PubMed Health⌕ Search

Biomedical subjects

Karl B Thor

Publications and source records attributed to Karl B Thor.

17 recordsLinked to original sources
PubMed2007

Activation of the external urethral sphincter central pattern generator by a 5-HT(1A) receptor agonist in rats with chronic spinal cord injury.

We recently demonstrated that treatment with the 5-HT(1A/7) receptor agonist [(R)-(+)-8-hydroxy-2-di-n-propylamino]tetralin (8-OH-DPAT) increases bladder capacity in chloralose-anesthetized female cats with chronic spinal cord injury. In the current study, we investigated the effects of 8-OH-DPAT on bladder capacity and external urethral sphincter (EUS) activity in urethane-anesthetized female rats (initial body mass 175-200 g) with chronic spinal cord injury (transsection at T10). Cystometric study took place 8-12 wk posttranssection. Intravesical pressure was monitored in urethane-anesthetized rats with a transvesical catheter, and EUS activity was assessed electromyographically. Spinal cord injury disrupts phasic activity of the EUS, resulting in decreased voiding efficiency and increased residual volume. 8-OH-DPAT induced a dose-dependent decrease in bladder capacity (the opposite of its effect in chronic spinal cord-injured cats) with an increase in micturition volume and decrease in residual volume resulting from improvement in voiding efficiency. The unexpected improvement in voiding efficiency can be explained by the 8-OH-DPAT-induced emergence of phasic EUS relaxation. Phasic EUS relaxation was also altered by 8-OH-DPAT in spinally intact rats, whereas the 5-HT(1A) receptor antagonist N-tert-butyl-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-phenylpropanamide (WAY-100635), on its own, was without effect. It remains to be determined when phasic relaxation is restored after spinal cord injury, and indeed whether it is ever truly lost or is only temporarily separated from excitatory input.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2006

Distribution and immunohistochemical characterization of primary afferent neurons innervating the levator ani muscle of the female squirrel monkey.

OBJECTIVE: This study was undertaken to examine the neurofilament and neurochemical composition of subpopulations of primary afferent neurons innervating the levator ani muscle by combining retrograde tracing and triple labeling immunofluorescence in the female squirrel monkey. STUDY DESIGN: Cholera toxin B subunit (CTB) was injected unilaterally into the levator ani muscle of 3 monkeys to identify primary sensory neurons in the dorsal root ganglia (DRG) and their central projections in the spinal cord. L7-S2 DRG were processed for dual or triple labeling immunofluorescence 3 days after injection to examine labeling of the 200 kD neurofilament marker RT97 (a marker of myelinated neurons), calcitonin gene-related peptide (CGRP; a marker of peptidergic neurons), isolectin B4 (IB4; a marker of small, unmyelinated neurons), and nerve growth factor receptor (TrkA) in CTB-positive neurons. RESULTS: RT97-negative (C-fiber) neurons were more numerous (74% of total CTB-labeled neurons) and smaller in size than RT97-positive (A-fiber) afferent neurons (26% of CTB-labeled neurons). IB4 labeling was almost exclusively found in RT97-negative afferent neurons. Approximately 43% of all CTB-labeled DRG neurons expressed CGRP, and the majority of these were small. The distribution and sizes of CTB-labeled TrkA-positive DRG neurons were similar to those of CTB-labeled CGRP-positive DRG neurons. CONCLUSION: The levator ani muscle is innervated by 3 major subpopulations of primary afferent neurons consisting of cells with large, neurofilament-rich soma and A fibers (putative proprioceptive neurons) and those with small, peptidergic or nonpeptidergic, neurofilament-poor soma and C fibers (putative nociceptive, mechanoreceptive, ergoreceptive, and thermoreceptive neurons). Future investigation is needed to elucidate the relationship between primary sensory neuron subpopulations and changes in neuropeptide and neurotrophin expression on experimental levator ani nerve damage, childbirth, and aging.

Animals↗
PubMed2005

Immunohistochemical evidence for the interaction between levator ani and pudendal motor neurons in the coordination of pelvic floor and visceral activity in the squirrel monkey.

