PD24-04 DYSREGULATED NO/PDE5 SIGNALING IN THE SICKLE CELL MOUSE LOWER URINARY TRACT: REVERSAL BY ORAL NITRATE THERAPY

Abstract

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology II (PD24)1 Apr 2020PD24-04 DYSREGULATED NO/PDE5 SIGNALING IN THE SICKLE CELL MOUSE LOWER URINARY TRACT: REVERSAL BY ORAL NITRATE THERAPY Biljana Musicki, Serkan Karakus*, Uzoma Anele, Jeffrey Campbell, Sruti Shiva, Fabio Silva, and Arthur L. Burnett Biljana MusickiBiljana Musicki More articles by this author , Serkan Karakus*Serkan Karakus* More articles by this author , Uzoma AneleUzoma Anele More articles by this author , Jeffrey CampbellJeffrey Campbell More articles by this author , Sruti ShivaSruti Shiva More articles by this author , Fabio SilvaFabio Silva More articles by this author , and Arthur L. BurnettArthur L. Burnett More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000881.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Nitric oxide (NO) has a critical, but not well understood, influence in the physiology of the lower urinary tract. We evaluated the effect of NO/phosphodiesterase (PDE)5 signaling in voiding dysfunction in the sickle cell disease (SCD) mouse, characterized by low NO bioavailability. METHODS: Adult SCD (Sickle) and wild-type (WT) male mice were treated daily with sodium nitrate (10 mM) or vehicle. After 18 days, blood was obtained for nitrite measurement, urethra was collected for organ bath study, and bladder and urethra were collected for Western blot analysis of PDE5 phosphorylation (Ser-92) (activated form). Non-anesthetized mice underwent evaluation of urine volume by void spot assay. eNOS phosphorylation (Ser-1177) and nNOS phosphorylation (Ser-1412) (positive regulatory sites) were evaluated in the bladder and urethra of untreated mice. RESULTS: Sickle mice exhibited decreased eNOS, nNOS, and PDE5 phosphorylation in the bladder and urethra, decreased plasma nitrite levels, increased relaxation of phenylephrine-contracted urethral tissue to an NO donor sodium nitroprusside, and increased total urine volume, compared with WT mice. Nitrate treatment normalized plasma nitrite levels, relaxation of urethra to sodium nitroprusside, PDE5 phosphorylation in the urethra and bladder, and urine volume in Sickle mice. CONCLUSIONS: Derangement in PDE5 activity associated with basally low NO bioavailability in the bladder and urethra contributes to the molecular basis for voiding abnormalities in Sickle mice. Inorganic nitrate supplementation normalized voiding in Sickle mice through mechanisms likely involving upregulation of PDE5 activity. These findings suggest that interventions targeting dysregulatory NO/PDE5 signaling may ameliorate overactive bladder in SCD. Source of Funding: The study was supported by grant from the National Institutes of Health, USA (NIH/NIDDK grant R56DK114095 to A.L.B.) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e533-e533 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Biljana Musicki More articles by this author Serkan Karakus* More articles by this author Uzoma Anele More articles by this author Jeffrey Campbell More articles by this author Sruti Shiva More articles by this author Fabio Silva More articles by this author Arthur L. Burnett More articles by this author Expand All Advertisement PDF downloadLoading ...