Publications by authors named "Christopher L Langdale"

11 Publications

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Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats.

Am J Physiol Renal Physiol 2021 06 21. Epub 2021 Jun 21.

Department of Biomedical Engineering, Duke University, Durham, NC, United States.

The spontaneously hypertensive rat (SHR), a genetic model of high blood pressure, has also been studied as a potential model of overactive bladder (OAB). In vivo studies confirmed the presence of surrogate markers of OAB, including detrusor overactivity (DO), increased urinary frequency, decreased bladder capacity and voided volume, and afferent hypersensitivity to bladder irritation. However, these observations were during awake cystometry (CMG) using implanted bladder catheters tethered to an infusion pump and artificially filled. We conducted studies in awake unrestrained untethered age-matched female SHR and Wistar rats to quantify naïve consumption and voiding behavior and the effect of capsaicin desensitization on consumption and voiding behavior. Food and water consumption, body weight, voiding frequency (VF), and voided volume (VV) were recorded. Rats were placed in metabolism cages for 24 h, up to twice a week, from 17 to 37 weeks of age. In SHRs, body weight, food, and water consumption were decreased compared to Wistars. However, after normalizing for body weight, only water consumption was reduced. Wistars exhibited a diurnal pattern of voiding behavior. Compared to Wistars, SHRs showed smaller VV and lacked a diurnal voiding pattern such that VV was similar during both light cycles. No difference in VF was observed after normalizing for water consumption. We observed no change in SHR voiding behavior following capsaicin desensitization, which was in contrast to a prior awake in vivo cystometry study describing increased VV and micturition interval in SHRs, and suggests that C-fiber activity may not contribute to bladder hypersensitivity in SHRs.
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http://dx.doi.org/10.1152/ajprenal.00564.2020DOI Listing
June 2021

State-dependent bioelectronic interface to control bladder function.

Sci Rep 2021 01 11;11(1):314. Epub 2021 Jan 11.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

Electrical stimulation therapies to promote bladder filling and prevent incontinence deliver continuous inhibitory stimulation, even during bladder emptying. However, continuous inhibitory stimulation that increases bladder capacity (BC) can reduce the efficiency of subsequent voiding (VE). Here we demonstrate that state-dependent stimulation, with different electrical stimulation parameters delivered during filling and emptying can increase both BC and VE relative to continuous stimulation in rats and cats of both sexes. We show that continuous 10 Hz pudendal nerve stimulation increased BC (120-180% of control) but decreased VE (12-71%, relative to control). In addition to increasing BC, state-dependent stimulation in both rats and cats increased VE (280-759% relative to continuous stimulation); motor bursting in cats increased VE beyond the control (no stimulation) condition (males: 323%; females: 161%). These results suggest that a bioelectronic bladder pacemaker can treat complex voiding disorders, including both incontinence and retention, which paradoxically are often present in the same individual.
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http://dx.doi.org/10.1038/s41598-020-79493-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801663PMC
January 2021

Effects of intravesical prostaglandin E on bladder function are preserved in capsaicin-desensitized rats.

Am J Physiol Renal Physiol 2021 02 7;320(2):F212-F223. Epub 2020 Dec 7.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Prostaglandin E (PGE) instilled into the bladder generates symptoms of urinary urgency in healthy women and reduces bladder capacity and urethral pressure in both humans and female rats. Systemic capsaicin desensitization, which causes degeneration of C-fibers, prevented PGE-mediated reductions in bladder capacity, suggesting that PGE acts as an irritant (Maggi CA, Giuliani S, Conte B, Furio M, Santicioli P, Meli P, Gragnani L, Meli A. 145: 105-112, 1988). In the present study, we instilled PGE in female rats after capsaicin desensitization but without the hypogastric nerve transection that was conducted in the Maggi et al. study. One week after capsaicin injection (125 mg/kg sc), rats underwent cystometric and urethral perfusion testing under urethane anesthesia with saline and 100 µM PGE. Similar to naïve rats, capsaicin-desensitized rats exhibited a reduction in bladder capacity from 1.23 ± 0.08 mL to 0.70 ± 0.10 mL ( = 0.002, = 9), a reduction in urethral perfusion pressure from 19.3 ± 2.1 cmHO to 10.9 ± 1.2 cmHO ( = 0.004, = 9), and a reduction in bladder compliance from 0.13 ± 0.020 mL/cmHO to 0.090 ± 0.014 mL/cmHO ( = 0.011, = 9). Thus, changes in bladder function following the instillation of PGE were not dependent on capsaicin-sensitive pathways. Further, these results suggest that urethral relaxation/weakness and/or increased detrusor pressure as a result of decreased compliance may contribute to urinary urgency and highlight potential targets for new therapies for overactive bladder.
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http://dx.doi.org/10.1152/ajprenal.00302.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948121PMC
February 2021

