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1Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont; and 2Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California
Submitted 11 February 2005 ; accepted in final form 11 April 2005
Overactive bladder and incontinence are major medical issues, which lack effective therapy. Previously, we showed (Meredith AL, Thornloe KS, Werner ME, Nelson MT, and Aldrich RW. J Biol Chem 279: 36746–36752, 2004) that the gene mSlo1 encodes large-conductance Ca2+-activated K+ (BK) channels of urinary bladder smooth muscle (UBSM) and that ablation of mSlo1 leads to enhanced myogenic and nerve-mediated contractility and increased urination frequency. Here, we examine the in vivo urodynamic consequences and neurotransmitter dependence in the absence of the BK channel. The sensitivity of contractility to nerve stimulation was greatly enhanced in UBSM strips from Slo–/– mice. The stimulation frequency required to obtain a 50% maximal contraction was 8.3 ± 0.9 and 19.1 ± 1.8 Hz in Slo–/– and Slo+/+ mice, respectively. This enhancement is at least partially due to alterations in UBSM excitability, as muscarinic-induced Slo–/– contractility is elevated in the absence of neuronal activity. Muscarinic-induced Slo–/– contractility was mimicked by blocking BK channels with iberiotoxin (IBTX) in Slo+/+ strips, whereas IBTX had no effect on Slo–/– strips. IBTX also enhanced purinergic contractions of Slo+/+ UBSM but was without effect on purinergic contractions of Slo–/– strips. In vivo bladder pressure and urine output measurements (cystometry) were performed on conscious, freely moving mice. Slo–/– mice exhibited increased bladder pressures, pronounced pressure oscillations, and urine dripping. Our results indicate that the BK channel in UBSM has a very significant role in urinary function and dysfunction and as such likely represents an important therapeutic target.
incontinence; bladder dysfunction; cystometry; K+ channel
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