OBJECTIVE: The purpose of this study was to characterize the spinal distribution of afferent and efferent pathways that innervate the levator ani (LA) muscle in the female squirrel monkey. STUDY DESIGN: Cholera toxin B (CTB) was injected unilaterally into the LA muscle of 5 monkeys to identify primary sensory neurons in the dorsal root ganglia (DRG) and motor neurons in the spinal cord that contribute fibers to the LA nerve. Fluoro-Gold (FG) was injected into the external anal sphincter of 2 of these animals to label pudendal motor neurons (1 of these animals underwent unilateral LA neurectomy before CTB injection). Spinal cord and DRG were processed for immunofluorescence 3 to 7 days after injections. RESULTS: Retrograde transport of CTB from the LA muscle labeled primary afferent neurons in the ipsilateral DRG, their central projections, and motor neurons in the medial portion of the ipsilateral ventral horn of the spinal cord (L7-S2 segments). Injection of FG into the external anal sphincter labeled cells in Onuf's nucleus, primarily in L7. Importantly, CTB-labeled LA motor neurons were virtually absent in Onuf's nucleus, where all pudendal motor neurons are located. CTB-labeled processes were observed within Onuf's nucleus, adjacent to FG-labeled pudendal motor neurons, and appeared to derive from dendrites of LA motor neurons that project into Onuf's nucleus. CONCLUSION: The LA muscle has a distinct innervation with very little or no contribution from the pudendal nerve. The intriguing labeling of LA neural elements within a nucleus that innervates the external urethral and anal sphincters (involved in pelvic visceral control) may represent a neuroanatomic substrate for physiologic integration of spinal and supraspinal inputs for the coordination of pelvic floor and visceral activity.

Afferent Pathways↗
PubMed2005

New pharmacological treatments for urinary incontinence and overactive bladder.

Lower urinary tract dysfunction encompasses a number of different pathologies, and affects the lives of millions of patients worldwide. Although several pharmaceutical companies have been involved in urological drug discovery over the last several years, therapeutic options remain limited. The mainstay of treatment for overactive bladder and urinary incontinence for several years has been antimuscarinic agents. While additional antimuscarinic compounds are currently undergoing clinical development, next generation compounds aimed at novel targets and mechanisms of action are in clinical and preclinical development. This review highlights new compounds and approaches under clinical investigation by various pharmaceutical companies. These novel therapeutic strategies offer the promise of expanded treatment options for patients suffering from these disorders.

Animals↗
PubMed2004

Inhibition of bladder activity by 5-hydroxytryptamine1 serotonin receptor agonists in cats with chronic spinal cord injury.

The serotonin (5-hydroxytryptamine1A) 5-HT1A receptor agonist 8-OH-DPAT [(R)- (+)-8-hydroxy-2-(di-n-propylamino)tetralin] inhibits bladder activity under nociceptive but not innocuous conditions in cats with an intact spinal cord, suggestive of an effect on primary afferent C fibers or their targets. Because C fibers play a key role in reflex micturition in chronic spinal cord injury (SCI), we investigated the effect of 8-OH-DPAT on micturition in SCI cats. We also investigated GR-46611 (3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide), which has agonist activity predominantly at 5-HT1B and 5-HT1D receptors but also at the 5-HT1A receptor. Chloralose-anesthetized cats were catheterized through the bladder dome for saline-filling cystometry. Dose-response curves for i.v. 8-OH-DPAT (0.3-30 microg/kg) and GR-46611 (0.03-300 microg/kg) were followed in three cases each by 5-HT1A antagonist WAY-100635 [N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide] at 300 microg/kg. Threshold volume, capacity, residual volume, micturition volume, and arterial pressure were measured. Intact cats showed few significant changes in cystometric variables. SCI cats responded to both 8-OH-DPAT and GR-46611 with dose-dependent increases in threshold volume, capacity, and residual volume, significant at > or =10 microg/kg for 8-OH-DPAT and at > or =3 microg/kg for GR-46611. Effects of 8-OH-DPAT but not GR-46611 were largely reversed by WAY-100635. Both 5-HT1A and 5-HT1B/1D agonists may offer a promising means of reducing bladder hyperactivity and increasing bladder capacity in patients with chronic SCI.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2004

Induction of bladder sphincter dyssynergia by kappa-2 opioid receptor agonists in the female rat.

