Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4-10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats.

The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK2 receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4-10) (LMN-NKA). Cystometry and colorectal pressure measurements were performed in urethane-anesthetized, intact, and acutely spinalized female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. LMN-NKA (0.1-300 µg/kg) produced dose-dependent, rapid (<60 s), short-duration (<15 min) increases in bladder pressure. In intact rats, doses above 0.3-1 µg/kg induced urine release (voiding efficiency of ~70% at ≥1 µg/kg). In spinalized rats, urine release required higher doses (≥10 µg/kg) and was less efficient (30-50%). LMN-NKA (0.1-100 µg/kg) also produced dose-dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK2 receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. These results suggest that rapid-onset, short-duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK2 receptor agonist. Future challenges remain in regard to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI.

Maintenance of bladder innervation in diabetes: a stereological study of streptozotocin-treated female rats.

Neuropathy and cystopathy are two common conditions in patients with chronic diabetes. Despite obvious bladder sensory and motor nerve dysfunction in diabetes, no studies have selectively explored whether sensory or motor innervation is affected in the bladder. In the present study, we tested the hypothesis that loss of bladder sensory and motor fibers is responsible for bladder sensory and motor dysfunction. Parasympathetic and sensory innervation of the bladder dome and neck were examined using immunohistochemistry (IHC) and stereology in adult female rats 12weeks after induction of diabetes by streptozotocin. Naïve and age matched rats were evaluated as controls. Diabetic rats had mean blood glucose level of >400mg/dl, and bladder weights and thicknesses that were more than doubled compared to naïve rats. In naïve rats, parasympathetic vesicular acetylcholine transporter (VAT) and sensory calcitonin gene-related peptide (CGRP) immunopositive nerve fibers were located in bladder smooth muscle and were more densely distributed in the neck compared to the dome. Within the urothelial region, CGRP nerve fibers were densely distributed while VAT nerve fibers were sparsely distributed in the bladder neck and both were virtually absent in the bladder dome. Streptozotocin induced diabetes did not change the total nerve fiber length of either VAT or CGRP stained fibers in either the neck or dome. These studies indicate that hyperglycemia, induced by streptozotocin treatment, does not result in a loss of parasympathetic VAT or CGRP sensory nerve fibers, per se, but the doubling of bladder weight and mass does indicate a decrease in innervation density.

Nitrergic relaxations and phenylephrine contractions are not compromised in isolated urethra in a rat model of diabetes.

In vivo experiments in a diabetic rat model revealed compromised nitrergic urethral relaxations and increased sensitivity to adrenergic agonists. This study evaluated contractile and relaxation properties of urethral smooth muscle after streptozotocin (STZ)-induced diabetes, in vitro, with the aim of determining whether in vivo deficiencies are related to smooth muscle dysfunction. Urethral tissue was collected from adult female Sprague-Dawley rats naive, STZ-treated, vehicle-treated and sucrose-fed at 9-12 week post treatment. Strips from proximal, mid, and distal urethra were placed in tissue baths and stimulated using electric field stimulation (EFS) and pharmacological agents. nNOS staining was evaluated using immunohistochemistry. Phenylephrine (PE, 10µM) contracted all urethral strips with the highest amplitude in mid urethra, in all treatment groups. Likewise, EFS-induced relaxation amplitudes were larger and were observed more frequently in mid urethra. Relaxations were inhibited by the NOS inhibitor, L-NAME (1-100µM). Sodium nitroprusside (0.01-1µM), an NO donor, reversed PE-induced contractions. No statistical differences were observed between treatment groups with respect to any parameters. Qualitative immunohistochemistry showed no differences in the urethral nNOS innervation patterns across the treatment groups. In summary, nitrergic relaxations and adrenergic-induced contractions in the isolated diabetic rat urethra display similar properties to controls, suggesting no dysfunction on the nitrergic or alpha1 adrenergic receptor function in the smooth muscle. This further implies that compromised urethral relaxation and increased adrenergic agonist sensitivity observed in vivo in this model may be due to the disruption of neural signaling between the urethra and the spinal cord, or within the CNS.

A positive modulator of K Ca 2 and K Ca 3 channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591), inhibits bladder afferent firing in vitro and bladder overactivity in vivo.

