title: BRL37344, a β3-adrenergic receptor agonist, decreases nerve-evoked contractions in human detrusor smooth muscle isolated strips: role of BK channels.
abstract: OBJECTIVE
  To investigate the mechanism by which BRL37344, a β3-adrenergic receptor (β3-ARs) agonist, facilitates the inhibition of nerve-evoked contractions in human detrusor smooth muscle (DSM) isolated strips and to identify the role of large-conductance Ca(2+)-activated K(+) (BK) channels in this process.
  
  
  METHODS
  Human DSM specimens were obtained from open bladder surgeries on patients without preoperative history of overactive bladder symptoms. Isometric DSM tension recordings were conducted using force-displacement transducers and thermostatically controlled tissue baths. Nerve-evoked contractions were generated by electrical field stimulation (EFS).
  
  
  RESULTS
  BRL37344, a β3-AR agonist, significantly decreased the amplitude, muscle force, and duration of the DSM contractions induced by 20 Hz EFS, in a concentration-dependent manner. This BRL37344-mediated inhibition of the amplitude and muscle force of the nerve-evoked DSM contraction was significantly reduced by iberiotoxin, a highly selective inhibitor of the BK channel, revealing a role for BK channels in the β3-AR-induced inhibition of human DSM nerve-evoked contractions. We further used atropine, α,β-methylene-ATP, and suramin to separate the cholinergic and purinergic components of human DSM nerve-evoked contractions. We found that the β3-AR agonist, BRL37344, inhibited both components of the EFS-induced (0.5-50 Hz) DSM contractions.
  
  
  CONCLUSIONS
  This study supports the concept that β3-AR agonists inhibit nerve-evoked contractions in human DSM. We have further revealed that BK channels play a critical role in BRL37344-mediated relaxation of nerve-evoked contractions in human DSM. The study suggests that in addition to β3-ARs, BK channels may also represent promising pharmacologic targets in the treatment of urinary bladder dysfunction.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA.
authors.forename: Serge A Y
authors.initials: SA
authors.lastname: Afeli
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rovner
authors.forename: Georgi V
authors.initials: GV
authors.lastname: Petkov
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000368:Aged; D001285:Atropine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D058913:Purinergic Agonists / Q000494:pharmacology; D058914:Purinergic Antagonists / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D004983:Ethanolamines; D051036:Large-Conductance Calcium-Activated Potassium Channels; D018727:Muscarinic Antagonists; D010455:Peptides; D026902:Potassium Channel Blockers; D058913:Purinergic Agonists; D058914:Purinergic Antagonists; C057368:BRL 37344; D013498:Suramin; C064719:iberiotoxin; D001285:Atropine; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R616-24
references.pmid: 16931654
references.citation: Int Braz J Urol. 2009 Jan-Feb;35(1):76-83
references.pmid: 19254402
references.citation: Am J Physiol Cell Physiol. 2011 Oct;301(4):C903-12
references.pmid: 21697543
references.citation: Br J Pharmacol. 2006 Feb;147 Suppl 2:S88-119
references.pmid: 16465187
references.citation: J Physiol. 2000 Apr 15;524 Pt 2:565-79
references.pmid: 10766934
references.citation: J Urol. 1995 Sep;154(3):1241-5
references.pmid: 7637095
references.citation: Nat Rev Urol. 2011 Dec 13;9(1):30-40
references.pmid: 22158596
references.citation: World J Urol. 2009 Dec;27(6):711-5
references.pmid: 19449014
references.citation: J Physiol. 1984 Sep;354:431-43
references.pmid: 6481641
references.citation: Am J Physiol Renal Physiol. 2008 Oct;295(4):F1149-57
references.pmid: 18701628
references.citation: Pharmacology. 2008;81(3):251-8
references.pmid: 18253064
references.citation: Am J Physiol Cell Physiol. 2005 Jun;288(6):C1255-63
references.pmid: 15677377
references.citation: Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R60-8
references.pmid: 10896865
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):862-9
references.pmid: 11082418
references.citation: BJU Int. 2006 Dec;98(6):1310-4
references.pmid: 17026593
references.citation: J Physiol. 2009 Nov 1;587(Pt 21):5275-88
references.pmid: 19736301
references.citation: J Pharmacol Exp Ther. 2003 Apr;305(1):106-13
references.pmid: 12649358
references.citation: J Pharmacol Exp Ther. 2005 Apr;313(1):260-7
references.pmid: 15576470
references.citation: Br J Pharmacol. 2000 Dec;131(7):1489-95
references.pmid: 11090125
references.citation: Am J Physiol Cell Physiol. 2012 Jun 1;302(11):C1632-41
references.pmid: 22422396
references.citation: J Urol. 2002 Jan;167(1):157-64
references.pmid: 11743296
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2012 Aug;385(8):759-67
references.pmid: 22644105
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):449-62
references.pmid: 18060543
references.citation: Am J Physiol Cell Physiol. 2008 Nov;295(5):C1344-53
references.pmid: 18799656
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9579-84
references.pmid: 10944224
references.citation: J Urol. 2001 Jul;166(1):335-40
references.pmid: 11435896
references.citation: J Pharmacol Exp Ther. 1999 Mar;288(3):1367-73
references.pmid: 10027879
references.citation: Br J Pharmacol. 2004 Jan;141(1):183-93
references.pmid: 14662721
references.citation: Br J Pharmacol. 2010 Jul;160(5):1048-61
references.pmid: 20590599