PURPOSE: The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral sphincter (EUS) reflexes in cats. We examined the role of spinal kappa-opioid receptor subtypes in the control of EUS function in rats using selective kappa-1 (U-50,488) or kappa-2 (GR-89,696) opiate receptor agonists. MATERIALS AND METHODS: Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. RESULTS: Micturition in rats is accompanied at different times by tonic (continuous) EUS spike activity and by phasic bursts of spikes separated by pauses. GR-89,696 (0.05 to 5 microg intrathecally) caused a dose dependent decrease in the number of bursts per micturition without affecting spike frequency within individual bursts or during periods of tonic activity. It resulted in decreased voiding efficiency and at high doses dyssynergia and overflow incontinence. The nonselective opiate receptor antagonist naloxone (1 mg/kg intravenously) blocked GR-89,696 effects. U-50,488H (0.05 to 15 microg intrathecally) caused no change in cystometric parameters or in EUS-electromyography. CONCLUSIONS: Efficient voiding in rats depends on a spinal pattern generator causing EUS motor neuron firing to occur in bursts, resulting in rapid urethral contraction and relaxation. Intrathecal kappa-2-opiate receptor agonists suppress this pattern generator, decreasing the number of bursts occurring during each micturition without decreasing motor neuron spike frequency during individual bursts or during tonic spike activity associated with urethral closure. Resultant dyssynergia leads to decreased voiding efficiency. The relevance of kappa-2 opioid receptors should be explored in higher species, especially regarding spinal cord injury induced dyssynergia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2004

Central nervous system control of the lower urinary tract: new pharmacological approaches to stress urinary incontinence in women.

PURPOSE: Despite the prevalence of stress urinary incontinence in women there are no approved drugs for the disease. MATERIALS AND METHODS: Designing medical therapies requires a comprehensive understanding of how the internal and external sphincters are neurologically controlled. In this review recent advances in mapping storage and micturition reflexes, and the association of serotonergic and noradrenergic systems with these reflexes are discussed. RESULTS: Urine storage and micturition are controlled by a series of hard wired reflexes that are under the modulatory influence of serotonin and norepinephrine. Augmentation of the serotonergic and noradrenergic systems with duloxetine increases bladder capacity and urethral rhabdosphincter activity. The increase in sphincter activity is mediated by alpha1 adrenergic receptors and 5-hydroxytryptamine receptors. CONCLUSIONS: Increasing rhabdosphincter activity with duloxetine may offer a therapeutic benefit in women with stress urinary incontinence.

Central Nervous System↗
PubMed2004

Effects of alpha 1-adrenergic receptor subtype selective antagonists on lower urinary tract function in rats with bladder outlet obstruction.

PURPOSE: Antagonists of alpha 1-adrenergic receptors (alpha 1ARs) relieve obstructive and irritative symptoms in patients with bladder outlet obstruction. However, to our knowledge mechanisms underlying the relief of irritative symptoms remain unknown. Because bladder alpha 1dARs are up-regulated in some rats with bladder outlet obstruction, we investigated the effect of the alpha 1aAR antagonist 5-methyl urapidil (5MU) vs the alpha 1a/alpha 1dAR antagonist tamsulosin on urinary frequency in obstructed rats. MATERIALS AND METHODS: Baseline frequency was measured using a chronic micturition recording system and then obstruction (40 rats) or sham obstruction surgery (11 rats) was performed. After 6 weeks frequency was reassessed, followed by subcutaneous implantation of osmotic pumps to deliver 5MU, tamsulosin or vehicle for 1 week. Upon the completion of drug treatment urinary frequency was again measured and the pressor response to the alpha 1AR agonist phenylephrine was documented. RESULTS: Obstructed bladder mass was an average of 4.9 times greater than bladder mass in sham operated rats (p <0.001). Urinary frequency was elevated in obstructed rats with a bladder mass of greater than 500 mg vs all rats with a bladder mass of under 255 mg (p = 0.01). Of rats with a bladder mass of greater than 500 mg frequency was decreased in those treated with tamsulosin (p = 0.03) but not in those treated with 5MU. Tamsulosin and 5MU inhibited the pressor response to phenylephrine. CONCLUSIONS: Urinary frequency is increased in rats with a bladder mass of greater than 500 mg. The combined alpha 1a/alpha 1dAR antagonist tamsulosin decreases urinary frequency more than the alpha 1aAR selective antagonist 5MU. This finding supports the hypothesis that the alpha 1dAR is important for mediating irritative symptoms.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2003

Innervation of the levator ani and coccygeus muscles of the female rat.

