Attenuated BK channel function promotes overactive bladder in a rat model of obesity

Abstract

Overactive bladder (OAB) is mostly observed in obese individuals, and is associated with enhanced excitability and contractility of the detrusor smooth muscle (DSM). Large-conductance voltage- and Ca2+-activated K+ (BK) channels reduce the excitability and contractility of the DSM. We tested whether obesity-induced OAB is associated with altered BK channel expression and activity in the DSM. Seven-week-old female Sprague-Dawley rats (N=80) were fed a normal or high-fat diet (HFD) for 12 weeks. HFD-fed rats exhibited a higher average bodyweight and urodynamically established detrusor overactivity. mRNA levels of the Kcnma1 (BKα subunit) and Kcnmb1 (BKβ1 subunit) in whole tissues and cells from the DSM were reduced in HFD-fed rats. A selective BK channel opener, NS1619, was then applied to DSM cells from the two groups of rats. Patch-clamp techniques revealed that spontaneous transient outward currents, NS1619-induced activation of spontaneous transient outward currents, and whole-cell BK currents, as well as NS1619-induced membrane hyperpolarization, were attenuated in DSM cells from HFD-fed rats. The relaxation effect of NS1619 on contractility was reduced in DSM strips from HFD-fed rats. Thus, impaired expression of Kcnma1 and Kcnmb1 in the DSM contributes to obesity-induced OAB, suggesting that BK channels could be a useful treatment targets in OAB.

Solifenacin/Mirabegron Induces an Acute Compliance Increase in the Filling Phase of the Capacity-Reduced Urinary Bladder: A Pressure-Volume Analysis in Rats

“…Even though the etiology of urinary frequency/urgency in OAB patients seems to be multiple, studies have suggested lesions in the visco-elastic property ( Cullingsworth et al, 2020 ) and contractility ( Li et al, 2019 ) of the bladder as well as enhanced excitability in bladder sensory endings ( Meng et al, 2012 ) and the nervous system in the lumbosacral spinal cord ( Reynolds et al, 2016 ) and pontine micturition centers ( Zorba et al, 2013 ) could underlie the development of symptoms. In addition to their well-established effects on the detrusor, the results of the present study revealed that the therapeutic effects of solifenacin and mirabegron on OAB-like symptoms could be attributed to an increased compliance, the visco-elastic property of the bladder itself.…”

Reduced Ca2+ spark activity contributes to detrusor overactivity of rats with partial bladder outlet obstruction

“…In our previous study, we conducted detrusor strip experiments and found that measures for negative feedback regulation as related to RyRs/BK channels were weakened in DO muscle, which consequently resulted in spontaneous contractile overactivity [16]. Similarly oriented studies from within our own research lab [17] and other from others [18][19][20] have indicated that the levels of expression and functions of BK channels were found to have been decreased and diminished. These effects and findings provoked the idea that greater cell excitability could have been partly attributed to have accounted for the weakened measures of observed negative feedback regulation in DO muscle.…”

A Comprehensive Review of the Therapeutic Value of Urine-Derived Stem Cells

“…Overactive bladder (OAB), manifesting as urinary urgency and frequent nocturia, is often treated with invasive botulinum toxin or neuromodulation and reconstructive surgery ( Robinson and Cardozo, 2019 ). Large conductance voltage and Ca2+-activated K+ (BK) channels have been noted as excellent therapeutic candidates for OAB based on their effectiveness at reducing sexual excitability and the contractility of bladder smooth muscle by hyperpolarizing the membrane ( Li et al, 2019 ). Interestingly, stem cells have multifarious ion channels that are thought to be involved in cell proliferation.…”