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Residents' Research 2017

Development of Bladder Sensation During Urodynamics Compared to During a Non-Invasive Accelerated Hydration Protocol

Authors:

Randy Vince Jr., Anna Nagle, John Speich, David Le, Peter Ghamarian, Andrew Colhoun, R. Wayne Barbee, Paul Ratz, and Adam Klausner

Objective:

This study’s goal was to compare the development of real-time bladder sensation in patients with OAB undergoing an accelerated hydration protocol with both normal participants and different OAB patients undergoing urodynamics (UDS).

Materials & Methods:

Individuals with OAB and normal bladder function were enrolled in a hydration study and a separate OAB group was enrolled into an UD study. The hydration group drank 2L of Gatorade-G2® and complete two fill/void cycles. Both groups recorded standardized verbal sensory thresholds and real-time sensation (0-100% scale) using a touch-screen sensation meter.

Results:

In the hydration study, filling duration decreased and voided volume did not significantly change from fill1 to fill2 in both the normal (n=14) and OAB (n=12) groups. In the UD study (n=14), duration was shorter than either hydration fill. The UD fill volume was not statistically different than the OAB hydration group total fill volume in a t-test adjusted for repeated measures. In the normal group, a right-shift was noted in the %sensation-%capacity curve consistent with viscoelastic effects, but a left shift was noted in the OAB group (fig.1), inconsistent with viscoelastic effects. OAB undergoing UDS had a %sensation-%capacity curve that was significantly lower than hydration fill2 at 20% and 50% sensation and was significantly lower than hydration fill1 at 75%-90% sensation.

Conclusions:

This study shows a non-invasive hydration protocol to characterize bladder sensation in participants with OAB, which provides data that could potentially be used to sub-type patients. Differences between fill1 and fill2 may reveal dynamic characteristics of the bladder not found with single UD fill and suggest that bladders in subjects with OAB may undergo acute changes in compliance, tone, and/or sensitization. The trend in OAB patients to have lower bladder sensation with faster filling may be related to desensitization, hydration level, training, or other factors.

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Muscarinic Receptor Activation in Mouse and Rabbit Bladder Causes Delayed Activation of AMP-Dependent Protein Kinase (AMPK): Potential Novel Mechanism of Detrusor Underactivity

Authors:

Randy Vince Jr., John E. Speich, Adam P. Klausner, Amy S. Miner and Paul H. Ratz

Introduction:

Muscarinic receptor stimuli such as carbachol (CCh) cause increases in detrusor smooth muscle (DSM) myosin light chain (MLC) phosphorylation and contraction. Notably, upon stimulation with CCh, DSM force rises rapidly to a peak value, then gradually declines (fades) despite the continued presence of CCh. The mechanism behind the fade in force over time is not understood. There is evidence that, in addition to causing contraction, muscarinic receptor stimulation can activate AMPK, and AMPK has been shown to negatively regulate smooth muscle contraction. The purpose of this study was to test the hypothesis that DSM contraction fade is due to the delayed activation of AMPK.

Methods:

Mouse bladder with mucosa were cut into rings ~3 mm wide, and strips of DSM free from underlying mucosa were removed from rabbit bladders. Each tissue was placed in an organ bath connected to a force transducer and length-adjuster and subjected to a length-tension protocol to identify the length (Lref) that produced the strongest active force induced by KCl. Each ring was subsequently set to 95% Lref. Three tissues were then contracted by exposure to 10 microM CCh and quick-frozen at 5, 30 and 180 seconds. A fourth tissue was not contracted and quick-frozen to assess the basal-state. Tissues were subsequently processed to quantify the level of phosphoproteins that are indices of activation of AMPK (ACC-pS79 and AMPK-p172) and of actomyosin crossbridges (MLC-pS19 and MYPT1-pT853).

Results:

Compared to the basal-state, CCh induced a strong increase in force in mouse bladder and rabbit DSM that peaked at, respectively, 60 sec and 20 sec, before declining to ~50% of the peak values within 180 sec (n=3). MLC-pS19 also displayed this biphasic response. AMPK-pT172 and ACC-pS79 displayed a delayed increase corresponding with the decrease in contractile force.

Conclusion:

The muscarinic receptor stimulus CCh caused a rapid increase in force in mouse bladder and rabbit DSM that faded with time despite the continued presence of CCh. The fade in force correlated with the delayed increase in AMPK activity as assessed by increases in the phosphoproteins, ACC-pS79 and AMPK-pT172. Because AMPK has been shown to inhibit smooth muscle contraction, the correlation of an increase in AMPK activity with the decrease in force supports the hypothesis that AMPK may be responsible for fade in DSM force. Because AMPK activity is also elevated during ischemia/hypoxia, a condition known to cause bladder underactivity, these data warrant further studies to investigate the potential role of AMPK in bladder underactivity.

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updated: June 23, 2017