Elsevier

Experimental Neurology

Volume 285, Part B, November 2016, Pages 173-181
Experimental Neurology

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

https://doi.org/10.1016/j.expneurol.2016.05.030Get rights and content

Abstract

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.

Introduction

Electrical stimulation of the pudendal nerve is under investigation for restoration of bladder emptying in persons with spinal cord injury (Kennelly et al., 2011, Yoo et al., 2009, Yoo et al., 2011). Selective electrical stimulation of individual branches of the pudendal nerve evokes sustained bladder contractions and increases voiding efficiency (VE) beyond that of distention-evoked reflex voiding in cats (Woock et al., 2008, Yoo et al., 2008a). However, while pudendal nerve stimulation is a promising approach, VE is limited to 60–70% in anesthetized cats (Boggs et al., 2006, Woock et al., 2008, Yoo et al., 2008a), and larger VE is desirable for clinical translation. The objective of the present study was to test the hypothesis that artificial phasic activation of the external urethral sphincter (EUS), as is observed during voiding in rats and dogs, would enhance VE in cats.

Phasic bursting activity in the EUS, which occurs during voiding in rats (Chen et al., 2011, Chen et al., 2012, Kakizaki et al., 1997, Kruse et al., 1990, Peng et al., 2008, Vera and Nadelhaft, 2001) and dogs (Nishizawa et al., 1984a, Nishizawa et al., 1984b), is observed in the electromyogram (EMG) of the striated EUS and as high frequency oscillations (HFOs) in intravesical pressure. While the origin and function of this activity remain unclear, elimination of phasic EUS activity either by transection of the pudendal nerve innervating the EUS in the rat (Cruz and Downie, 2005, Peng et al., 2006) and dog (Nishizawa et al., 1984a) or by neuromuscular blockade in the rat (Conte et al., 1991, Kruse et al., 1993, Maggi et al., 1986, Peng et al., 2006, Vera and Nadelhaft, 2001, Yoshiyama et al., 2000) causes a significant reduction in VE.

We conducted a series of experiments in rats and cats to investigate the hypothesis that introduction of artificial EUS bursting activity by electrical stimulation could increase VE under conditions where such activity was absent. We first conducted a series of experiments in rats to verify the role of phasic EUS bursting in efficient voiding and to test the hypothesis that re-introduction of phasic EUS activity following motor nerve transection could restore efficient voiding. Subsequently, we quantified the effects of introducing phasic EUS bursting activity on bladder contractions and VE in the cat, which, unlike the rat, normally exhibits relaxation of the EUS while voiding (Fedirchuk and Shefchyk, 1993). Finally, in both rats and cats, transection of the sensory branches of the pudendal nerves revealed that phasic EUS activity increased voiding efficiency through a sensory pathway, presumably by amplifying the sensory input to the augmenting reflex (Barrington, 1941). Collectively, 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.

Section snippets

Materials and methods

All animal care and experimental procedures were reviewed and approved by the Duke University Institutional Animal Care and Use Committee.

Results

Artificial phasic bursting activity of the EUS increased voiding efficiency in both rats and cats, and selective nerve transections revealed that this effect was mediated by sensory feedback via pudendal afferents.

Discussion

Artificial phasic burst activation of the external urethral sphincter (EUS) evoked by electrical stimulation of the pudendal motor branch increased voiding efficiency in both rats and cats. Our initial experiments verified the importance of phasic EUS bursting for efficient voiding in rats. Phasic bursting of the EUS was present during micturition in control conditions (see Fig 1A-B) (Chen et al., 2011, Chen et al., 2012, D'Amico and Collins, 2012, Kakizaki et al., 1997, Kruse et al., 1990,

Conclusions

Phasic bursting activity of the EUS is critical for efficient voiding in rats, and artificial restoration of phasic bursting lost following nerve transection could restore efficient voiding in rats. Imposition of artificial phasic bursting in cats, which normally exhibits EUS relaxation while voiding, was also effective in promoting efficient voiding. In both species phasic EUS activity increased voiding efficiency through activation of pudendal sensory pathways. Phasic bursting is presumably

Acknowledgements

The authors thank Gilda Mills for her assistance during these experiments. This work was supported by a grant from the National Institutes of Health (R01 NS050514).

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