Beta-adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+ channel

Am J Physiol Renal Physiol. 2008 Oct;295(4):F1149-57. doi: 10.1152/ajprenal.00440.2007. Epub 2008 Aug 13.


In urinary bladder smooth muscle (UBSM), stimulation of beta-adrenergic receptors (beta-ARs) leads to activation of the large-conductance Ca2+-activated K+ (BK) channel currents (Petkov GV and Nelson MT. Am J Physiol Cell Physiol 288: C1255-C1263, 2005). In this study we tested the hypothesis that the BK channel mediates UBSM relaxation in response to beta-AR stimulation using the highly specific BK channel inhibitor iberiotoxin (IBTX) and a BK channel knockout (BK-KO) mouse model in which the gene for the pore-forming subunit was deleted. UBSM strips isolated from wild-type (WT) and BK-KO mice were stimulated with 20 mM K+ or 1 microM carbachol to induce phasic and tonic contractions. BK-KO and WT UBSM strips pretreated with IBTX had increased overall contractility, and UBSM BK-KO cells were depolarized with approximately 12 mV. Isoproterenol, a nonspecific beta-AR agonist, and forskolin, an adenylate cyclase activator, decreased phasic and tonic contractions of WT UBSM strips in a concentration-dependent manner. In the presence of IBTX, the concentration-response curves to isoproterenol and forskolin were shifted to the right in WT UBSM strips. Isoproterenol- and forskolin-mediated relaxations were enhanced in BK-KO UBSM strips, and a leftward shift in the concentration-response curves was observed. The leftward shift was eliminated upon PKA inhibition with H-89, suggesting upregulation of the beta-AR-cAMP pathway in BK-KO mice. These results indicate that the BK channel is a key modulator in beta-AR-mediated relaxation of UBSM and further suggest that alterations in BK channel expression or function could contribute to some pathophysiological conditions such as overactive bladder and urinary incontinence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Calcium / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Isoproterenol / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Relaxation / drug effects
  • Muscle Relaxation / physiology*
  • Muscle, Smooth / physiology*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Peptides / pharmacology
  • Receptors, Adrenergic, beta / metabolism
  • Synaptotagmins
  • Urinary Bladder / physiology*
  • Urinary Incontinence / physiopathology


  • Adrenergic beta-Agonists
  • Nerve Tissue Proteins
  • Peptides
  • Receptors, Adrenergic, beta
  • Syt17 protein, mouse
  • Synaptotagmins
  • Colforsin
  • iberiotoxin
  • Cyclic AMP-Dependent Protein Kinases
  • Isoproterenol
  • Calcium