Karl Thor - Academia.edu (original) (raw)
Papers by Karl Thor
Annual Reports in Medicinal Chemistry, 2003
Publisher Summary This chapter discusses neuropharmacological approaches to urinary incontinence ... more Publisher Summary This chapter discusses neuropharmacological approaches to urinary incontinence (UI). UI occurs when the lower urinary tract does not store urine properly and there is an involuntary loss of urine. There are three types of UI: urge, stress, and mixed. Urge is considered to be due to an overactive bladder, while stress UI is considered to be due to decreased urethral outlet resistance. In urge incontinence, the reformulations of oxybutynin and other muscarinic cholinergic receptor antagonists continue to dominate the market and late stage clinical development programs. Enterprising clinicians have taken matters into their own hands and applied off label-use of various toxins as they try to find remedies for their patients, but safe, effective, and convenient therapy is needed to compliment the anticholinergics. The chapter describes the neural reflex pathways that control urine storage and micturition and describes pharmacological targets and drug discovery strategies within the context of these reflexes. It also elaborates the function and dysfunction of the lower urinary tract and discusses the reflex control of the lower urinary tract, along with the sites of drug action for the inhibition of micturition reflexes.
International journal of gynaecology and obstetrics, Jul 1, 2004
Stress urinary incontinence (SUI) in women is prevalent, and there are no globally developed or w... more 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.
Urology, Oct 1, 2003
Stress urinary incontinence (SUI), the most common form of incontinence, continues to be a largel... more 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 ␣ 1-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. UROLOGY 62 (Suppl 4A): 3-9, 2003.
The Journal of Urology, Mar 1, 2002
ABSTRACT
Neurourology and Urodynamics, Jun 28, 2018
Background and Aims: Stakeholders from around the world came together to address the unmet needs ... more Background and Aims: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. Methods: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. Results: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. Discussion and Conclusion: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.
PubMed, Aug 1, 1995
Norepinephrine (NE)-containing terminals densely innervate sympathetic preganglionic neurons in t... more 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.
Neuroreport, Aug 1, 1994
Spinal cord injury disrupts micturition reflexes, which produces morbidity. The contribution of e... more Spinal cord injury disrupts micturition reflexes, which produces morbidity. The contribution of endogenous opioid systems to urinary retention were assessed in chronic spinal cats by administering the opioid receptor antagonist, naloxone (5-500 micrograms kg-1, i.p.), to unanesthetized paraplegic cats while monitoring lower urinary tract function and observing hind limb reflexes. While naloxone had no overt effect in acute spinal cats, in chronic spinal cats naloxone induced the release of large volumes of urine and produced marked hind limb hyper-reflexia. Prominent tachyphylaxis and tolerance to the effects of naloxone were evident. Immunohistochemical studies indicated a marked increase in leucine enkephalin and dynorphin in sacral spinal neurons. Together, these data indicate hyperactivity of the endogenous spinal opioid system following recovery from spinal cord injury and, furthermore, suggest that the spinal neural circuitry may become 'dependent' upon elevated levels of endogenous opioid peptides.
PubMed, May 1, 1989
Serotonin (5HT) and substance P (SP) are colocalized in terminals within the nucleus tractus soli... more Serotonin (5HT) and substance P (SP) are colocalized in terminals within the nucleus tractus solitarius (NTS). The purpose of the present study was to determine the origin of these terminals. 5HT- and SP-immunoreactivities (IR) were visualized using dual-colour immunofluorescence histochemistry with amino-4-methylcoumarin-3-acetic acid- and fluorescein isothiocyanate-conjugated secondary antisera, while NTS-afferent neurons were visualized by retrograde labelling with rhodamine beads. Extensive colocalization of 5HT- and SP-IR was seen in NTS-afferent neurons located in the nucleus raphe pallidus, nucleus raphe obscurus, nucleus raphe magnus, and in the parapyramidal region. Over 80 per cent of the SP-IR NTS-afferent neurons contained 5HT-IR, while 68 per cent of the 5HT-IR neurons contained SP-IR. Thus, 5HT- and SP-IR are extensively colocalized in NTS-afferent neurons in the medullary raphe nuclei and associated areas of the ventral medulla.
The Journal of Urology, 2004
The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral ... more 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. Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. 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. 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.