Calcium-activated potassium channels are attractive targets for the development of therapeutics for overactive bladder. In the current study, we addressed the role of calcium-activated potassium channels of small (SK; K(Ca)2) and intermediate (IK; K(Ca)3) conductance in bladder function pharmacologically. We identified and characterized a novel positive modulator of SK/IK channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591). In whole-cell patch-clamp experiments, NS4591 doubled IK-mediated currents at a concentration of 45 +/- 6 nM(n = 16), whereas 530 +/- 100 nM (n = 7) was required for doubling of SK3-mediated currents. In acutely dissociated bladder primary afferent neurons, the presence of SK channels was verified using apamin and 1-ethyl-2-benzimidazolinone. In these neurons, NS4591 (10 microM) inhibited the number of action potentials generated by suprathreshold depolarizing pulses. NS4591 also reduced carbachol-induced twitches in rat bladder detrusor rings in an apamin-sensitive manner. In vivo, NS4591 (30 mg/kg) inhibited bladder overactivity in rats and cats induced by capsaicin and acetic acid, respectively. In conclusion, the present study supports the involvement of calcium-activated potassium channels in bladder function and identifies NS4591 as a potent modulator of IK and SK channels that is effective in animal models of bladder overactivity.

Serotonin and noradrenaline involvement in urinary incontinence, depression and pain: scientific basis for overlapping clinical efficacy from a single drug, duloxetine.

AIMS: Serotonin (5-HT) and noradrenaline (NA) are important monoamine neurotransmitters that are ubiquitously distributed throughout the peripheral and central nervous system and modulate functions that are vital to survive. Both neurotransmitters may be involved in the pathophysiological process or the treatment of--at first glance--divergent disease areas, namely stress urinary incontinence, major depressive disorder and neuropathic pain. The present review aims at describing the neurophysiological similarities between these disease areas, focussing on the role of the neurotransmitters 5-HT and NA at synapses of the spinal and supraspinal neural circuitry. RESULTS/DISCUSSION: Recent clinical studies show convergence of symptoms (i.e. comorbidity) for incontinence, depression and pain, suggesting common biochemical imbalances. Duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, has a central mechanism of action at different locations in the central nervous system and has proven to be a sound treatment of all these different diseases. Data obtained from animal model studies, randomised placebo-controlled clinical trials, as well as open label trials have provided evidence of the efficacy and safety of duloxetine as a suitable compound for the treatment of stress urinary incontinence in women as well as major depressive disorder and diabetic neuropathic pain in both men and women.

Open vs laparoscopic partial posterior fundoplication. A prospective randomized trial.

OBJECTIVE: This study compares outcomes following open and laparoscopic partial posterior fundoplication for gastroesophageal reflux disease concerning perioperative course, postoperative complications, symptomatic relief, recurrent disease, and the need for reinterventional surgery. METHODS: A prospective randomized trial was performed. Pre- and postoperative testing included endoscopy, esophageal function testing, patient questionnaire, and clinical assessment. Patients were followed for three years. MATERIALS: Ninety-three patients were randomized to open and 99 to laparoscopic surgery. RESULTS: Complication rates were higher, and length of stay (LOS) [5 (3-36) vs 3 (1-12) days] and time off work [42 (12-76) vs 28 (0-108) days] was longer in the open group (p < 0.01). Early side effects and recurrences were more common (p < 0.05) in the laparoscopic group. One patient in the open group and 8 patients in the laparoscopic group required surgery for recurrent disease and 7 patients required surgery for incisional hernias after open surgery. Overall, at one and three years, there were no differences in patient-assessed satisfactory outcome (93.5/93.5 vs 88.8/90.8%) or reflux control (p = 0.53) between the open and laparoscopic groups. CONCLUSIONS: The finding of fewer general complications, shorter length of stay and recovery, similar need for reoperations, and comparable 3-year outcomes, makes the laparoscopic approach the primary choice when considering surgical options for the treatment of gastroesophageal reflux disease (GERD).

Differential effects of simultaneous or sequential administration of paroxetine and WAY-100,635 on ejaculatory behavior.

Clinical treatment of depression or anxiety with selective serotonin reuptake inhibitors (SSRIs) often results in delayed ejaculation or anorgasmia. Co-treatment with subtype-selective serotonin receptor antagonists may alter the timing of onset of action and potentiate or reduce sexual side effects. Sexual behavior in male Sprague-Dawley rats was examined after acute administration of the SSRI, paroxetine and the serotonin1A antagonist, WAY-100,635. Acute administration of paroxetine alone did not alter male ejaculatory behavior. However, administration of paroxetine plus WAY-100,635 resulted in a significant delay in mounting behavior and increased the time to ejaculation. Simultaneous administration of paroxetine and WAY-100,635 produced a greater delay in initiation of mounting behavior and ejaculation compared to sequential administration of paroxetine followed by WAY-100,635. The differential effect on sexual behavior or addition of specific serotonin receptor antagonists may be relevant for clinical treatment therapies of premature ejaculation.