Stimulation of the pelvic nerve increases bladder capacity in the PGE cat model of overactive bladder.

Am J Physiol Renal Physiol 2020 06 20;318(6):F1357-F1368. Epub 2020 Apr 20.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Selective electrical stimulation of the pudendal nerve exhibits promise as a potential therapy for treating overactive bladder (OAB) across species (rats, cats, and humans). More recently, pelvic nerve (PelN) stimulation was demonstrated to improve cystometric bladder capacity in a PGE rat model of OAB. However, PelN stimulation in humans or in an animal model that is more closely related to humans has not been explored. Therefore, our objective was to quantify the effects of PGE and PelN stimulation in the cat. Acute cystometry experiments were conducted in 14 α-chloralose-anesthetized adult, neurologically intact female cats. Intravesical PGE decreased bladder capacity, residual volume, threshold contraction pressure, and mean contraction pressure. PelN stimulation reversed the PGE-induced decrease in bladder capacity and increased evoked external urethral sphincter electromyographic activity without influencing voiding efficiency. The increases in bladder capacity generated by PelN stimulation were similar in the rat and cat, but the stimulation parameters to achieve this effect differed (threshold amplitude at 10 Hz in the rat vs. twice threshold amplitude at 1 Hz in the cat). These results highlight the potential of PGE as a model of OAB and provide further evidence that PelN stimulation is a promising approach for the treatment of OAB symptoms.
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http://dx.doi.org/10.1152/ajprenal.00068.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717121PMC
June 2020

Detection of Bladder Contractions From the Activity of the External Urethral Sphincter in Rats Using Sparse Regression.

IEEE Trans Neural Syst Rehabil Eng 2018 08 9;26(8):1636-1644. Epub 2018 Jul 9.

Bladder overactivity and incontinence and dysfunction can be mitigated by electrical stimulation of the pudendal nerve applied at the onset of a bladder contraction. Thus, it is important to predict accurately both bladder pressure and the onset of bladder contractions. We propose a novel method for prediction of bladder pressure using a time-dependent spectrogram representation of external urethral sphincter electromyographic (EUS EMG) activity and a least absolute shrinkage and selection operator regression model. There was a statistically significant improvement in prediction of bladder pressure compared with methods based on the firing rate of EUS EMG activity. This approach enabled prediction of the onset of bladder contractions with 91% specificity and 96% sensitivity and may be suitable for closed-loop control of bladder continence.
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http://dx.doi.org/10.1109/TNSRE.2018.2854675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531051PMC
August 2018

Stimulation of the sensory pudendal nerve increases bladder capacity in the rat.

Am J Physiol Renal Physiol 2018 04 15;314(4):F543-F550. Epub 2017 Nov 15.

Department of Biomedical Engineering, Duke University , Durham, North Carolina.

Pudendal nerve stimulation is a promising treatment approach for lower urinary tract dysfunction, including symptoms of overactive bladder. Despite some promising clinical studies, there remain many unknowns as to how best to stimulate the pudendal nerve to maximize therapeutic efficacy. We quantified changes in bladder capacity and voiding efficiency during single-fill cystometry in response to electrical stimulation of the sensory branch of the pudendal nerve in urethane-anesthetized female Wistar rats. Increases in bladder capacity were dependent on both stimulation amplitude and rate. Stimulation that produced increases in bladder capacity also led to reductions in voiding efficiency. Also, there was a stimulation carryover effect, and increases in bladder capacity persisted during several nonstimulated trials following stimulated trials. Intravesically administered PGE reduced bladder capacity, producing a model of overactive bladder (OAB), and sensory pudendal nerve stimulation again increased bladder capacity but also reduced voiding efficiency. This study serves as a basis for future studies that seek to maximize the therapeutic efficacy of sensory pudendal nerve stimulation for the symptoms of OAB.
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http://dx.doi.org/10.1152/ajprenal.00373.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966759PMC
April 2018

OAB without an overactive bladder in the acute prostaglandin E2 rat model.

