1950 PROTEIN KINASE C INHIBITS SPONTANEOUS AND NON-VOIDING CONTRACTIONS IN DETRUSOR SMOOTH MUSCLE: ROLE AND INTERACTION WITH BK CHANNELS

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Non-Neurogenic Voiding Dysfunction1 Apr 20111950 PROTEIN KINASE C INHIBITS SPONTANEOUS AND NON-VOIDING CONTRACTIONS IN DETRUSOR SMOOTH MUSCLE: ROLE AND INTERACTION WITH BK CHANNELS Joseph Hypolite, Qi Lei, Shaohua Chang, Anna Malykhina, Stephen Zderic, Alan Wein, Stephan Butler, and Samuel Chacko Joseph HypoliteJoseph Hypolite Glenolden, PA More articles by this author , Qi LeiQi Lei Glenolden, PA More articles by this author , Shaohua ChangShaohua Chang Glenolden, PA More articles by this author , Anna MalykhinaAnna Malykhina Glenolden, PA More articles by this author , Stephen ZdericStephen Zderic Philadelphia, PA More articles by this author , Alan WeinAlan Wein Philadelphia, PA More articles by this author , Stephan ButlerStephan Butler Philadelphia, PA More articles by this author , and Samuel ChackoSamuel Chacko Glenolden, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2154AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Partial bladder outlet obstruction (PBOO)-induced detrusor smooth muscle hypertrophy is associated with a downregulation of protein kinase C (PKC) and large conductance calcium-activated potassium channels (BK) channels, and an increase in spontaneous contractions in isolated muscle strips, and non-voiding contractions in patients with BPH-induced PBOO. The purpose of this study is to examine whether or not PKC is involved in the regulation of spontaneous and non-voiding contractions in DSM, and whether inhibition of PKC contributes to increased detrusor excitability. METHODS DSM strips (∼2mm × 10mm) were removed from 2-week PBOO rabbits and used for in vitro contractile studies. Sham-operated animals served as controls. The effect of inhibition of PKC on non-voiding contractions was studied using in vivo cystometry in rats, and whole cell patch clamping was used to study the effect of phorbol 12,13-dibutyrate (PDBU), a PKC activator, on the BK channel current. Iberiotoxin (IBX), a BK-channel inhibitor, was used to study its effect on spontaneous contractions and PDBU-induced inhibition of spontaneous contraction. RESULTS The results indicate that the PKC inhibitor, bisindolylmaleimide1, (BIS-1) and IBX increased the amplitude of spontaneous contractions in detrusor smooth muscle strips from normal rabbit bladders but that there was no significant change in the strips from PBOO. BIS-1 also increased the frequency of non-voiding contractions in normal rat bladder. Both BIS-1- and IBX-induced spontaneous contractions were inhibited by PDBU (10-50 nM). BIS-1-induced spontaneous contractions were significantly reduced by BK channel openers, NS1619 and isopimeric acid. Pre-treatment of isolated muscle strips with IBX significantly delayed the inhibitory effect of PDBU on spontaneous contractions. Whole cell patch clamp studies revealed that PDBU caused an increase in the BK channel current in detrusor myocytes isolated from both sham-operated and PBOO animals. CONCLUSIONS The data suggest that PKC may play an important role in maintaining the relatively quiescent, non-excitable state of the normal bladder by suppressing spontaneous and non-voiding contractions, and that down-regulation of PKC in PBOO may contribute to detrusor overactivity. The data also suggests that the mechanism of action may involve the ability of PKC to increase the BK-channel current during the filling phase of the micturition cycle. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e780 Peer Review Report Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Hypolite Glenolden, PA More articles by this author Qi Lei Glenolden, PA More articles by this author Shaohua Chang Glenolden, PA More articles by this author Anna Malykhina Glenolden, PA More articles by this author Stephen Zderic Philadelphia, PA More articles by this author Alan Wein Philadelphia, PA More articles by this author Stephan Butler Philadelphia, PA More articles by this author Samuel Chacko Glenolden, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...