Submitted on September 19, 2007
Accepted on July 17, 2008
-adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large conductance Ca2+-activated K+ channel
Sean M Brown1, Lilia M Bentcheva-Petkova1, Liu Lei1, Kiril L Hristov1, Muyan Chen1, Whitney F Kellett1, Andrea L. Meredith2, Richard W. Aldrich3, Mark T Nelson4, and Georgi V. Petkov1*
1 PBS, University of South Carolina, Columbia, South Carolina, United States
2 Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
3 Section of Neurobiology, University of Texas at Austin, Austin, Texas, United States
4 Pharmacology, University of Vermont, Burlington, Vermont, United States
* To whom correspondence should be addressed. E-mail: petkov{at}cop.sc.edu.
In urinary bladder smooth muscle (UBSM), stimulation of 
-adrenergic receptors (-ARs) leads to activation of the large-conductance Ca2+-activated K+ (BK) channel currents (Petkov & Nelson, Am. J. Physiol., 2005, 288(6): C1255-63). Here we tested the hypothesis that the BK channel mediates UBSM relaxation in response to -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 µM carbachol to induce phasic and tonic contractions. BK-KO UBSM and WT UBSM strips pretreated with IBTX had increased overall contractility and UBSM BK-KO cells were depolarized with ~12 mV. Isoproterenol, a non-specific -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 H89 suggesting up-regulation of the -AR-cAMP pathway in BK-KO mouse. These results indicate that the BK channel is a key modulator in β-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.
