Abstract: PD70-08
Sources of Funding: Supported by NIH R01DK084284 grant to Georgi V. Petkov and NIH F31DK104528 fellowship to Aaron Provence

Introduction

Recent studies on rodents suggest that voltage-gated K_V7 channels (K_V7.1-K_V7.5) are functionally expressed in detrusor smooth muscle (DSM). Here, we sought to validate the K_V7 channels as potential novel targets in the pharmacological treatment of overactive bladder and/or underactive bladder by elucidating their functional role in human freshly-isolated DSM cells and tissues.

Methods

Human DSM tissues were collected from patient-donors undergoing routine open bladder surgeries in accordance with IRB protocol Pro00045232. Combined methodology including isometric DSM tension recordings, ratiometric fluorescence Ca²⁺ imaging, and perforated patch-clamp electrophysiology, was applied to ascertain the role of the K_V7 channel subtypes in human DSM function.

Results

The K_V7 channel activator, retigabine, decreased global Ca²⁺ concentrations in DSM isolated strips, while the K_V7 channel inhibitor XE991 increased global DSM Ca²⁺ concentrations. Retigabine decreased spontaneous phasic and nerve-evoked contractions in DSM isolated strips. On the contrary, XE991 increased spontaneous phasic and nerve-evoked contractions in DSM isolated strips. Retigabine-induced DSM relaxation was attenuated in the presence of XE991. The K_V7.2/K_V7.3 channel activator ICA-069673 and K_V7.1 activator L-364,373 also inhibited DSM spontaneous phasic contractions. In freshly-isolated DSM cells, retigabine hyperpolarized the DSM cell membrane potential, while XE991 induced membrane depolarization. Consistent with retigabine, the novel and selective K_V7.4/K_V7.5 channel activator ML213, also hyperpolarized the DSM cell membrane potential.

Conclusions

Collectively, these data provide promising evidence for the potential therapeutic utility of selective K_V7 channel pharmacological modulators. DSM K_V7 channels appear to be a universal therapeutic switch for bladder dysfunction treatment. Pharmacological opening of K_V7 channels may be an effective novel approach to treat overactive bladder, whereas K_V7 channel inhibitors can potentially be used as novel therapeutics for underactive bladder.

Funding

Supported by NIH R01DK084284 grant to Georgi V. Petkov and NIH F31DK104528 fellowship to Aaron Provence