Targeting serotonin and norepinephrine receptors in stress urinary incontinence.

Stress urinary incontinence (SUI) in women is prevalent, and there are no globally developed or widely approved drugs for the disease. One strategy for improving urinary continence is to augment the function of the urethral rhabdosphincter through neuropharmacology. The present review describes the innervation of the urethra, and the role of the central nervous system in controlling nerve activity. Targeting serotonin and norepinephrine (or noradrenaline) receptors in Onuf's nucleus is shown to augment the function of the urethral rhabdosphincter by increasing pudendal nerve efferent activity. It is proposed that the ability of serotonin and norepinephrine to enhance the effects of glutamate (the primary excitatory neurotransmitter for pudendal sphincter motor neurons) while having no direct effects of their own, allow facilitation of rhabdosphincter activity during urine storage while allowing complete relaxation during micturition. Duloxetine, a potent and balanced dual serotonin (5-HT)-norepinephrine reuptake inhibitor (SNRI), potentiates these physiological effects of endogenous serotonin and norepinephrine (by inhibiting the reuptake of these neurotransmitters in the pre-synaptic element) and thereby enhances the central nervous system's natural continence control mechanisms.

Preoperative oesophageal motor activity does not predict postoperative dysphagia.

OBJECTIVE: To evaluate the ability of preoperative manometric examinations to predict temporary or permanent dysphagia after antireflux procedures. DESIGN: Retrospective study. SETTING: Teaching hospital, Sweden. SUBJECTS: 191 patients who had partial fundoplication. INTERVENTIONS: Stationary manometry with a perfused catheter system. MAIN OUTCOME MEASURES: Correlation between preoperative manometric examinations and the incidence of dysphagia before and after operation. RESULTS: 98 of 191 patients had dysphagia preoperatively (51%), but 52 of the 98 had no stricture or motor disorder to explain it; 25 of 59 patients with motor disorders shown manometrically (42%) did not complain of dysphagia. The number of patients with dysphagia was reduced to 43 postoperatively. 8 who did not complain of dysphagia preoperatively did so postoperatively; 4 of 8 had defective peristalsis and 4 had normal preoperative tracings. CONCLUSIONS: Manometric examination does not help us to understand the mechanism of preoperative dysphagia, nor does it predict who will develop dysphagia postoperatively.

Central muscarinic inhibition of lower urinary tract nociception.

Previous studies indicate cholinergic systems suppress somatic nociception. The present studies determined if cholinergic muscarinic systems suppress visceral nociception, specifically, chemical irritation of the lower urinary tract. Bladders of urethane-anesthetized rats were cannulated through the dome for continuous-infusion cystometrogram recordings. EMG electrodes recorded anal sphincter activity. Infusion of 0.5% acetic acid into the bladder to produce irritation increased bladder activity and anal sphincter activity (i.e. activation of a nociceptive vesicoanal reflex). Oxotremorine (a muscarinic agonist) and (-)butylthio[2.2.2] (a mixed muscarinic agonist/antagonist) dose-dependently inhibited vesicoanal reflex activity. This inhibition was antagonized by atropine (a centrally active muscarinic antagonist) but not by scopolamine methylbromide (a peripherally restricted muscarinic antagonist). Physostigmine (a centrally active cholinesterase inhibitor) also dose-dependently inhibited vesicoanal reflex activity in an atropine-sensitive manner, while neostigmine (a peripherally restricted cholinesterase inhibitor) did not. Atropine alone (i.e. administered without prior administration of muscarinic agonist or cholinesterase inhibitor) produced robust but transient (15 min) increases in vesicoanal activity and bladder activity under conditions of acetic acid infusion into the bladder. Under conditions of saline infusion into the bladder, atropine had the opposite effect on bladder activity (i.e. inhibition). These studies indicate that an endogenous cholinergic muscarinic system can be activated by lower urinary tract irritation to suppress visceral nociception through central nervous system mechanisms.

Vesicoanal, urethroanal, and urethrovesical reflexes initiated by lower urinary tract irritation in the rat.

