Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling

Heppner, Thomas J.; Tykocki, Nathan R.; Hill-Eubanks, David C.; Nelson, Mark T.

doi:10.1085/jgp.201511550

Cited by 61 publications

(95 citation statements)

References 58 publications

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“…; Sidaway & Teramoto, ; Heppner et al . ). In addition to activating K V 7 channels, retigabine has been reported to inhibit peak inward current through VDCCs by greater than 50% in vascular smooth muscle (Mani et al .…”

Section: Resultsmentioning

confidence: 97%

“…This technique allowed for the measurement of TC‐dependent afferent activity without engaging VDCCs in UBSM (Heppner et al . ). To investigate how afferent bursting activity during a TC is affected by K V 7 modulators, we simultaneously measured intravesical pressure and afferent nerve activity in an ex vivo bladder preparation during simulated TCs (sTCs) (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…We previously showed that the major part of the afferent nerve activity generated by the bladder occurs as bursts during TCs, and that these bursts could be simulated by gently compressing the bladder wall (Heppner et al . ). Retigabine nearly abolished these bursts of afferent activity (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…; Heppner et al . ), ‘afferent activity’ was defined as the frequency of action potentials per second (Hz). All data were analysed using LabChart 7 Pro software (ADInstruments, Dunedin, New Zealand).…”

Section: Methodsmentioning

confidence: 99%

“…These TCs also activate bursts of sensory afferent nerve activity, which may convey to the central nervous system both a sense of bladder fullness and an indication that wall tension is optimal for efficient voiding (de Groat & Yoshimura, ; Heppner et al . ). This makes afferent activity associated with TCs an attractive strategy for regulating bladder function; however, it is unclear what generates TCs and how TCs activate sensory nerves.…”

Section: Introductionmentioning

confidence: 97%

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The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

Tykocki

Heppner

Dalsgaard³

et al. 2018

The Journal of Physiology

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Key points KV7 channels are a family of voltage‐dependent K+ channels expressed in many cell types, which open in response to membrane depolarization to regulate cell excitability. Drugs that target KV7 channels are used clinically to treat epilepsy. Interestingly, these drugs also cause urinary retention, but it was unclear how. In this study, we focused on two possible mechanisms by which retigabine could cause urinary retention: by decreasing smooth muscle excitability, or by decreasing sensory nerve outflow. Urinary bladder smooth muscle had no measurable KV7 channel currents. However, the KV7 channel agonist retigabine nearly abolished sensory nerve outflow from the urinary bladder during bladder filling. We conclude that KV7 channel activation likely affects urinary bladder function by blocking afferent nerve outflow to the brain, which is key to sensing bladder fullness. Abstract KV7 channels are voltage‐dependent K+ channels that open in response to membrane depolarization to regulate cell excitability. KV7 activators, such as retigabine, were used to treat epilepsy but caused urinary retention. Using electrophysiological recordings from freshly isolated mouse urinary bladder smooth muscle (UBSM) cells, isometric contractility of bladder strips, and ex vivo measurements of bladder afferent activity, we explored the role of KV7 channels as regulators of murine urinary bladder function. The KV7 activator retigabine (10 μM) had no effect on voltage‐dependent K+ currents or resting membrane potential of UBSM cells, suggesting that these cells lacked retigabine‐sensitive KV7 channels. The KV7 inhibitor XE‐991 (10 μM) inhibited UBSM K+ currents; the properties of these currents, however, were typical of KV2 channels and not KV7 channels. Retigabine inhibited voltage‐dependent Ca2+ channel (VDCC) currents and reduced steady‐state contractions to 60 mM KCl in bladder strips, suggesting that reduction in VDCC current was sufficient to directly affect UBSM function. To determine if retigabine altered ex vivo bladder sensory outflow, we measured afferent activity during simulated transient contractions (TCs) of the bladder wall. Simulated TCs caused bursts of afferent activity that were nearly abolished by retigabine. The effects of retigabine were blocked by co‐incubation with XE‐991, suggesting specific activation of KV7 channels on afferent nerves. These results indicate that retigabine primarily affects urinary bladder function by inhibiting TC generation and afferent nerve activity, which are key to sensing bladder fullness. Any direct inhibition of UBSM contractility is likely to be from non‐specific effects on VDCCs and KV2 channels.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

Tykocki

Heppner

Dalsgaard³

et al. 2018

The Journal of Physiology

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Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy

Chuang

Tyagi

Wang

et al. 2017

Neurourology and Urodynamics

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Characterization of mouse neuro‐urological dynamics in a novel decerebrate arterially perfused mouse (DAPM) preparation

Ito

Drake

Fry

et al. 2018

Neurourology and Urodynamics

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AimTo develop the decerebrate arterially perfused mouse (DAPM) preparation, a novel voiding model of the lower urinary tract (LUT) that enables in vitro‐like access with in vivo‐like neural connectivity.MethodsAdult male mice were decerebrated and arterially perfused with a carbogenated, Ringer's solution to establish the DAPM. To allow distinction between central and peripheral actions of interventions, experiments were conducted in both the DAPM and in a “pithed” DAPM which has no brainstem or spinal cord control.ResultsFunctional micturition cycles were observed in response to bladder filling. During each void, the bladder showed strong contractions and the external urethral sphincter (EUS) showed bursting activity. Both the frequency and amplitude of non‐voiding contractions (NVCs) in DAPM and putative micromotions (pMM) in pithed DAPM increased with bladder filling. Vasopressin (>400 pM) caused dyssynergy of the LUT resulting in retention in DAPM as it increased tonic EUS activity and basal bladder pressure in a dose‐dependent manner (basal pressure increase also noted in pithed DAPM). Both neuromuscular blockade (vecuronium) and autonomic ganglion blockade (hexamethonium), initially caused incomplete voiding, and both drugs eventually stopped voiding in DAPM. Intravesical acetic acid (0.2%) decreased the micturition interval. Recordings from the pelvic nerve in the pithed DAPM showed bladder distention‐induced activity in the non‐noxious range which was associated with pMM.ConclusionsThis study demonstrates the utility of the DAPM which allows a detailed characterization of LUT function in mice.

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Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling

Abstract: As the urinary bladder fills, the rate of rise (but not the frequency) of spontaneous contractions of smooth muscle in the bladder wall increases, thereby eliciting increased afferent nerve activity that signals the fullness of the bladder.

Cited by 61 publications

References 58 publications

The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy

Characterization of mouse neuro‐urological dynamics in a novel decerebrate arterially perfused mouse (DAPM) preparation

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Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling

Abstract: As the urinary bladder fills, the rate of rise (but not the frequency) of spontaneous contractions of smooth muscle in the bladder wall increases, thereby eliciting increased afferent nerve activity that signals the fullness of the bladder.

Cited by 61 publications

References 58 publications

The KV7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K+ channel currents

The KV7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K+ channel currents

Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy

Characterization of mouse neuro‐urological dynamics in a novel decerebrate arterially perfused mouse (DAPM) preparation

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The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

The K_V7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents