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Durham, NC, United States

Thor K.B.,Urogenix Incorporated | De Groat W.C.,University of Pittsburgh
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2010

The urethral rhabdosphincter and pelvic floor muscles are important in maintenance of urinary continence and in preventing descent of pelvic organs [i.e., pelvic organ prolapse (POP)]. Despite its clinical importance and complexity, a comprehensive review of neural control of the rhabdosphincter and pelvic floor muscles is lacking. The present review places historical and recent basic science findings on neural control into the context of functional anatomy of the pelvic muscles and their coordination with visceral function and correlates basic science findings with clinical findings when possible. This review briefly describes the striated muscles of the pelvis and then provides details on the peripheral innervation and, in particular, the contributions of the pudendal and levator ani nerves to the function of the various pelvic muscles. The locations and unique phenotypic characteristics of rhabdosphincter motor neurons located in Onuf's nucleus, and levator ani motor neurons located diffusely in the sacral ventral horn, are provided along with the locations and phenotypes of primary afferent neurons that convey sensory information from these muscles. Spinal and supraspinal pathways mediating excitatory and inhibitory inputs to the motor neurons are described; the relative contributions of the nerves to urethral function and their involvement in POP and incontinence are discussed. Finally, a detailed summary of the neurochemical anatomy of Onuf's nucleus and the pharmacological control of the rhabdosphincter are provided. Copyright © 2010 the American Physiological Society.

Limberg B.J.,Procter and Gamble | Andersson K.-E.,Wake forest University | Aura Kullmann F.,University of Pittsburgh | Aura Kullmann F.,Urogenix Incorporated | And 4 more authors.
Cell and Tissue Research | Year: 2010

β 3-Adrenergic receptor agonists are currently under clinical development for the treatment of overactive bladder, a condition that is prevalent in postmenopausal women. These agents purportedly relax bladder smooth muscle through a direct action at the myocyte β 3- receptor. The aim of this study was to examine the expression of the individual beta-adrenergic receptors in full thickness sections from ageing human female bladder. We obtained a series of rabbit polyclonal antibodies generated against each of the three β-adrenergic receptors, and validated their receptor specificity in CHOK1 cells expressing each of the individual receptors. Immunostaining for β 1, β 2, and β 3 were each more prominent in the urothelium than in the detrusor, with all receptors expressed in the same cell types, indicating co-expression of all three receptors throughout the urothelium in addition to the detrusor. Staining of all receptors was also observed in suburothelial myofibroblast-like cells, intramural ganglion cells, and in Schwann cells of intramural nerves. The β 3-receptor in the human urothelium appears to be functional, as two different selective β 3-receptor agonists, TAK677 and BRL37344, stimulate cAMP formation in UROtsa cells. Densitometry analysis indicates a persistent expression of all receptors throughout the bladder with increasing age, with the exception of the β 2-receptor in the urothelium of the trigone, which appears to decrease slightly in older women. These data indicate that β 3- receptor expression is maintained with age, but may function in concert with other β-receptors. Activation of the myocyte receptor may be influenced by action on non-myocyte structures including the intramural ganglion cells and myofibroblasts. © 2010 Springer-Verlag.

Ishigami T.,Astellas Pharma Inc. | Yoshioka K.,Astellas Pharma Inc. | Karicheti V.,Urogenix Incorporated | Marson L.,Urogenix Incorporated
Journal of Sexual Medicine | Year: 2013

Introduction: The urethrogenital reflex (UGR) is used as a physiological animal model of the autonomic and somatic activity that accompanies ejaculatory-like reflexes (ELRs). Serotonin (5-HT) plays an important role in regulating ejaculation. Aim: To examine the effects of intraurethral 5-HT on ELRs and to examine the effects of various 5-HT receptor subtypes on the 5-HT-induced changes in the ELRs. Methods: The effects of intraurethral infusion of 5-HT on ELRs were examined by monitoring the urethrogenital reflex in male rats. The effects of various 5-HT receptor-specific antagonists on the 5-HT-induced responses were examined. Main Outcome Measures: Main outcome measures were urethral pressure threshold required to elicit the UGR and bulbospongiosus activity or ELRs. Results: Intraurethral infusion of 5-HT (10-1,000μM) produced a dose-dependent facilitation of the UGR, i.e., decrease in threshold urethral perfusion pressure and an increase in number of ELRs. The 5-HT3 receptor antagonists tropisetron (1 and 3mg/kg, i.v.) and ramosetron (0.1 and 1mg/kg, i.v.), the 5-HT7 receptor antagonist SB269970 (3mg/kg, i.v.), and the 5-HT1A receptor antagonist WAY-100635 (1mg/kg, i.v.) all failed to inhibit 5-HT-induced facilitation of the UGR. However, ritanserin (1mg/kg, i.v.), a nonselective 5-HT2 receptor antagonist, and xylamidine (0.01-1mg/kg, i.v.), a peripherally restricted nonselective 5-HT2 receptor antagonist, significantly inhibited both the decrease in urethral pressure threshold and the increase in number of ELRs induced by intraurethral infusion of 5-HT. Conclusion: These results suggest that in the male rat urethra, peripheral 5-HT2 receptors are involved in the 5-HT-induced facilitation of the expulsion phase of ejaculation. © 2013 International Society for Sexual Medicine.

Birder L.,University of Pittsburgh | De Groat W.,University of Pittsburgh | Mills I.,Pfizer | Morrison J.,University of Leeds | And 2 more authors.
Neurourology and Urodynamics | Year: 2010

This review deals with individual components regulating the neural control of the urinary bladder. This article will focus on factors and processes involved in the two modes of operation of the bladder: storage and elimination. Topics included in this review include: (1) The urothelium and its roles in sensor and transducer functions including interactions with other cell types within the bladder wall (''sensory web''), (2) The location and properties of bladder afferents including factors involved in regulating afferent sensitization, (3) The neural control of the pelvic floor muscle and pharmacology of urethral and anal sphincters (focusing on monoamine pathways), (4) Efferent pathways to the urinary bladder, and (5) Abnormalities in bladder function including mechanisms underlying comorbid disorders associated with bladder pain syndrome and incontinence. © 2009 Wiley-Liss, Inc.

Fry C.H.,University of Surrey | Daneshgari F.,Case Western Reserve University | Thor K.,Urogenix Incorporated | Drake M.,Bristol Urological Institute | And 3 more authors.
Neurourology and Urodynamics | Year: 2010

This review will highlight appropriate animal models for the study of a number of disorders involving changes to lower urinary tract function. A major hurdle to the development of animal models for human lower urinary tract disorders is that the clinical pathophysiology of the latter mostly remain idiopathic. Acute injury/inflammation of otherwise healthy animals has often been used to study effects on a target tissue/organ. However, these "acute" models may not adequately address the characteristics of "chronic" visceral disorders. In addition, the relevance of observed changes following acute injury/inflammation, in terms of possible therapeutic targets, may not reflect that which occurs in the human condition. We have therefore emphasized the situations when animal models are required to investigate lower urinary tract disorders and what they should set out to achieve. In particular we have discussed the merits and disadvantages of a number of paradigms that set out to investigate specific lower urinary tract disorders or situations associated with these conditions. These include animal models of overactive bladder, stress urinary incontinence, ageing and congenital defects of the urinary tract and bladder pain syndrome. Neurourol. Urodynam. 29:603-608, 2010. © 2010 Wiley-Liss, Inc.

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