In humans, the pelvic floor skeletal muscles support the viscera. Damage to innervation of these muscles during parturition may contribute to pelvic organ prolapse and urinary incontinence. Unfortunately, animal models that are suitable for studying parturition-induced pelvic floor neuropathy and its treatment are rare. The present study describes the intrapelvic skeletal muscles (i.e., the iliocaudalis, pubocaudalis, and coccygeus) and their innervation in the rat to assess its usefulness as a model for studies of pelvic floor nerve damage and repair. Dissection of rat intrapelvic skeletal muscles demonstrated a general similarity with human pelvic floor muscles. Innervation of the iliocaudalis and pubocaudalis muscles (which together constitute the levator ani muscles) was provided by a nerve (the "levator ani nerve") that entered the pelvic cavity alongside the pelvic nerve, and then branched and penetrated the ventromedial (i.e., intrapelvic) surface of these muscles. Innervation of the rat coccygeus muscle (the "coccygeal nerve") was derived from two adjacent branches of the L6-S1 trunk that penetrated the muscle on its rostral edge. Acetylcholinesterase staining revealed a single motor endplate zone in each muscle, closely adjacent to the point of nerve penetration. Transection of the levator ani or coccygeal nerves (with a 2-week survival time) reduced muscle mass and myocyte diameter in the iliocaudalis and pubocaudalis or coccygeus muscles, respectively. The pudendal nerve did not innervate the intrapelvic skeletal muscles. We conclude that the intrapelvic skeletal muscles in the rat are similar to those described in our previous studies of humans and that they have a distinct innervation with no contribution from the pudendal nerve.

Animals↗
PubMed2003

Serotonergic modulation of bladder afferent pathways.

Normal bladder function is based on activation and maintenance of a sophisticated reflex mechanism involving sympathetic, parasympathetic, and somatic control of the lower urinary tract. The spinal and supraspinal neuronal pathways involved can be modulated by activation or inhibition of neurons in the periphery, at the lumbosacral and thoracolumbar spinal levels, and at supraspinal regulatory sites. Activation of the primary afferent neurons that innervate the lower urinary tract is the first step on this reflex pathway. Under conditions in which bladder function is compromised, abnormal activity in these afferent neurons can induce changes in these circuits, resulting in bladder dysfunction. Control and modulation of afferent pathways is a recent focus for the development of novel treatments for lower urinary tract disorders. This review focuses on the central regulation of bladder function by central serotonergic modulation of sensory pathways. Modulation of this monoaminergic system has dramatic effects on bladder activity and can be a target for pharmacologic treatment of bladder disorders.

Adrenergic Uptake Inhibitors↗
PubMed2003

Serotonin and norepinephrine involvement in efferent pathways to the urethral rhabdosphincter: implications for treating stress urinary incontinence.