American Journal of Obstetrics and Gynecology, May 1, 2003
The purpose of this study was to characterize the innervation of the levator ani muscles in the f... more 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.
European Journal of Pharmacology, Oct 1, 1979
The effects of clonidine on lumbar sympathetic outflow to the colon and urinary bladder were exam... more The effects of clonidine on lumbar sympathetic outflow to the colon and urinary bladder were examined by recording drug-induced changes in spontaneous postganglionic firing and spinal viscero-sympathetic reflexes in the lumbar colonic and hypogastric nerves of the cat. Clonidine in doses between 2--40 micrograms/kg produced a dose dependent depression of spontaneous and evoked discharges in efferents of the hypogastric nerve but did not alter activity in the lumbar colonic nerves. Clonidine also reduced arterial blood pressure and spontaneous firing in the renal nerves. These data coupled with previous observations in this laboratory indicate that spinal sympathetic pathways can exhibit a considerable variation in the sensitivity to the depressant actions of clonidine. This variation in sensitivity may reflect the relative importance of noradrenergic inhibitory mechanisms in the respective pathways.
Neuroscience, Jul 1, 1993
The Society for Neuroscience Abstracts, Feb 17, 1992
The Journal of Urology, Jun 1, 1996
To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. Ninetee... more To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. 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. 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. Small intestinal submucosa acts as a scaffold for bladder augmentation through regeneration and could be a potential option for bladder reconstruction.
The Journal of Urology, Jun 1, 1996
To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. Ninetee... more To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. 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. 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. Small intestinal submucosa acts as a scaffold for bladder augmentation through regeneration and could be a potential option for bladder reconstruction.
The Journal of Urology, Apr 1, 2005
day recovery period. The responses to all frequencies of FS were significantly reduced at the 7 d... more day recovery period. The responses to all frequencies of FS were significantly reduced at the 7 day period of recovery, but no significant changes were noted for ATP, carbachol, or KCl. The responses to FS returned fully to control by 14 days. For the mature and old bladders, there were no significant differences in response to any form of stimulation following either the 2 hour ischemia or the I day recovery period. The responses to all forms of stimulation were significantly reduced at the 7 day period of recovery (to a greater degree than for the young [in regard to FS]). The responses to FS only partially returned by 14 days whereas the responses to pharmacological agents returned to control levels. CONCLUSIONS: The bladders of the mature and old rabbits were significantly more sensitive to ischemic I reperfusion damage than the bladders of the young rabbits indicating that the cellular protective mechanisms decrease with age.
Autonomic Neuroscience: Basic and Clinical, Jul 1, 2014
In vivo experiments in a diabetic rat model revealed compromised nitrergic urethral relaxations a... more 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.
The Journal of Urology, Mar 1, 2002
Neuropeptides, Oct 1, 2013
Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the low... more Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the lower urinary tract, though their function and distribution in different species is largely unknown. This study examines whether BB receptor agonists can contract bladder smooth muscle in rats, mice, pigs and humans. Methods: Bladder strips were placed in tissue baths for in vitro contractility. Neuronally evoked contractions were elicited using electric field stimulation (EFS). Effects of the BB receptor agonists, neuromedin B (NMB; BB1 receptor agonist) and gastrin-releasing peptide (GRP; BB2 receptor agonist) on baseline tone and EFS-induced contractions were monitored. Results: In rat and human bladder strips, NMB and GRP (10 À11-10 À6 M) increased EFS-induced contractions in a concentration dependent manner. In these species, NMB and GRP also increased baseline tension. In mouse and pig bladder strips, NMB and GRP (10 À8-3 Â 10 À6 M) had no effects on either parameter. Conclusions: These data suggest that bombesin receptors BB receptor 1 and/or BB receptor 2 increase bladder contractions in rat and human. The site of action of these receptors may be pre-and/or post-synaptic, increasing release of transmitters or enhancing smooth muscle excitability, respectively. Thus, BB1 receptor and/or BB2 receptor may offer therapeutic targets for voiding dysfunction associated with impaired bladder contractility; however, species differences must be considered when studying these receptors.
