186 LARGE CONDUCTANCE CALCIUM- AND VOLTAGE-ACTIVATED POTASSIUM CHANNEL (BK) OPENER INHIBITS SPONTANEOUS OVERACTIVE CONTRACTION OF DETRUSOR SMOOTH MUSCLE IN OBSTRUCTED BLADDERS

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2010186 LARGE CONDUCTANCE CALCIUM- AND VOLTAGE-ACTIVATED POTASSIUM CHANNEL (BK) OPENER INHIBITS SPONTANEOUS OVERACTIVE CONTRACTION OF DETRUSOR SMOOTH MUSCLE IN OBSTRUCTED BLADDERS Joseph Hypolite, Shaohua Chang, Stephen Zderic, Alan Wein, Stephan Butler, and Samuel Chacko Joseph HypoliteJoseph Hypolite Philadelphia, PA More articles by this author , Shaohua ChangShaohua Chang Philadelphia, 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.2010.02.242AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Benign prostatic hyperplasia (BPH)-induced partial bladder outlet obstruction (PBOO) in men is often associated with overactivity of the detrusor smooth muscle (DSM). Our previous studies show that PBOO in a rabbit model is characterized by enhanced spontaneous DSM contractions, similar to that seen in men with overactive bladders, and the PBOO-induced DSM remodeling is associated with a downregulation of BK channel proteins. The goal of this study is to investigate whether BK channel openers can suppress PBOO-induced overactive contraction in detrusor smooth muscle. METHODS PBOO was surgically produced in adult male New Zealand White rabbits. Two weeks after the operation, rabbits were sacrificed, and DSM strips (∼2 mm X 10 mm) were prepared and used for in vitro muscle contraction studies. BK openers, NS 1619 and isopimaric acid (Sigma) were used to evaluate their effects on the frequency and amplitude of spontaneous contractions. When the maximum effect of drugs was observed strips were snap frozen in liquid N2 and the myosin light chain (MLC20) phosphorylation levels were determined using 2-D gel electrophoresis. RESULTS Detrusor muscle strips from PBOO rabbits showed spontaneous contractions which are more frequent and higher in amplitude compared to those exhibited by the DSM from normal rabbits. In the obstructed group, NS 1619 and Isopimaric acid caused, respectively, 71% and 60% decreases in the amplitude of the overactive contractions between 1 and 3 hours after the administration of drugs. In the absence of drugs, the amplitude of the contractions declined by 28% over the course of the initial measurement. Both drugs caused a significant decline in amplitude between 1 to 3 hours after drug administration. The amplitude of the isopimaric group continued to decline down to 90% at 12 hours, while the NS 1619 group remained relatively stable between 3 and 12 hours. There was no significant effect on the frequency of contractions to either drugs. The BK channel openers also reduced MLC20 phosphorylation and the lower phosphorylation correlated with reduced spontaneous contractions. CONCLUSIONS Our data show that BK channel openers inhibit PBOO-induced detrusor overactive contractions and the inhibition may be through reducing MLC20 phosphorylation, a key Ca2+-dependent regulatory mechanism for smooth muscle contraction. Moreover, the inhibition is long lasting which indicates a high potential for BK openers to be used as a therapeutic agent for overactive bladder. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e74 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joseph Hypolite Philadelphia, PA More articles by this author Shaohua Chang Philadelphia, 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 ...