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MP12-12 ENHANCED SPINAL GLYCINERGIC SYSTEM BY GLYCINE TRANSPORTER TYPE 2 (GLYT2) INHIBITION REDUCES NEUROGENIC DETRUSOR OVERACTIVITY IN RATS WITH SPINAL CORD INJURY
THE JOURNAL OF UROLOGYâ
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CONCLUSIONS: In older women with UUI, there are subcortical abnormalities that may cause or contribute to the incontinence: they include atrophy of the hippocampus and loss of white-matter integrity specifically in the fornix e a sub-cortical tract connecting hippocampus with hypothalamus. Treatments such as exercise to increase hippocampal size, or deep brain stimulation to improve white-matter integrity, might prove useful in refractory cases of extreme incontinence in the elderly.
Source of Funding: NIH AG20629
MP12-11 URODYNAMIC INVESTIGATION: A SENSIBLE TOOL TO DEFINE NORMAL LOWER URINARY TRACT FUNCTION? Lorenz Leitner*, Matthias Walter, Ulrich Mehnert, Thomas M. Kessler, €rich, Switzerland Zu INTRODUCTION AND OBJECTIVES: Urodynamic investigation (UDI) is the gold standard to assess refractory lower urinary tract symptoms (LUTS), i.e. to detect pathological patterns of the lower urinary tract. However, it is unclear whether UDI might also be appropriate in healthy volunteers to select for comparative studies control subjects with normal lower urinary tract function. METHODS: 40 healthy subjects (22 woman, mean age 32 10 years; 18 men mean age 37 12 years) without LUTS were included into this prospective single-centre cohort study. All subjects recorded a 3-day bladder diary and completed validated urological questionnaires regarding LUTS. Medical history and neuro-urological examination were assessed. UDI was performed according to “Good Urodynamic Practice” recommended by the International Continence Society (Schafer et al 2002). Bladder outlet obstruction was defined as maximum flow rate <12mL/s and detrusor pressure at maximum flow rate >25cmH2O for women and according to the Abrams-Griffiths nomogram for men. RESULTS: Medical history, neuro-urological examination 3-day bladder diary and LUTS questionnaires were inconspicuous in all subjects. UDI revealed pathological findings in 73% (29/40) of our presumably healthy subjects: Detrusor overactivity was detected in 9% (2/22) and 33% (6/18), post void residual >100mL in 14% (3/22) and 22% (4/18), bladder outlet obstruction in 9% (2/22) and 44% (8/18), and detrusor sphincter dyssynergia in 73% (16/22) and 72% (13/18) of our women and men, respectively. CONCLUSIONS: Almost 3 of 4 of our healthy subjects showed pathological urodynamic findings. Although UDI is the gold standard to assess refractory LUTS, it seems not to be a sensible tool to define normal lower urinary tract function. UDI is an invasive and non-physiological examination with a relevant risk for UDI-induced pathological findings. Thus, we do not recommend to identify “healthy control subjects” based on UDI only since many candidates will be excluded due to false positive UDI-induced results. Source of Funding: Wings for Life, Swiss National Science Foundation, Emily Dorothy Lagemann Stiftung and Swiss Continence Foundation
Vol. 193, No. 4S, Supplement, Friday, May 15, 2015
MP12-12 ENHANCED SPINAL GLYCINERGIC SYSTEM BY GLYCINE TRANSPORTER TYPE 2 (GLYT2) INHIBITION REDUCES NEUROGENIC DETRUSOR OVERACTIVITY IN RATS WITH SPINAL CORD INJURY Tsuyoshi Yoshizawa*, Satoru Yoshikawa, Hiroki Okada, Pittsburgh, PA; Satoru Takahashi, Tokyo, Japan; Naoki Yoshimura, Pittsburgh, PA INTRODUCTION AND OBJECTIVES: Glycine is a major inhibitory neurotransmitter in the central nervous system including the spinal cord. The concentration of glycine at synaptic nerve terminals is regulated by two types of glycine transporters (GlyTs): GlyT1 and GlyT2. This study investigated the effects of GlyT inhibitors, which can increase the glycine concentration at nerve terminals, on neurogenic detrusor overactivity as 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 4 weeks, cystometry under an awake condition was performed with continuous infusion of saline (0.08 ml/min) into the bladder. Selective GlyT1 or GlyT2 inhibitors (Sarcosine or ALX-1393, respectively) were administered intrathecally via a PE-10 catheter connected with a 30G needle