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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/F1149    most recent 00440.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Brown, S. M. Articles by Petkov, G. V. Search for Related Content PubMed PubMed Citation Articles by Brown, S. M. Articles by Petkov, G. V.

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

¹Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; ²Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; ³Section of Neurobiology, University of Texas at Austin, Austin, Texas; and ⁴Department of Pharmacology, University of Vermont, Burlington, Vermont

Submitted 19 September 2007 ; accepted in final form 17 July 2008

In urinary bladder smooth muscle (UBSM), stimulation of β-adrenergic receptors (β-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 β-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 and WT UBSM strips pretreated with IBTX had increased overall contractility, and UBSM BK-KO cells were depolarized with 12 mV. Isoproterenol, a nonspecific β-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 β-AR-cAMP pathway in BK-KO mice. 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.

BK channel knockout mouse; isoproterenol; forskolin; iberiotoxin