Poster, Podium & Video Sessions
Presentation Authors: Aaron Provence, Damiano Angoli, Columbia, SC, Eric Rovner, Charleston, SC, Georgi Petkov*, Columbia, SC
Introduction: Recent studies on rodents suggest that voltage-gated KV7 channels (KV7.1-KV7.5) are functionally expressed in detrusor smooth muscle (DSM). Here, we sought to validate the KV7 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 KV7 channel subtypes in human DSM function.
Results: The KV7 channel activator, retigabine, decreased global Ca2+ concentrations in DSM isolated strips, while the KV7 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 KV7.2/KV7.3 channel activator ICA-069673 and KV7.1 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 KV7.4/KV7.5 channel activator ML213, also hyperpolarized the DSM cell membrane potential.
Conclusions: Collectively, these data provide promising evidence for the potential therapeutic utility of selective KV7 channel pharmacological modulators. DSM KV7 channels appear to be a universal therapeutic switch for bladder dysfunction treatment. Pharmacological opening of KV7 channels may be an effective novel approach to treat overactive bladder, whereas KV7 channel inhibitors can potentially be used as novel therapeutics for underactive bladder.
Source Of Funding: Supported by NIH R01DK084284 grant to Georgi V. Petkov and NIH F31DK104528 fellowship to Aaron Provence