship between radiation dose and BC for both sets. Exp1 - the 0 and 5 Gy doses had no effect. 10 Gy dose was also without effect until week 4, with w30% drop under saline. The 20 Gy dose resulted in a w50% reduction in BC by Week 1, that evolved to a w60% decrease by Week 4. KCl sensitivity was evident by Week 1 following 20 Gy, and BC was reduced w50% and w75% by 10 and 20 Gy, resp. by Week 4. Exp2 e KCL decreased BC at 3 and 4 weeks for 40 and 30 Gy by 87 and 70%, resp. BC under saline alone was reduced 65% by Week 6 for 40 Gy. CONCLUSIONS: The results clearly support a dose-response relationship between radiation exposure and bladder physiology using serial cystometric evaluation intravesical KCl challenge. Intensity of effect was + and e related to RT intensity and field size, resp. These preliminary results set the stage for the development of therapeutic approaches directed toward the treatment and prevention of radiation cystitis. Source of Funding: Division of Urology, DUMC
MP1-17 THERAPEUTIC EFFECTS OF INTRAVESICAL APPLICATION OF LIPOSOME CONJUGATED WITH ANTISENSE OLIGONUCLEOTIDE TARGETING NERVE GROWTH FACTOR ON NEUROGENIC DETRUSOR OVERACTIVITY IN RATS WITH SPINAL CORD INJURY Tsuyoshi Yoshizawa*, Pradeep Tyagi, Pittsburgh, PA; Michael B. Chancellor, Royal Oak, MI; Satoru Takahashi, Tokyo, Japan; Naoki Yoshimura, Pittsburgh, PA
Source of Funding: National Science Council, Taiwan
INTRODUCTION AND OBJECTIVES: We recently reported that instillation of liposome conjugated with antisense oligonucleotide (OND) targeting nerve growth factor (NGF) into the bladder suppressed bladder overactivity in a rat model of acute cystitis (Kashyap et al., J Urol, 2013). Therefore, this study investigated whether instillation of liposome with NGF-targeting antisense OND into the bladder can suppress neurogenic detrusor overactivity shown by non-voiding contractions (NVCs) during the storage phase in rats with spinal cord injury (SCI). METHODS: Adult female Sprague-Dawley rats were used. SCI was produced by complete transection of the Th8-9 spinal cord. After 3 weeks, SCI rats were divided into three groups; (a) Control group (no treatment), (b) Liposome without antisense OND group, (c) Liposome