title: Spontaneous and evoked contractions are regulated by PKC-mediated signaling in detrusor smooth muscle: involvement of BK channels.
abstract: Protein kinase C (PKC) and large conductance Ca(2+)-activated potassium channels (BK) are downregulated in the detrusor smooth muscle (DSM) in partial bladder outlet obstruction (PBOO). DSM from these bladders display increased spontaneous activity. This study examines the involvement of PKC in the regulation of spontaneous and evoked DSM contractions and whether pharmacologic inhibition of PKC in normal DSM contributes to increased detrusor excitability. Results indicate the PKC inhibitor bisindolylmaleimide 1 (Bim-1) prevented a decline in the amplitude of spontaneous DSM contractions over time in vitro, and these contractions persist in the presence of tetrodotoxin. Bim-1 also reduced the basal DSM tone, and the ability to maintain force in response to electrical field stimulation, but did not affect maximum contraction. The PKC activator phorbol-12,13-dibutyrate (PDBu) significantly reduced the amplitude and increased the frequency of spontaneous contractions at low concentrations (10 nM), while causing an increase in force at higher concentrations (1 μM). Preincubation of DSM strips with iberiotoxin prevented the inhibition of spontaneous contractions by PDBu. The BK channel openers isopimaric acid and NS1619 reduced the Bim-1-induced enhancement of spontaneous contractions in DSM strips. Our data suggest that PKC has a biphasic activation profile in the DSM and that it may play an important role in maintaining the quiescent state of the normal bladder during storage through the effects on BK channel, while helping to maintain force required for bladder emptying. The data also suggest that PKC dysfunction, as seen in PBOO, contributes to detrusor overactivity.
authors.affiliation: Division of Urology, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hypolite
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
authors.forename: Stephan
authors.initials: S
authors.lastname: Butler
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.forename: Anna P
authors.initials: AP
authors.lastname: Malykhina
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D001562:Benzimidazoles; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010616:Phenanthrenes; C086491:NS 1619; C115138:isopimaric acid; D011493:Protein Kinase C