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Am J Physiol Cell Physiol 295: C1344-C1353, 2008. First published September 17, 2008; doi:10.1152/ajpcell.00001.2008
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RECEPTORS AND SIGNAL TRANSDUCTION

Stimulation of β3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels

Kiril L. Hristov,* Xiangli Cui,* Sean M. Brown, Lei Liu, Whitney F. Kellett, and Georgi V. Petkov

Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina

Submitted 2 January 2008 ; accepted in final form 4 September 2008

We investigated the role of large-conductance Ca2+-activated K+ (BK) channels in β3-adrenoceptor (β3-AR)-induced relaxation in rat urinary bladder smooth muscle (UBSM). BRL 37344, a specific β3-AR agonist, inhibits spontaneous contractions of isolated UBSM strips. SR59230A, a specific β3-AR antagonist, and H89, a PKA inhibitor, reduced the inhibitory effect of BRL 37344. Iberiotoxin, a specific BK channel inhibitor, shifts the BRL 37344 concentration response curves for contraction amplitude, net muscle force, and tone to the right. Freshly dispersed UBSM cells and the perforated mode of the patch-clamp technique were used to determine further the role of β3-AR stimulation by BRL 37344 on BK channel activity. BRL 37344 increased spontaneous, transient, outward BK current (STOC) frequency by 46.0 ± 20.1%. In whole cell mode at a holding potential of Vh = 0 mV, the single BK channel amplitude was 5.17 ± 0.28 pA, whereas in the presence of BRL 37344, it was 5.55 ± 0.41 pA. The BK channel open probability was also unchanged. In the presence of ryanodine and nifedipine, the current-voltage relationship in response to depolarization steps in the presence and absence of BRL 37344 was identical. In current-clamp mode, BRL 37344 caused membrane potential hyperpolarization from –26.1 ± 2.1 mV (control) to –29.0 ± 2.2 mV. The BRL 37344-induced hyperpolarization was eliminated by application of iberiotoxin, tetraethylammonium or ryanodine. The data indicate that stimulation of β3-AR relaxes rat UBSM by increasing the BK channel STOC frequency, which causes membrane hyperpolarization and thus relaxation.

BRL 37344; SR59230a; H89; iberiotoxin; detrusor; patch-clamp; spontaneous, transient, outward large-conductance current


Address for reprint requests and other correspondence: G. V. Petkov, Associate Professor of Pharmacology, Dept. of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Univ. of South Carolina, Coker Life Sciences Bldg., Rm. 709, 715 Sumter St., Columbia, SC 29208 (e-mail: petkov{at}cop.sc.edu)






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