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Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12,13-didecanoate contributes to altered bladder reflexes in the rat.
J Pharmacol Exp Ther. 2007 Oct; 323(1):227-35.JP

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 4alpha-phorbol 12,13-didecanoate (4alpha-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 4alpha-PDD (10-100 microM) 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 microM), 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 micromol/kg), or urethane anesthesia, but was unaffected by capsaicin pretreatment (100 mg/kg s.c.) or denervation of the urethral sphincter. 4Alpha-PDD (1-100 microM) did not alter the contractility to electrical stimulation of excised bladder strips. We conclude that activation of urothelial TRPV4 by 4alpha-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.

Authors+Show Affiliations

Department of Medicine, University of Pittsburgh School of Medicine, A 1207 Scaife Hall, Pittsburgh, PA 15261, USA. lbirder@pitt.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17636010

Citation

Birder, Lori, et al. "Activation of Urothelial Transient Receptor Potential Vanilloid 4 By 4alpha-phorbol 12,13-didecanoate Contributes to Altered Bladder Reflexes in the Rat." The Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 1, 2007, pp. 227-35.
Birder L, Kullmann FA, Lee H, et al. Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12,13-didecanoate contributes to altered bladder reflexes in the rat. J Pharmacol Exp Ther. 2007;323(1):227-35.
Birder, L., Kullmann, F. A., Lee, H., Barrick, S., de Groat, W., Kanai, A., & Caterina, M. (2007). Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12,13-didecanoate contributes to altered bladder reflexes in the rat. The Journal of Pharmacology and Experimental Therapeutics, 323(1), 227-35.
Birder L, et al. Activation of Urothelial Transient Receptor Potential Vanilloid 4 By 4alpha-phorbol 12,13-didecanoate Contributes to Altered Bladder Reflexes in the Rat. J Pharmacol Exp Ther. 2007;323(1):227-35. PubMed PMID: 17636010.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of urothelial transient receptor potential vanilloid 4 by 4alpha-phorbol 12,13-didecanoate contributes to altered bladder reflexes in the rat. AU - Birder,Lori, AU - Kullmann,F Aura, AU - Lee,Hyosang, AU - Barrick,Stacey, AU - de Groat,William, AU - Kanai,Anthony, AU - Caterina,Michael, Y1 - 2007/07/17/ PY - 2007/7/20/pubmed PY - 2007/11/6/medline PY - 2007/7/20/entrez SP - 227 EP - 35 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 323 IS - 1 N2 - 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 4alpha-phorbol 12,13-didecanoate (4alpha-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 4alpha-PDD (10-100 microM) 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 microM), 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 micromol/kg), or urethane anesthesia, but was unaffected by capsaicin pretreatment (100 mg/kg s.c.) or denervation of the urethral sphincter. 4Alpha-PDD (1-100 microM) did not alter the contractility to electrical stimulation of excised bladder strips. We conclude that activation of urothelial TRPV4 by 4alpha-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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17636010/Activation_of_urothelial_transient_receptor_potential_vanilloid_4_by_4alpha_phorbol_1213_didecanoate_contributes_to_altered_bladder_reflexes_in_the_rat_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17636010 DB - PRIME DP - Unbound Medicine ER -