M.B. Chancellor

The effects of periurethral muscle-derived stem cell injection on leak point pressure in a rat model of stress urinary incontinence

Abstract Our goal was to determine whether periurethral injection of allogenic muscle-derived stem cells (MDSC) could increase the leak point pressure (LPP) in a denervated female rat model of stress urinary incontinence. Cells isolated from the gastrocnemius muscle of normal female rats were purified for a myogenic population by the preplate technique. Three experimental groups were established: a control group (C) had a sham operation without injections; a sciatic nerve transection group (D) had periurethral saline injections; and a sciatic nerve transsection group had periurethral MDSC injections (M). One week following treatment the LPP of groups C, D and M were 25.2±1.9 cmH2O, 28.6±0.8 cmH2O and 36.7±2.3 cmH2O, respectively. At 4 weeks the LPP of groups C, D and M were 25.8±2.5 cmH2O, 18.6±5.2 cmH2O and 44.1±6.6 cmH2O, respectively. Allogenic MDSC significantly improved the LPP in sciatic nerve-transected animals after both 1 and 4 weeks compared to denervated animals injected with saline.

Neural Control of the Urethra

Coordination between the urinary bladder and the urethra is mediated by multiple reflex pathways organized in the brain and spinal cord. Some reflexes promote urine storage; whereas other reflexes facilitate voiding. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter (EUS) and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes are dependent upon interneuronal circuitry in the spinal cord. During voiding the spinal storage reflexes are inhibited by supraspinal mechanisms which originate in the pontine micturition center. Glutamatergic, serotonergic and alpha 1 adrenergic excitatory transmission as well as GABAergic/glycinergic inhibitory transmission have been implicated in the central control of sphincter reflexes. During voiding, a parasympathetic nitrergic inhibitory input to the urethral smooth is activated. This reflex mechanism which is triggered by bladder afferents persists in paraplegic rats and therefore must be mediated at least in part by spinal interneuronal circuitry. In female rats, the parasympathetic nitrergic pathway is prominent; but in male rats it is obscured by a dominant parasympathetic cholinergic excitatory input to the urethral smooth muscle. The function of the cholinergic pathway in voiding is uncertain. Stimulation of urethral afferents can also influence bladder activity. Contraction of the external urethral sphincter activates afferents that inhibit reflex bladder contractions; whereas infusion of fluid through the urethra facilitates bladder contractions. These reflexes are also organized in the spinal cord and presumably play a role in urine storage and elimination. Alterations in primitive bladder-to-urethra and urethra-to-bladder reflex mechanisms may contribute to neurogenic bladder dysfunction.Coordination between the urinary bladder and the urethra is mediated by multiple reflex pathways organized in the brain and spinal cord. Some reflexes promote urine storage; whereas other reflexes facilitate voiding. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter (EUS) and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes are dependent upon interneuronal circuitry in the spinal cord. During voiding the spinal storage reflexes are inhibited by supraspinal mechanisms which originate in the pontine micturition center. Glutamatergic, serotonergic and alpha, adrenergic excitatory transmission as well as GABAergic/glycinergic inhibitory transmission have been implicated in the central control of sphincter reflexes. During voiding, a parasympathetic nitrergic inhibitory input to the urethral smooth is activated. This reflex mechanism which is triggered by bladder afferents persists in paraplegic rats and therefore must be mediated at least in part by spinal interneuronal circuitry. In female rats, the parasympathetic nitrergic pathway is prominent; but in male rats it is obscured by a dominant parasympathetic cholinergic excitatory input to the urethral smooth muscle. The function of the cholinergic pathway in voiding is uncertain. Stimulation of urethral afferents can also influence bladder activity. Contraction of the external urethral sphincter activates afferents that inhibit reflex bladder contractions; whereas infusion of fluid through the urethra facilitates bladder contractions. These reflexes are also organized in the spinal cord and presumably play a role in urine storage and elimination. Alterations in primitive bladder-to-urethra and urethra-to-bladder reflex mechanisms may contribute to neurogenic bladder dysfunction.

Nitric oxide synthase gene transfer for erectile dysfunction in a rat model

To determine whether over‐expression of nitric oxide synthase (NOS) in the corpus cavernosum of the penis improves erectile function, as NO is an important transmitter for genitourinary tract function, mediating smooth muscle relaxation and being essential for penile erection.

Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence

This review discusses the control of the urethra by the central nervous system, emphasizing the importance of nervous system control and the role of serotonin and noradrenaline in storage, micturition and sphincter reflexes. The concept of pharmacological neuromodulation and the use of pharmacological therapy as first‐line therapy for stress urinary incontinence (SUI) is presented. Coordination between the urinary bladder and urethra is mediated by many reflex pathways organized in the brain and spinal cord. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes depend on interneuronal circuitry in the spinal cord and are modulated by descending pathways. It would therefore seem that neurotransmission in the central nervous system and periphery may be important in SUI, and moreover that pharmacological agents affecting these neurotransmitter pathways may be used to treat SUI. The central and peripheral mechanisms of action of duloxetine affect serotonin and noradrenaline neurotransmission in ways that may ameliorate the symptoms of SUI.

Botulinum toxin urethral sphincter injection resolves urinary retention after pubovaginal sling operation.

Abstract: The management of prolonged urinary retention following pubovaginal sling surgery typically involves transvaginal urethrolysis for anatomical urethral obstruction. Brubaker [1] recently reported on urethral sphincter abnormalities as a cause of postoperative urinary retention following either Burch suspension or a pubovaginal sling procedure. We report a case of functional urethral obstruction and detrusor acontractility following pubovaginal sling surgery that was successfully treated by botulinum A toxin urethral sphincter injection.

Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord injured rats

We examined whether replication-defective herpes simplex virus (HSV) vectors encoding the 67 kDa form of the glutamic acid decarboxylase (GAD67) gene product, the γ-aminobutyric acid (GABA) synthesis enzyme, can suppress detrusor overactivity (DO) in rats with spinal cord injury (SCI). One week after spinalization, HSV vectors expressing GAD and green fluorescent protein (GFP) (HSV-GAD) were injected into the bladder wall. Rats with SCI without HSV injection (HSV-untreated) and those injected with lacZ-encoding reporter gene HSV vectors (HSV-LacZ) were used as controls. Three weeks after viral injection, continuous cystometry was performed under awake conditions in all three groups. In the HSV-GAD group, the number and amplitude of non-voiding contractions (NVCs) were significantly decreased (40–45% and 38–40%, respectively) along with an increase in voiding efficiency, compared with HSV-untreated and HSV-LacZ groups, but micturition pressure was not different among the three groups. Intrathecal application of bicuculline partly reversed the decreased number and amplitude of NVCs, and decreased voiding efficiency in the HSV-GAD group. In the HSV-GAD group, GAD67 mRNA and protein levels were significantly increased in the L6-S1 dorsal root ganglia (DRG) compared with the HSV-LacZ group, while 57% of DRG cells were GFP-positive, and these neurons showed increased GAD67-like immunoreactivity compared with the HSV-LacZ group. These results indicate that GAD gene therapy effectively suppresses DO after SCI predominantly through the activation of spinal GABAA receptors. Thus, HSV-based GAD gene transfer to bladder afferent pathways may represent a novel approach for treatment of neurogenic DO.

A urethral stent for the treatment of detrusor-striated sphincter dyssynergia

Objective To assess the technique, efficacy and complications of the Ultraflex® urethral stent (Boston Scientific Corp., Boston, MA) for the treatment of detrusor‐striated sphincter dyssynergia (DSD).

Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a painful debilitating chronic visceral pain disorder of unknown etiology that affects an estimated 1 million people in the United States alone. It is characterized by inflammation of the bladder that results in chronic pelvic pain associated with bladder symptoms of urinary frequency and urgency. Regardless of the etiology, IC/PBS involves either increased and/or abnormal activity in afferent nociceptive sensory neurons. Pain-related symptoms in patients with IC/PBS are often very difficult to treat. Both medical and surgical therapies have had limited clinical utility in this debilitating disease and numerous drug treatments, such as heparin, dimethylsulfoxide and amitriptyline, have proven to be palliative at best, and in some IC/PBS patients provide no relief whatsoever. Although opiate narcotics have been employed to help alleviate IC/PBS pain, this strategy is fraught with problems as systemic narcotic administration causes multiple unwanted side effects including mental status change and constipation. Moreover, chronic systemic narcotic use leads to dependency and need for dose escalation due to tolerance; therefore, new therapies are desperately needed to treat refractory IC/PBS. This has led our group to develop a gene therapy strategy that could potentially alleviate chronic pelvic pain using the herpes simplex virus-directed delivery of analgesic proteins to the bladder.

Muscarinic receptor activation in the lumbosacral spinal cord ameliorates bladder irritation in rat cystitis models

To investigate whether activation of spinal cholinergic pathways affects bladder activity in rats with chemical cystitis induced by acetic acid (AA) and cyclophosphamide (CYP).

Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats

To investigate whether activation of brain and spinal cholinergic pathways affects the micturition reflex in rats.