and placed at the L6 spinal cord level. Cystometric parameters evaluated included the amplitude (cmH2O) and frequency (number/min) of NVCs, voiding intervals (VI) and maximal voiding pressure (MVP). GlyT and glycine receptor (GlyR) levels in the L6-S1 spinal cord were measured by RT-PCR. RESULTS: Intrathecal application of Sarcosine (250mg), a selective GlyT1 inhibitor, did not elicit significant changes in any cystometric parameters (n¼5). In contrast, intrathecal application of ALX1393 (3, 10 and 30mg, n¼5), a selective GlyT2 inhibitor, dose-dependently reduced the amplitude and frequency of NVCs with significant changes at 10mg (26 and 65% reductions, respectively) and 30mg (37 and 76 % reductions, respectively) without affecting VI or MVP. SCI rats had higher GlyT2 mRNA levels without changes of GlyR levels in the L6-S1 spinal cord compared to spinal intact rats. CONCLUSIONS: These results indicate that GlyT2 inhibition that enhances the spinal glycinergic system by inhibiting the glycine uptake at nerve terminals can suppress neurogenic detrusor overactivity as evidenced by the inhibition of NVCs in chronic SCI rats. Because sensitization of bladder afferent pathways and increased signal transduction in the spinal cord have been proposed as important mechanisms inducing bladder overactivity, GlyT2 inhibitors could be a novel option for the treatment of overactive bladder with neurogenic detrusor overactivity by suppressing sensory inputs from the bladder to the spinal cord. Source of Funding: PVA 2793, DOD W81XWH-11-1-0763 and NIH DK088836, P01 DK093424
MP12-13 COITAL URINARY INCONTINENCE IN RATS Luis Palacios*, Margarita Jua rez, Rau rez, Alfonso Medel, l Jua Jose Yolanda Cruz, Tlaxcala, Mexico INTRODUCTION AND OBJECTIVES: Urinary incontinence during sexual intercourse, referred as coital urinary incontinence, has a devastating impact on female sexuality and quality of life. The aim of the present study was to determine the effect of the bilateral neurectomy of the DNC on micturition in female rats. METHODS: Fifteen anesthetized Wistar virgin female rats underwent bilateral neurectomy of the DNC (DNCNX, n¼9) or sham surgery (SH, n¼6). The micturition was recorded in awake animals 3 and 10 days post-surgery, during 6 h of the dark phase cycle. Sexual
e132
CONCLUSIONS: In older women with UUI, there are subcortical abnormalities that may cause or contribute to the incontinence: they include atrophy of the hippocampus and loss of white-matter integrity specifically in the fornix e a sub-cortical tract connecting hippocampus with hypothalamus. Treatments such as exercise to increase hippocampal size, or deep brain stimulation to improve white-matter integrity, might prove useful in refractory cases of extreme incontinence in the elderly.
Source of Funding: NIH AG20629
MP12-11 URODYNAMIC INVESTIGATION: A SENSIBLE TOOL TO DEFINE NORMAL LOWER URINARY TRACT FUNCTION? Lorenz Leitner*, Matthias Walter, Ulrich Mehnert, Thomas M. Kessler, €rich, Switzerland Zu INTRODUCTION AND OBJECTIVES: Urodynamic investigation (UDI) is the gold standard to assess refractory lower urinary tract symptoms (LUTS), i.e. to detect pathological patterns of the lower urinary tract. However, it is unclear whether UDI might also be appropriate in healthy volunteers to select for comparative studies control subjects with normal lower urinary tract function. METHODS: 40 healthy subjects (22 woman, mean age 32 10 years; 18 men mean age 37 12 years) without LUTS were included into this prospective single-centre cohort study. All subjects recorded a 3-day bladder diary and completed validated urological questionnaires regarding LUTS. Medical history and neuro-urological examination were assessed. UDI was performed according to “Good Urodynamic Practice” recommended by the International Continence Society (Schafer et al 2002). Bladder outlet obstruction was defined as maximum flow rate <12mL/s and detrusor pressure at maximum flow rate >25cmH2O for women and according to the Abrams-Griffiths nomogram for men. RESULTS: Medical history, neuro-urological examination 3-day bladder diary and LUTS questionnaires were inconspicuous in all subjects. UDI revealed pathological findings in 73% (29/40) of our presumably healthy subjects: Detrusor overactivity was