Abstract
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.
Footnotes
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This work was supported by the National Institutes of Health (Grants R37 DK54824 and R01 DK57284 to L.A.B., R01 DK 64280 to A.K., and R01 NS051551 to M.J.C.), by an American Foundation of Urological Diseases/American Urological Association Research Scholar Grant (to F.A.K.), and by the American Cancer Society (Research Scholar Grant RSG 01-063-05-CSM to M.J.C).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.125435.
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ABBREVIATIONS: TRPV, transient receptor potential vanilloid; 5′,6′-EET, 5′,6′-epoxyeicosatrienoic acid; 4α-PDD, 4α-phorbol 12,13-didecanoate; HEK, human embryonic kidney; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; A317491, 5-([(3-phenoxybenzyl)[1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid; GAPDH, glyceraldehyde phosphate dehydrogenase; TRPV4-LI, TRPV4-like immunoreactivity; RR, ruthenium red; ICI, intercontraction interval; PKC, protein kinase C; HFO, high-frequency oscillation; PPADS, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid.
- Received May 9, 2007.
- Accepted July 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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