Annual Reports in Medicinal Chemistry, 2003
Publisher Summary This chapter discusses neuropharmacological approaches to urinary incontinence ... more Publisher Summary This chapter discusses neuropharmacological approaches to urinary incontinence (UI). UI occurs when the lower urinary tract does not store urine properly and there is an involuntary loss of urine. There are three types of UI: urge, stress, and mixed. Urge is considered to be due to an overactive bladder, while stress UI is considered to be due to decreased urethral outlet resistance. In urge incontinence, the reformulations of oxybutynin and other muscarinic cholinergic receptor antagonists continue to dominate the market and late stage clinical development programs. Enterprising clinicians have taken matters into their own hands and applied off label-use of various toxins as they try to find remedies for their patients, but safe, effective, and convenient therapy is needed to compliment the anticholinergics. The chapter describes the neural reflex pathways that control urine storage and micturition and describes pharmacological targets and drug discovery strategies within the context of these reflexes. It also elaborates the function and dysfunction of the lower urinary tract and discusses the reflex control of the lower urinary tract, along with the sites of drug action for the inhibition of micturition reflexes.
International journal of gynaecology and obstetrics, Jul 1, 2004
Stress urinary incontinence (SUI) in women is prevalent, and there are no globally developed or w... more 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.
Urology, Oct 1, 2003
Stress urinary incontinence (SUI), the most common form of incontinence, continues to be a largel... more 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 ␣ 1-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. UROLOGY 62 (Suppl 4A): 3-9, 2003.
The Journal of Urology, Mar 1, 2002
ABSTRACT
Neurourology and Urodynamics, Jun 28, 2018
Background and Aims: Stakeholders from around the world came together to address the unmet needs ... more Background and Aims: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder. Methods: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB. Results: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria. 2) Should residual urine volume be the primary outcome parameter and how often should it be measured? 3) Are there secondary measures that should have a place in UAB trials, such as change in the number of catheterizations, quality of life measures, etc.? 4) Use and format of bladder voiding and catheterization diary for trials. 5) Define role and technique of urodynamics in UAB trials. Are urodynamics required to monitor, and possibly exclude, individuals with high pressure voiding induced by bladder prokinetic therapies? 6) Development and use of UAB questionnaires. Discussion and Conclusion: The UAB regulatory working group recognizes the path forward should include engaging the FDA and other regulatory organizations that may harmonize and formalize guidance for regulatory trial designs for therapeutics for UAB.
PubMed, Aug 1, 1995
Norepinephrine (NE)-containing terminals densely innervate sympathetic preganglionic neurons in t... more 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.
Neuroreport, Aug 1, 1994
Spinal cord injury disrupts micturition reflexes, which produces morbidity. The contribution of e... more Spinal cord injury disrupts micturition reflexes, which produces morbidity. The contribution of endogenous opioid systems to urinary retention were assessed in chronic spinal cats by administering the opioid receptor antagonist, naloxone (5-500 micrograms kg-1, i.p.), to unanesthetized paraplegic cats while monitoring lower urinary tract function and observing hind limb reflexes. While naloxone had no overt effect in acute spinal cats, in chronic spinal cats naloxone induced the release of large volumes of urine and produced marked hind limb hyper-reflexia. Prominent tachyphylaxis and tolerance to the effects of naloxone were evident. Immunohistochemical studies indicated a marked increase in leucine enkephalin and dynorphin in sacral spinal neurons. Together, these data indicate hyperactivity of the endogenous spinal opioid system following recovery from spinal cord injury and, furthermore, suggest that the spinal neural circuitry may become 'dependent' upon elevated levels of endogenous opioid peptides.
PubMed, May 1, 1989
Serotonin (5HT) and substance P (SP) are colocalized in terminals within the nucleus tractus soli... more Serotonin (5HT) and substance P (SP) are colocalized in terminals within the nucleus tractus solitarius (NTS). The purpose of the present study was to determine the origin of these terminals. 5HT- and SP-immunoreactivities (IR) were visualized using dual-colour immunofluorescence histochemistry with amino-4-methylcoumarin-3-acetic acid- and fluorescein isothiocyanate-conjugated secondary antisera, while NTS-afferent neurons were visualized by retrograde labelling with rhodamine beads. Extensive colocalization of 5HT- and SP-IR was seen in NTS-afferent neurons located in the nucleus raphe pallidus, nucleus raphe obscurus, nucleus raphe magnus, and in the parapyramidal region. Over 80 per cent of the SP-IR NTS-afferent neurons contained 5HT-IR, while 68 per cent of the 5HT-IR neurons contained SP-IR. Thus, 5HT- and SP-IR are extensively colocalized in NTS-afferent neurons in the medullary raphe nuclei and associated areas of the ventral medulla.
