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

Ning Li,Ping Wang,Zizheng Li,Honglin Ding,Yili Liu,Peng Zhang

doi:10.18632/aging.102182

Ning Li, Ping Wang + Show 4 more

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https://doi.org/10.18632/aging.102182

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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.

Highlights

Overactive bladder (OAB) is characterized by urinary urgency, with or without urinary incontinence, and is usually associated with urodynamically demonstrable detrusor overactivity [1]
Our results demonstrated that Kcnma1 and Kcnmb1 mRNA levels in both detrusor smooth muscle (DSM) layers and cells were significantly lower in high-fat diet (HFD) rats than in ND animals (Figure 3A, 3B)
We investigated whether HFD feeding for 12 weeks altered the ability of large-conductance voltage- and Ca2+-activated K+ (BK) channels to hyperpolarize the membrane potential of DSM cells

Summary

Introduction

Overactive bladder (OAB) is characterized by urinary urgency, with or without urinary incontinence, and is usually associated with urodynamically demonstrable detrusor overactivity [1]. Rats fed a high-fat diet (HFD) were found to become overweight, to develop high blood glucose and insulin concentrations, and to exhibit urodynamically demonstrable non-voiding contractions suggestive of OAB [7, 10, 11]. Obesity is associated with systemic low-grade inflammation, which may contribute to bladder dysfunction (including OAB) by increasing the concentrations of inflammatory factors in the detrusor smooth muscle (DSM) [7, 10, 11]. OAB is associated with increased DSM excitability, contractility and spontaneous phasic contractions. Changes in the expression and function of DSM regulatory proteins may alter the contractility of the DSM [12,13,14]

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