detected in 9% (2/22) and 33% (6/18), post void residual >100mL in 14% (3/22) and 22% (4/18), bladder outlet obstruction in 9% (2/22) and 44% (8/18), and detrusor sphincter dyssynergia in 73% (16/22) and 72% (13/18) of our women and men, respectively. CONCLUSIONS: Almost 3 of 4 of our healthy subjects showed pathological urodynamic findings. Although UDI is the gold standard to assess refractory LUTS, it seems not to be a sensible tool to define normal lower urinary tract function. UDI is an invasive and non-physiological examination with a relevant risk for UDI-induced pathological findings. Thus, we do not recommend to identify “healthy control subjects” based on UDI only since many candidates will be excluded due to false positive UDI-induced results. Source of Funding: Wings for Life, Swiss National Science Foundation, Emily Dorothy Lagemann Stiftung and Swiss Continence Foundation
Vol. 193, No. 4S, Supplement, Friday, May 15, 2015
MP12-12 ENHANCED SPINAL GLYCINERGIC SYSTEM BY GLYCINE TRANSPORTER TYPE 2 (GLYT2) INHIBITION REDUCES NEUROGENIC DETRUSOR OVERACTIVITY IN RATS WITH SPINAL CORD INJURY Tsuyoshi Yoshizawa*, Satoru Yoshikawa, Hiroki Okada, Pittsburgh, PA; Satoru Takahashi, Tokyo, Japan; Naoki Yoshimura, Pittsburgh, PA INTRODUCTION AND OBJECTIVES: Glycine is a major inhibitory neurotransmitter in the central nervous system including the spinal cord. The concentration of glycine at synaptic nerve terminals is regulated by two types of glycine transporters (GlyTs): GlyT1 and GlyT2. This study investigated the effects of GlyT inhibitors, which can increase the glycine concentration at nerve terminals, on neurogenic detrusor overactivity as 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 4 weeks, cystometry under an awake condition was performed with continuous infusion of saline (0.08 ml/min) into the bladder. Selective GlyT1 or GlyT2 inhibitors (Sarcosine or ALX-1393, respectively) were administered intrathecally via a PE-10 catheter connected with a 30G needle and placed at the L6 spinal cord level. Cystometric parameters evaluated included the amplitude (cmH2O) and frequency (number/min) of NVCs, voiding intervals (VI) and maximal voiding pressure (MVP). GlyT and glycine receptor (GlyR) levels in the L6-S1 spinal cord were measured by RT-PCR. RESULTS: Intrathecal application of Sarcosine (250mg), a selective GlyT1 inhibitor, did not elicit significant changes in any cystometric parameters (n¼5). In contrast, intrathecal application of ALX1393 (3, 10 and 30mg, n¼5), a selective GlyT2 inhibitor, dose-dependently reduced the amplitude and frequency of NVCs with significant changes at 10mg (26 and 65% reductions, respectively) and 30mg (37 and 76 % reductions, respectively) without affecting VI or MVP. SCI rats had higher GlyT2 mRNA levels without changes of GlyR levels in the L6-S1 spinal cord compared to spinal intact rats. CONCLUSIONS: These results indicate that GlyT2 inhibition that enhances the spinal glycinergic system by inhibiting the glycine uptake at nerve terminals can suppress neurogenic detrusor overactivity as evidenced by the inhibition of NVCs in chronic SCI rats. Because sensitization of bladder afferent pathways and increased signal transduction in the spinal cord have been proposed as important mechanisms inducing bladder overactivity, GlyT2 inhibitors could be a novel option for the treatment of overactive bladder with neurogenic detrusor overactivity by suppressing sensory inputs from the bladder to the spinal cord. Source of Funding: PVA 2793, DOD W81XWH-11-1-0763 and NIH DK088836, P01 DK093424
MP12-13 COITAL URINARY INCONTINENCE IN RATS Luis Palacios*, Margarita Jua rez, Rau rez, Alfonso Medel, l Jua Jose Yolanda Cruz, Tlaxcala, Mexico INTRODUCTION AND OBJECTIVES: Urinary incontinence during sexual intercourse, referred as coital urinary incontinence, has a devastating impact on female sexuality and quality of life. The aim of the present study was to determine the effect of the bilateral neurectomy of the DNC on micturition in female rats. METHODS: Fifteen anesthetized Wistar virgin female rats underwent bilateral neurectomy of the DNC (DNCNX, n¼9) or sham surgery (SH, n¼6). The micturition was recorded in awake animals 3 and 10 days post-surgery, during 6 h of the dark phase cycle. Sexual