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NEUROPHARMACOLOGY

Activation of Urothelial Transient Receptor Potential Vanilloid 4 by 4-Phorbol 12,13-Didecanoate Contributes to Altered Bladder Reflexes in the Rat

Departments of Medicine, Laboratory of Epithelial Cell Biology, Renal-Electrolyte Division (L.B., S.B., A.K.) and Pharmacology (L.B., F.A.K., W.d.G., A.K.) University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Departments of Biological Chemistry and Neuroscience and Center for Sensory Biology (H.L., M.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland

The ion channel transient receptor potential vanilloid (TRPV) 4 can be activated by hypo-osmolarity, heat, or certain lipid compounds. Here, we demonstrate expression of functional TRPV4 protein in the urothelium lining the renal pelvis, ureters, urinary bladder, and urethra. Exposure of cultured rat urothelial cells from the urinary bladder to the TRPV4-selective agonist 4-phorbol 12,13-didecanoate (4-PDD) promoted Ca²⁺ influx, evoked ATP release, and augmented the ATP release evoked by hypo-osmolarity. In awake rats during continuous infusion cystometrograms, intravesical administration of 4-PDD (10–100 µM) increased maximal micturition pressure by 51%, specifically by augmenting the portion of each intravesical pressure wave that follows high-frequency urethral oscillations and voiding. This unusual pharmacological effect was prevented by intravesical pretreatment with the nonselective ATP receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (100 µM), systemic treatment with the selective P2X₃ purinergic antagonist 5-([(3-phenoxybenzyl)[1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid (A317491) (250 µmol/kg), or urethane anesthesia, but was unaffected by capsaicin pretreatment (100 mg/kg s.c.) or denervation of the urethral sphincter. 4-PDD (1–100 µM) did not alter the contractility to electrical stimulation of excised bladder strips. We conclude that activation of urothelial TRPV4 by 4-PDD and release of mediators such as ATP trigger a novel neural mechanism that regulates the late phase of detrusor muscle contraction after micturition. These data raise the possibility that TRPV4 channels in the urothelium could contribute to abnormal bladder activity.

Address correspondence to: Lori A. Birder, University of Pittsburgh School of Medicine, A 1207 Scaife Hall, Department of Medicine, Pittsburgh, PA 15261. E-mail: lbirder{at}pitt.edu

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