Am J Physiol Renal Physiol 2017 Nov 2;313(5):F1169-F1177. Epub 2017 Aug 2.

Department of Biomedical Engineering, Duke University, Durham, North Carolina;

Intravesical prostaglandin E2 (PGE2) was previously used to induce overactive bladder (OAB) symptoms, as it reduces bladder capacity in rats and causes a "strong urgency sensation" in healthy women. However, the mechanism by which this occurs is unclear. To clarify how PGE2 reduces bladder capacity, 100 µM PGE2 was administered intravesically during open, single-fill cystometry with simultaneous measurement of sphincter EMG in the urethane-anesthetized female Wistar rat. PGE2 was also applied to the urethra or bladder selectively by use of a ligature at the bladder neck before (urethra) or during (bladder) closed-outlet, single-fill cystometry. Additional tests of urethral perfusion with PGE2 were made. PGE2 decreased bladder capacity, increased voiding efficiency, and increased sphincter EMG during open cystometry compared with saline controls. The number of nonvoiding contractions did not change with PGE2; however, bladder compliance decreased. During closed-outlet cystometry, PGE2 applied only to the bladder or the urethra did not decrease bladder capacity. Urethral infusion of PGE2 decreased urethral perfusion pressure. Taken together, these results suggest that intravesical PGE2 may decrease bladder capacity by targeting afferents in the proximal urethra. This may occur through urethral relaxation and decreased bladder compliance, both of which may increase activation of proximal urethra afferents from distension of the proximal urethra. This hypothesis stands in contrast to many hypotheses of urgency that focus on bladder dysfunction as the primary cause of OAB symptoms. Targeting the urethra, particularly urethral smooth muscle, may be a promising avenue for the design of drugs and devices to treat OAB.
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http://dx.doi.org/10.1152/ajprenal.00270.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792156PMC
November 2017

Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E rat model of overactive bladder.

Am J Physiol Renal Physiol 2017 09 14;313(3):F657-F665. Epub 2017 Jun 14.

Department of Biomedical Engineering, Duke University, Durham, North Carolina;

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E (PGE) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE vs. vehicle and PelN stimulation after intravesical PGE on cystometric parameters were quantified. Intravesical infusion of PGE resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE PelN stimulation reversed the PGE-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.
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http://dx.doi.org/10.1152/ajprenal.00116.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625104PMC
September 2017

Phasic activation of the external urethral sphincter increases voiding efficiency in the rat and the cat.

Exp Neurol 2016 Nov 25;285(Pt B):173-181. Epub 2016 May 25.

Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA; Department of Neurobiology, Duke University, Durham, NC, USA; Department of Surgery, Duke University, Durham, NC, USA. Electronic address:

Objective: Electrical stimulation of the pudendal nerve (PN) is a potential therapy for bladder dysfunction, but voiding efficiency (VE) produced by PN stimulation appears limited to 60-70%. We conducted experiments in rats and cats to investigate the hypothesis that introduction of artificial phasic bursting activity of the external urethral sphincter (EUS) would enhance VE under conditions where such activity was absent.

Materials And Methods: Cystometry experiments were conducted in 17 urethane anesthetized female Sprague-Dawley rats and 4 α-chloralose anesthetized male cats. The effects of phasic stimulation of the pudendal motor branch on VE were quantified in intact conditions, following bilateral transection of the motor branch of the PN, and following subsequent bilateral transection of the sensory branch of the PN.

Results: Artificial phasic bursting activity in the EUS generated by electrical stimulation of the motor branch of the PN increased VE in both rats and cats. Subsequent transection of the sensory branch of the PN abolished the increased VE elicited by phasic stimulation in both rats and cats.

