title: Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation.
abstract: Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of transient receptor potential vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2(-/-) mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca(2+) handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca(2+).
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Diseases, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Sheryl E
authors.initials: SE
authors.lastname: Koch
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Gao
authors.forename: Lauren
authors.initials: L
authors.lastname: Haar
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Lasko
authors.forename: Nathan
authors.initials: N
authors.lastname: Robbins
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.forename: Cole
authors.initials: C
authors.lastname: Brokamp
authors.forename: Priyanka
authors.initials: P
authors.lastname: Varma
authors.forename: Michael
authors.initials: M
authors.lastname: Tranter
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ren
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C485717:Trpv2 protein, mouse; D011339:Probenecid; D002118:Calcium