Stress urinary incontinence (SUI), the most common form of incontinence, continues to be a largely underdiagnosed problem that imposes large financial and quality-of-life burdens on many women but has few treatment options. Ongoing animal and early human studies have shown that monoamine neurotransmitters play key roles in controlling urethral storage and micturition reflexes. Motor neurons found in the Onuf nucleus of the sacral spinal cord control urethral function, and have several unique properties that distinguish them from other motor neurons. First, the neurons are uniformly smaller than other surrounding motor neurons and have bundled dendrites, allowing strong synchronous activation or inhibition. Second, the neurons demonstrate unique neurochemical profiles. Unlike neurons in surrounding areas, the motor neurons of the Onuf nucleus have dense populations of noradrenergic and serotonergic terminals. Animal studies have shown that alpha1-adrenoceptors and serotonin (5-hydroxytryptamine [5-HT]) receptors in the Onuf nucleus facilitate sphincter contraction. Agonists that stimulate these receptors facilitate the guarding or incontinence reflex, whereas antagonists that block the receptors inhibit this reflex. Therefore, boosting the effects of 5-HT and norepinephrine (NE) to enhance sphincter activity could be clinically promising for improving the symptoms of SUI. Importantly, the activity of the sphincter neurons can be increased pharmacologically during urine storage without interfering with bladder-sphincter synergy. Administering the 5-HT/NE uptake inhibitor duloxetine facilitates sphincter contraction during bladder filling but not during bladder contraction in micturition. This unique effect of duloxetine may be maintained by the selective neuromodulatory effects of 5-HT and NE on activation of sphincter motor neurons by the neurotransmitter glutamate. Prolonging the effect of naturally released NE and 5-HT with duloxetine could augment the body's normal processes for controlling urine storage and micturition. Early trials have demonstrated that duloxetine significantly reduces incontinence episodes and is well tolerated in the clinical setting.

Adrenergic Uptake Inhibitors↗
PubMed2003

Innervation of the levator ani muscles in the female squirrel monkey.

OBJECTIVE: The purpose of this study was to characterize the innervation of the levator ani muscles in the female squirrel monkey and to investigate its usefulness as an animal model of pelvic organ prolapse. STUDY DESIGN: Eleven nulliparous female squirrel monkeys with no pelvic organ prolapse were used in this study. Detailed pelvic dissections were conducted (n = 3), and the Koelle stain for acetylcholinesterase was used to identify the motor endplate zone in the levator ani muscles (n = 2). Unilateral levator ani (n = 4) and pudendal (n = 2) neurectomies were performed; changes in levator ani muscle mass and myocyte diameter were examined 14 days after neurectomy. Nerve biopsy specimens from each animal were processed for microscopy. RESULTS: The levator ani nerve originated from the S2 spinal root and entered the pelvic cavity adjacent to the pelvic nerve between the flexor caudalis brevis and iliocaudalis muscles. The levator ani nerve then projected caudally and bifurcated to penetrate the iliocaudalis and pubocaudalis. A single motor endplate zone in each muscle correlated with the point of levator ani nerve penetration. The pudendal nerve originated from the S1-S2 spinal roots to innervate the urethral and anal sphincters, clitoris, and perineum, but not the iliocaudalis or pubocaudalis. Significant atrophy and myocyte shrinkage occurred in the iliocaudalis and pubocaudalis ipsilateral to the levator ani nerve transection (P <.05). Pudendal neurectomy produced no levator ani muscle changes. CONCLUSION: Intrapelvic skeletal muscles in the female squirrel monkey are similar to humans and have distinct innervation with no contribution from the pudendal nerve. The squirrel monkey is likely to be a useful model of pelvic organ prolapse and warrants further study.

Animals↗
PubMed2002

The role of 5-HT(1A) receptors in control of lower urinary tract function in cats.

In the present study, the role of 5-HT(1A) receptors in control of lower urinary tract function in cats was examined using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) as agonists and WAY100635 and LY206130 as antagonists. Bladder function was assessed using cystometric infusion of saline or 0.5% acetic acid to produce bladder irritation. External urethral sphincter (EUS) function was assessed using electromyographic (EMG) recordings of activity recorded during cystometry or by recording electrically evoked pudendal reflexes. Both 5-HT(1A) receptor agonists caused dose-dependent decreases in bladder activity and increases in EUS EMG activity under conditions of acetic acid infusion. 5-HT(1A) receptor antagonists reversed both the bladder-inhibitory and sphincter-facilitatory effects. Thus, 5-HT(1A) receptor activation can have opposite effects on nociceptive afferent processing depending upon the efferent response being measured. During saline infusion of the bladder, 8-OH-DPAT produced moderate inhibition of bladder activity and had no significant effect on sphincter electromyographic (EMG) activity. 8-OH-DPAT either had no effect, or inhibited, low-threshold electrically evoked pudendal reflexes. These findings indicate that 5-HT(1A) receptor stimulation is inhibitory to bladder function in cats, especially under conditions where the bladder is hyperactive due to irritation. Furthermore, these bladder-inhibitory effects are the exact opposite of the bladder-excitatory effects of 8-OH-DPAT reported in rats. 5-HT(1A) receptor stimulation increases EUS motoneuron activity when driven by nociceptive bladder afferent inputs but not when driven by non-nociceptive afferent inputs. In summary, 5-HT(1A) receptor agonists facilitate a nociceptor-driven spinal reflex (sphincter activity) but inhibit a nociceptor-driven supraspinal reflex (micturition). This pattern of activity would facilitate urine storage and may be important under 'fight-or-flight' conditions when serotonergic activity is high.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats.