Conclusions: Artificial phasic EUS bursting restored efficient voiding in rats. Introduction of artificial phasic bursting in cats, which normally exhibit EUS relaxation while voiding, was also effective in promoting efficient voiding. In both species phasic EUS activity increased voiding efficiency via activation of pudendal sensory pathways. These results provide further insight into the function of phasic EUS activity in efficient voiding and highlight a novel approach to increase VE generated by pudendal afferent nerve stimulation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077676PMC
http://dx.doi.org/10.1016/j.expneurol.2016.05.030DOI Listing
November 2016

Stability of the acetic acid-induced bladder irritation model in alpha chloralose-anesthetized female cats.

PLoS One 2013 9;8(9):e73771. Epub 2013 Sep 9.

Urogenix Inc./Astellas, Durham, North Carolina, United States of America.

Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS) activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.5%) to irritate the bladder. One hour after starting acetic acid infusion, a protocol consisting of a cystometrogram, continuous infusion-induced rhythmic voiding contractions, and a 5 min "quiet period" (bladder emptied without infusion) was precisely repeated every 30 minutes. Administration of vehicle (saline i.v.) occurred 15 minutes after starting each of the first 7 cystometrograms and duloxetine (1mg/kg i.v.) after the 8(th). Acetic acid infusion into the bladder increased URS-EMG activity, bladder contraction frequency, and decreased contraction amplitude and capacity, compared to saline. Bladder activity and URS activity stabilized within 1 and 2 hours, respectively. Duloxetine administration significantly decreased bladder contraction frequency and increased URS-EMG activity to levels similar to previous reports. Cardiorespiratory parameters and blood gas levels remained consistent throughout the experiment. The epithelium of the bladder and urethra were greatly damaged and edema and infiltration of neutrophils in the lamina propria of urethra were observed. These data provide an ample evaluation of the health of the animals, stability of voiding function and appropriateness of the model for testing drugs designed to evaluate lower urinary tract as well as cardiovascular and respiratory systems function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0073771PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767621PMC
July 2014

Characterization of a spinal, urine storage reflex, inhibitory center and its regulation by 5-HT1A receptors in female cats.

Am J Physiol Regul Integr Comp Physiol 2010 May 17;298(5):R1198-208. Epub 2010 Feb 17.

Urogenix, Inc., Durham, NC 27709, USA.

Urine storage is facilitated by somatic (pudendal nerve) and sympathetic [hypogastric nerve (HgN)] reflexes to the urethral rhabdosphincter (URS) and urethral smooth muscle, respectively, initiated by primary afferent fibers in the pelvic nerve (PelN). Inhibition of storage reflexes is required for normal voiding. This study characterizes a urine storage reflex inhibitory network that can be activated by PelN afferent fibers concurrently with the reflexes themselves. Electrical stimulation of PelN produced evoked potentials recorded by URS EMG electrodes (10-ms latency) or HgN electrodes (60-ms latency) in chloralose-anesthetized cats. When a second (i.e., paired) pulse of the same stimulus intensity was applied to the PelN 50-500 ms after the first, the reflexes evoked by the second stimulus were inhibited. The inhibition was maximal at paired-pulse intervals of 50-100 ms and remained after acute spinal transection at T10, confirming that the inhibitory center is located in the spinal cord. The 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tertralin (8-OH-DPAT; 3-300 mug/kg iv) consistently reduced the paired-pulse inhibition from 20% to 60% of control in spinal-intact animals but had no effect in acute spinal animals (i.e., supraspinal site of action). N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclohexanecarboxamide maleate (300 mug/kg iv) completely reversed 8-OH-DPAT's effects. The PelN-HgN reflex paired-pulse inhibition was not affected by 8-OH-DPAT. These results indicate the presence of a spinal, urine storage reflex, inhibitory center (SUSRIC) that is activated within 50 ms after activation of the reflexes themselves. SUSRIC is inhibited (disfacilitated) by supraspinal 5-HT(1A) receptors.
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http://dx.doi.org/10.1152/ajpregu.00599.2009DOI Listing
May 2010