Karl Bruce Thor

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.

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.

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.

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.

Neural Control of the Lower Urinary Tract: Peripheral and Spinal Mechanisms

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. Neurourol. Urodynam. 29: 128–139, 2010.

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.

Inhibition of Central Sympathetic and Somatic Outflow to the Lower Urinary Tract of the Cat by the Alpha sub 1 Adrenergic Receptor Antagonist Prazosin

Selective alpha 1 adrenergic receptor antagonists are used to reduce the dynamic component of urethral obstruction in patients with benign prostatic hyperplasia. Their effectiveness is presumed to result from blockade of alpha 1 adrenergic receptors within the prostatic smooth muscle. However, a reduction in central sympathetic tone to the prostate might also contribute to their effectiveness. The present experiments examined the effects of the selective alpha 1 adrenergic receptor antagonist prazosin on sympathetic activity recorded from the hypogastric nerve in chloralose-anesthetized cats. For comparison, the effects of prazosin were also examined on somatic activity recorded from the pudendal nerve. When the urinary bladder was empty, prazosin reduced spontaneous activity recorded from the hypogastric nerve (to 65% of control) and reduced evoked reflex activity recorded from the hypogastric nerve (to 44% of control) and the pudendal nerve (to 48% of control). Interestingly, when the urinary bladder was filled, the inhibitory effects of prazosin on the pelvic to hypogastric reflex were overcome. These experiments indicate that central noradrenergic neurons mediate a tonic facilitation of sympathetic and somatic activity to pelvic viscera via activation of alpha 1 adrenergic receptors. Thus, alpha 1 adrenergic receptor antagonists may reduce the dynamic component of urethral outlet obstruction in patients with benign prostatic hyperplasia through dual mechanisms: first, through a blockade of alpha 1 adrenergic receptors on the prostatic smooth muscle itself and, second, by reducing the activity of the sympathetic neurons that innervate the prostate. Additional therapeutic relief may be provided through reduction of somatic neural activity to the external urethral sphincter, which might also reduce outlet resistance and improve flow.

Neural control of the female urethral and anal rhabdosphincters and pelvic floor muscles

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 Onufs 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 Onufs nucleus and the pharmacological control of the rhabdosphincter are provided.

Animal models and their use in understanding lower urinary tract dysfunction

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. Copyright

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.