RT Journal Article
SR Electronic
T1 Activation of Urothelial Transient Receptor Potential Vanilloid 4 by 4α-Phorbol 12,13-Didecanoate Contributes to Altered Bladder Reflexes in the Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 227
OP 235
DO 10.1124/jpet.107.125435
VO 323
IS 1
A1 Lori Birder
A1 F. Aura Kullmann
A1 Hyosang Lee
A1 Stacey Barrick
A1 William de Groat
A1 Anthony Kanai
A1 Michael Caterina
YR 2007
UL http://jpet.aspetjournals.org/content/323/1/227.abstract
AB 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 4α-phorbol 12,13-didecanoate (4α-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 4α-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. 4α-PDD (1–100 μM) did not alter the contractility to electrical stimulation of excised bladder strips. We conclude that activation of urothelial TRPV4 by 4α-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. The American Society for Pharmacology and Experimental Therapeutics