Irritation of the urinary bladder causes activation of normally "silent" nociceptive primary afferent fibers. In the present study, it is reported that irritation of the urinary bladder or urethra with infusion of 0.5% acetic acid robustly activates motoneurons that innervate the striated muscle of the external anal sphincter via spinal reflex mechanisms. The activation of anal motoneurons following irritation of the bladder and urethra are termed vesicoanal and urethroanal reflexes, respectively. The reflexes can be mimicked by acute application of capsaicin to the bladder and urethra, and they show desensitization following prolonged topical application of capsaicin or following chronic systemic pretreatment with capsaicin. The reflexes can be demonstrated in chronic spinal cord-transected animals, indicating that the reflex pathways are organized within the spinal cord. The urethroanal reflex is also physiologically activated by urethral distension and/or increases in intraluminal pressure. In addition to activation of anal sphincter activity, slight distension, pressure increases, or instillation of 0.5% acetic acid into the urethra inhibited bladder contractions through activation of an inhibitory urethrovesical reflex. These reflexes are discussed in terms of clinical characteristics of urethritis and prostatitis. Anecdotally, it was discovered that the bladder can buffer acetic acid.

Laparoscopic myotomy without fundoplication in patients with achalasia.

OBJECTIVE: Analysis of outcome after laparoscopic myotomy for achalasia. DESIGN: Prospective audit. SETTING: Teaching hospital, Sweden. SUBJECTS: All patients with achalasia who had a laparoscopic myotomy without a simultaneous fundoplication. INTERVENTIONS: Questionnaire, pH-measurements, radiography and manometry. MAIN OUTCOME MEASURES: Operative and postoperative complications and reoperations. RESULTS: Twenty-one patients were scheduled for laparoscopic myotomy. Three were converted to open operations, and four were reoperated on transabdominally for persistent or recurrent symptoms. All patients were satisfied afterwards. Follow-up in 14 patients, after a median of 22 months (range, 6-40), included manometry, questionnaire, and 24-hour pH measurements, and showed significant reduction in the lower oesophageal sphincter pressure together with relief of symptoms. Three patients had reflux symptoms and abnormal pH readings. An additional five patients had abnormal pH measurements but no symptoms of reflux. CONCLUSIONS: Heller myotomy can safely be done laparoscopically. Whether a simultaneous antireflux procedure is needed remains to be seen.

Rabbit urethral regeneration using small intestinal submucosa onlay grafts.

OBJECTIVES: To determine if small intestinal submucosa (SIS) can evoke urethral regeneration. METHODS: Twenty male white New Zealand rabbits were assigned to one of three experimental groups. Group 1 (n = 4) underwent simple urethrotomy and closure. Group 2 (n = 8), a second control group, underwent an onlay urethroplasty with a graft of full-thickness preputial skin from the host rabbit. Group 3 (n = 8) underwent an onlay urethroplasty with an SIS graft. RESULTS: All eight SIS onlay grafts promoted regeneration of the normal rabbit epithelium supported by a well-vascularized collagen and smooth muscle backing. Preputial free onlay grafts maintained a keratinizing squamous cell epithelium with a poor supportive backing, which resulted in the formation of urethral diverticulum. CONCLUSIONS: SIS onlay patch grafts for urethroplasty promote rabbit urethral regeneration.

Extrinsic innervation of the cat prostate gland: a combined tracing and immunohistochemical study.

PURPOSE: The purpose of the present study was to determine the peripheral neural pathways, spinal distribution, sizes, and peptide transmitter content of primary afferent and autonomic efferent neurons that innervate the prostate gland. METHODS: Retrograde transport of the fluorescent dye "fast blue" (injected into the prostate gland) was combined with neurotransmitter immunohistochemistry. Lesions of the pelvic and pudendal nerve were used to determine the peripheral neural pathways. RESULTS: The majority of the afferent innervation arose from the sacral dorsal root ganglia (DRG) and was equally comprised of small, substance P- and calcitonin gene-related peptide-immunoreactive (IR) neurons and large, non-IR neurons. The majority (70%) of the afferent axons traversed the pelvic nerve with the remainder traversing the pudendal nerve. Fewer afferent neurons were located in lumbar DRG; nearly all of these were small, peptidergic neurons. Efferent autonomic neurons were located in the inferior mesenteric ganglia (IMG), sympathetic chain ganglia (SCG), and pelvic plexus ganglia (PPG). Nearly all efferent neurons in the IMG and SCG, but only 2/3 of the PPG neurons, contained dopamine-beta-hydroxylase. Substantial neuropeptide Y innervation was derived from the SCG but not the IMG or PPG. CONCLUSIONS: First, clinical reports suggested that sensory innervation of the prostate would be purely nociceptive in nature (implied by small, peptide-IR neurons). However, the present study suggests that there may also be a substantial, presumably non-nociceptive, afferent innervation (implied by findings of large, non-IR neurons). Second, 3 sources of autonomic efferent innervation exist, each being different in the distribution of transmitter phenotypes. Understanding the physiological role of putative non-nociceptive primary afferent neurons, and the differential roles of the various autonomic neurons, is likely to be important in developing therapies for the treatment of prostatic diseases, such as benign prostatic hyperplasia and prostatodynia.

Characterization of small intestinal submucosa regenerated canine detrusor: assessment of reinnervation, in vitro compliance and contractility.

PURPOSE: We characterized small intestinal submucosa regenerated canine bladder. MATERIALS AND METHODS: We subjected 15-month small intestinal submucosa regenerated canine bladder strips to in vitro muscle bath compliance, contractility testing and immunohistochemical staining. RESULTS: Compliance studies demonstrated no significant difference between small intestinal submucosa regenerated and control bladders, which were 30-fold more compliant than native small intestinal submucosal graft material. Contractility studies demonstrated contractile responses and innervation similar to those of normal canine bladder. Afferent nerves were demonstrated through immunohistochemical techniques. CONCLUSIONS: These characteristics further support the regenerative capacity of small intestinal submucosa and its potential use as a bladder augmentation material.

Regenerative urinary bladder augmentation using small intestinal submucosa: urodynamic and histopathologic assessment in long-term canine bladder augmentations.

PURPOSE: To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. MATERIALS AND METHODS: Nineteen male dogs underwent 35 to 45% partial cystectomy with immediate augmentation with SIS grafts. All dogs were evaluated pre- and postoperatively with blood chemistries, urine cultures, intravenous urograms, cystograms and cystometrograms. Postoperatively (1 to 15 months), bladders were examined with routine histology and image analysis. RESULTS: All dogs survived their intended survival period without morbidity. All results were normal. Histologically, all 3 layers (mucosa, smooth muscle, serosa) of the normal bladder showed evidence of regeneration. CONCLUSIONS: Small intestinal submucosa acts as a scaffold for bladder augmentation through regeneration and could be a potential option for bladder reconstruction.

Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflexes in the anaesthetized cat.

1. 5-Hydroxytryptamine (5-HT) is intimately associated with central sympathetic and somatic control of the lower urinary tract. The sympathetic and somatic innervation of the lower urinary tract is conveyed through efferent axons of the hypogastric and pudendal nerves, respectively. 2. The present study examined the effects of 2,5-dimethoxy-4-iodophenylisopropylamine (DOI), a 5-HT2 receptor subtype-selective agonist, on evoked potentials recorded from the central ends of the hypogastric and pudendal nerves in response to electrical stimulation of afferent fibres in the pelvic and pudendal nerves, respectively. Various spinalization paradigms were employed to localize the site of action. All cats were pretreated with xylamidine (1 mg kg-1), a peripherally-restricted 5-HT2 receptor antagonist. 3. In acute spinal cats, DOI (0.01-3 mg kg-1, i.v.) reliably produced dose-dependent increases in the pudendal nerve reflex (to 228 +/- 31% of control). These increases were reversed by the 5-HT2 receptor-selective antagonist, LY53857 (0.3-3 mg kg-1, i.v.). On the other hand, in spinally-intact cats, DOI produced no significant changes in the pudendal reflex. However, within minutes of spinalization of DOI-pretreated cats, a marked increase (to 221 +/- 16% of control) in the pudendal reflex was observed which could be reversed by LY53857. No significant effects were observed on hypogastric reflexes in either acute spinal or spinally-intact cats following DOI administration. No effects were seen in either spinally-intact or acute spinal animals when LY53857 was administered as the initial drug. 4. These results indicate that activation of spinal 5-HT2 receptors facilitates pudendal reflexes. In spinally-intact cats, it is hypothesized that DOI activates supraspinal pathways that mediate inhibition of the pudendal reflexes and counteracts the facilitatory effects of spinal 5-HT2 receptor activation.

Detrusor regeneration in the rat using porcine small intestinal submucosal grafts: functional innervation and receptor expression.

PURPOSE: To evaluate functional characteristics of regenerated bladder induced by small intestinal submucosa (SIS). MATERIALS AND METHODS: Strips from bladder regenerated from SIS and normal rat bladder were evaluated by in vitro muscle bath contractility studies. RESULTS: The present results indicate that SIS-regenerated bladder 1) demonstrates contractile activity; 2) expresses muscarinic, purinergic and beta adrenergic receptors; and 3) exhibits functional cholinergic and purinergic innervation that is similar to the normal rat urinary bladder muscle. CONCLUSIONS: These functional characteristics of SIS-regenerated tissue demonstrated in the present study further support use of SIS material as a bladder augmentation material.

Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat.

Because all three components of lower urinary tract control (parasympathetic, sympathetic and somatic) are intimately associated with serotonin (5-hydroxytryptamine [5HT])- and norepinephrine (NE)- containing terminals and receptors, in the present study, we examined the effects of increasing extracellular levels of 5HT and NE with duloxetine, a 5HT and NE reuptake inhibitor, on lower urinary tract function under "normal" or nonirritated conditions (transvesical infusion of saline) and in a model of bladder irritation (i.e., transvesical infusion of 0.5% acetic acid) in chloralose-anesthetized cats. Irritation reduced bladder capacity (to 20% of control) and produced insignificant increases in periurethral electromyographic (EMG) activity compared with nonirritated control animals. Duloxetine produced insignificant increases in bladder capacity and sphincter EMG activity when administered under nonirritated bladder conditions. However, this duloxetine "pretreatment" did prevent the typical acetic acid-induced reductions in bladder capacity and unmasked a marked activation of sphincter EMG activity on acetic acid infusion (by 8-fold). Furthermore, when administered initially under irritated bladder conditions, duloxetine produced dose-dependent increases in bladder capacity (by 5-fold) and increased periurethral striated muscle EMG activity (by 8-fold). The effects on bladder activity were due to central mechanisms since bladder contractions evoked by direct electrical stimulation of efferent fibers in the pelvic nerve were not effected by duloxetine. The effects of duloxetine on bladder capacity were antagonized by methiothepin, a non-selective 5HT receptor antagonist, but not by the other 5HT and NE receptor antagonists examined: LY53857, a 5HT2 antagonist; prazosin, an alpha-1-adrenergic receptor antagonist; idazoxan, an alpha-2-adrenergic receptor antagonist; or propranolol, a beta-adrenergic receptor antagonist. The facilitatory effects of duloxetine on periurethral sphincter EMG were significantly antagonized to various degrees by methiothepin, LY53857 and prazosin but not by idazoxan or propranolol. These results indicate that duloxetine, through inhibition of 5HT and NE reuptake, has weak effects under normal conditions. However, under conditions of bladder irritation, duloxetine suppresses bladder activity through 5HT receptor mechanisms and enhances external urethral sphincter activity through 5HT2 and alpha-1-adrenergic mechanisms.

Pharmacological analysis of the noradrenergic control of central sympathetic and somatic reflexes controlling the lower urinary tract in the anesthetized cat.

Norepinephrine (NE)-containing terminals densely innervate sympathetic preganglionic neurons in the intermediolateral nucleus and somatic motor neurons in Onuf's nucleus that project through the hypogastric and pudendal nerves, respectively, to innervate the lower urinary tract. In the present study, we pharmacologically analyzed the role of noradrenergic systems on the sympathetic and somatic pathways to the lower urinary tract and asked: 1) Are alpha-1, alpha-2, or beta-adrenergic receptors tonically active along sympathetic and/or somatic reflex pathways? And 2) what is the net effect of increasing the extracellular levels of NE by administration of a NE reuptake inhibitor? To address these questions, we recorded evoked potentials from the central ends of the hypogastric and pudendal nerves in response to electrical stimulation of the pelvic and pudendal nerves in chloralose-anesthetized cats, and the effects of prazosin (1-300 micrograms/kg i.v.), an alpha-1-adrenergic receptor antagonist; idazoxan (1-300 micrograms/kg i.v.), an alpha-2-adrenergic receptor antagonist; propranolol (1 mg/kg i.v.), a beta-adrenergic receptor antagonist; and tomoxetine (0.003-3 mg/kg i.v.), a selective NE reuptake inhibitor, were examined. The results indicate that facilitatory alpha-1-adrenergic receptors are tonically active along both sympathetic and somatic reflex pathways, whereas inhibitory alpha-2-adrenergic receptors are not tonically active. The net effect of acute inhibition of NE reuptake along sympathetic reflex pathways is increased activation of inhibitory alpha-2-adrenergic receptors. Along somatic reflex pathways, increased activation of both facilitatory alpha-1- and inhibitory alpha-2-adrenergic receptors were recorded after acute NE reuptake inhibition. No role for central beta-adrenergic receptors was noted.