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.

Acetic Acid↗
PubMed2002

Innervation of the female levator ani muscles.

OBJECTIVE: The objective of this study was to characterize the innervation of the human female levator ani muscles. STUDY DESIGN: Detailed dissections of the peripheral innervation of the iliococcygeal, pubococcygeal, puborectal, and coccygeal muscles were performed in 12 fresh-frozen female cadavers (aged, 32-100 years) with the use of transabdominal, gluteal, and perineal approaches. Both the pudendal nerve and the sacral nerve roots that enter the pelvis from the cephalic side were followed from their origin at the sacral foramina to their termination. Pelvic floor innervation was described with reference to fixed bony landmarks, particularly the coccyx, the ischial spine and the inferior pubis. Photographs were taken, and nerve biopsies were performed to confirm the gross findings histologically. Biopsy specimens were stained with Masson's trichrome. RESULTS: In each dissection, a nerve originated from the S3 to S5 foramina (S4 alone, 30%; from S3 and S4, 40%; from S4 and S5, 30%), crossed the superior surface of the coccygeal muscle (3.0 +/- 1.4 cm medial to the ischial spine [range, 1.0-4.2 cm]), traveled on the superior surface of the iliococcygeal muscle innervating it at its approximate midpoint, and continued on to innervate both the pubococcygeal and puborectal muscles at their approximate midpoint. The pudendal nerve originated from the S2 to S4 foramina, exited the pelvis through the greater sciatic foramen, traversed Alcock's canal, and branched to innervate the external anal sphincter, the external urethral sphincter, the perineal musculature, the clitoris, and the skin. Despite specific attempts to locate pudendal branches to the levator ani, none could be demonstrated. Nerve biopsy specimens that were obtained at gross dissection were confirmed histologically. CONCLUSION: Gross dissections suggest that the female levator ani muscle is not innervated by the pudendal nerve but rather by innervation that originates the sacral nerve roots (S3-S5) that travels on the superior surface of the pelvic floor (levator ani nerve). Because definitive studies (eg, nerve transection or neurotracer studies) cannot be performed in humans, further studies that will use appropriate animal models are necessary to confirm and extend our findings.

Adult↗
PubMed2002

Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction.

PURPOSE: alpha1-Adrenergic receptor (alpha1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the alpha1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder alpha1AR subtypes may be involved in this process. MATERIALS AND METHODS: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. alpha1AR subtype messenger (m)RNA was quantitated using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the alpha1AR antagonist [125iodine]2-(-[4-hydroxyphenyl]-ethyl-aminomethyl)tetralone (saturation analysis for total alpha1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine alpha1AR subtypes). RESULTS: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder alpha1AR density did not increase overall with obstruction, striking changes in alpha1AR subtype expression occurred. In control animals 70% of alpha1AR mRNA was the alpha1a subtype, 5% were alpha1b and 25% were alpha1d, whereas in obstructed animals bladder alpha1AR expression changed to 23% alpha1a, 2% alpha1b and 75% alpha1d. Changes in alpha1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% alpha1aAR expression in control animals changing to new onset alpha1dAR expression (mean plus or minus standard error of mean 36% +/- 7%) in animals with a 5-fold or greater increase in bladder weight. CONCLUSIONS: Our findings indicate a remarkable increase in bladder alpha1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since alpha1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the alpha1a or alpha1bAR subtypes. These findings imply that targeting alpha1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

Animals↗