PD7-03 IMPAIRED EXPRESSION AND FUNCTION OF TREK-1, A STRETCH-ACTIVATED TWO-PORE DOMAIN POTASSIUM CHANNEL, UNDERLIES DETRUSOR OVERACTIVITY IN HUMANS

Abstract

INTRODUCTION AND OBJECTIVES: Afferent signals during bladder filling and voiding are important in lower urinary tract (LUT) function. The sensory cation channel transient receptor potential channel vanilloid 4 (TRPV4) is a key mediator in the generation of afferent signals towards the central nervous system (CNS). It has become possible to study this central neural control by means of positron emission tomography (PET) of the brain. We hypothetized that deletion of TRPV4 would influence brain control of the LUT by decreasing afferent input. METHODS: 12 Female Sprague-Dawley rats and 10 trpv4-/rats were used. Under urethane anesthesia a catheter was inserted in the bladder and the urethra was ligated. The animal was placed in a FOCUS 220 PET scan. The catheter was connected to a syringe pump and pressure transducer. Wild type and trpv4-/rats were equally divided into two conditions; an empty bladder condition, without infusion, and a full bladder condition, with infusion of saline until spontaneous contractions occurred. During cystometry, brain imaging was performed after injection of [18F]-FDG in the tail vein. For analysis PET images were normalized to a stereotactic space based on the rat brain Paxinos atlas using PMOD . We analysed on voxel basis using SPM8. RESULTS: In WT rats clusters of increased FDG uptake in the full bladder condition were observed in the insular, cingulate and posterior temporal cortex, while uptake was decreased in a cerebellar cluster (fig). Trpv4-/showed a different activation pattern during bladder fullness, with increased uptake in the orbitofrontal cortex and cerebellar peduncle. A cluster of decreased FDG uptake was also detected in the cerebellum. Wild type and trpv4-/rats showed differences in glucose uptake in the cerebellar and temporal cortex, thalamus, hypothalamus and hippocampus. CONCLUSIONS: In wild type rats a full bladder activated the insular and cingulate cortex. Both regions are key areas in the central neural control of the bladder; the insular cortex being the main endpoint for bladder afferent signals and the cingulate cortex the origin of motivation to void. This brain activation pattern was not seen in trpv4-/rats representing decreased afferent input into the CNS that contributes to a diminished motivation to void. Source of Funding: none