MP4-09 EXOGENOUS OVEREXPRESSION OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) IN RAT BLADDER EVOKES BLADDER OVERACTIVITY

Abstract

INTRODUCTION AND OBJECTIVES: Detrusor underactivity (DU) is defined by the International Continence Society as a detrusor contraction of inadequate magnitude and/or duration, resulting in prolonged or incomplete emptying of the bladder. DU is observed in elderly patients and patients with diabetes, bladder outlet obstruction, and neurogenic symptoms, but has received little attention. Current therapy for DU primarily includes clean intermittent catheterization. Drug therapy such as muscarinic receptor agonists, acetylcholinesterase inhibitors, and alpha-1 blockers have been used, but with minimal efficacy. Thus, an efficacious drug therapy to avoid catheterization is required to treat these patients. Use of 5-HT4 receptor agonists, such as cisapride, has reportedly enhanced acetylcholine release and electrical field stimulation-induced bladder contraction in vitro. Therefore, in the present study, we aimed to confirm the efficacy and potency of cisapride on bladder contractility and urethral function in rats. METHODS: Adult female SpragueeDawley rats were used. A PE-10 polyethylene catheter was inserted into a jugular vein for drug administration. A PE-90 polyethylene catheter was also inserted into the bladder through the dome to record intravesical pressure. Continuous cystometry was performed under urethane anesthesia to examine the effect of intravenous (i.v.) cisapride (4 mg/kg) therapy on the bladder function. The effect of i.v. cisapride (4 mg/kg) therapy in the presence of i.v. naftopidil (4 mg/kg) therapy, an alpha-1D antagonist, was also evaluated. RESULTS: Cisapride therapy (i.v.) increased the baseline pressure (from 2.8 to 9.2 cm H2O) by 229%, increased maximal bladder contraction (from 24.5 to 28.4 cm H2O) by 16%, and prolonged the intercontraction interval (from 4.8 to 14.4 min) by 197%. Cisapride therapy also increased residual urine volume (0.56 mL). Administration of i.v. cisapride therapy with i.v. naftopidil therapy prolonged the intercontraction interval, but did not affect the baseline pressure, maximal bladder contraction, or residual urine volume. CONCLUSIONS: These results suggest that 5-HT4 receptor agonists enhance bladder and urethral function, which results in an increase in bladder contractility and residual urine volume. This increase in the residual urine volume is probably caused by alpha-1 adrenergic stimulation of the urethra because of cisapride therapy. Therefore, if the influence of cisapride on the urethra is blocked by the use of alpha-1 blockers, it may be possible to use cisapride therapy as a novel treatment for DU.