The Journal of Urology, 2004
The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral ... more 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. Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. 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. 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.
American Journal of Obstetrics and Gynecology, May 1, 2003
The purpose of this study was to characterize the innervation of the levator ani muscles in the f... more 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.
European Journal of Pharmacology, Oct 1, 1979
The effects of clonidine on lumbar sympathetic outflow to the colon and urinary bladder were exam... more The effects of clonidine on lumbar sympathetic outflow to the colon and urinary bladder were examined by recording drug-induced changes in spontaneous postganglionic firing and spinal viscero-sympathetic reflexes in the lumbar colonic and hypogastric nerves of the cat. Clonidine in doses between 2--40 micrograms/kg produced a dose dependent depression of spontaneous and evoked discharges in efferents of the hypogastric nerve but did not alter activity in the lumbar colonic nerves. Clonidine also reduced arterial blood pressure and spontaneous firing in the renal nerves. These data coupled with previous observations in this laboratory indicate that spinal sympathetic pathways can exhibit a considerable variation in the sensitivity to the depressant actions of clonidine. This variation in sensitivity may reflect the relative importance of noradrenergic inhibitory mechanisms in the respective pathways.
Neuroscience, Jul 1, 1993
The Society for Neuroscience Abstracts, Feb 17, 1992
The Journal of Urology, Jun 1, 1996
To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. Ninetee... more To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. 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. 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. Small intestinal submucosa acts as a scaffold for bladder augmentation through regeneration and could be a potential option for bladder reconstruction.
The Journal of Urology, Jun 1, 1996
To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. Ninetee... more To evaluate small intestinal submucosa (SIS) as a possible bladder augmentation material. 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. 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. Small intestinal submucosa acts as a scaffold for bladder augmentation through regeneration and could be a potential option for bladder reconstruction.
The Journal of Urology, Apr 1, 2005
day recovery period. The responses to all frequencies of FS were significantly reduced at the 7 d... more day recovery period. The responses to all frequencies of FS were significantly reduced at the 7 day period of recovery, but no significant changes were noted for ATP, carbachol, or KCl. The responses to FS returned fully to control by 14 days. For the mature and old bladders, there were no significant differences in response to any form of stimulation following either the 2 hour ischemia or the I day recovery period. The responses to all forms of stimulation were significantly reduced at the 7 day period of recovery (to a greater degree than for the young [in regard to FS]). The responses to FS only partially returned by 14 days whereas the responses to pharmacological agents returned to control levels. CONCLUSIONS: The bladders of the mature and old rabbits were significantly more sensitive to ischemic I reperfusion damage than the bladders of the young rabbits indicating that the cellular protective mechanisms decrease with age.
Autonomic Neuroscience: Basic and Clinical, Jul 1, 2014
In vivo experiments in a diabetic rat model revealed compromised nitrergic urethral relaxations a... more 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.
The Journal of Urology, Mar 1, 2002
Neuropeptides, Oct 1, 2013
Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the low... more Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the lower urinary tract, though their function and distribution in different species is largely unknown. This study examines whether BB receptor agonists can contract bladder smooth muscle in rats, mice, pigs and humans. Methods: Bladder strips were placed in tissue baths for in vitro contractility. Neuronally evoked contractions were elicited using electric field stimulation (EFS). Effects of the BB receptor agonists, neuromedin B (NMB; BB1 receptor agonist) and gastrin-releasing peptide (GRP; BB2 receptor agonist) on baseline tone and EFS-induced contractions were monitored. Results: In rat and human bladder strips, NMB and GRP (10 À11-10 À6 M) increased EFS-induced contractions in a concentration dependent manner. In these species, NMB and GRP also increased baseline tension. In mouse and pig bladder strips, NMB and GRP (10 À8-3 Â 10 À6 M) had no effects on either parameter. Conclusions: These data suggest that bombesin receptors BB receptor 1 and/or BB receptor 2 increase bladder contractions in rat and human. The site of action of these receptors may be pre-and/or post-synaptic, increasing release of transmitters or enhancing smooth muscle excitability, respectively. Thus, BB1 receptor and/or BB2 receptor may offer therapeutic targets for voiding dysfunction associated with impaired bladder contractility; however, species differences must be considered when studying these receptors.