Diagnostic Value of Systematic Biopsy Methods in the Investigation of Prostate Cancer: A Systematic Review

Diagnostic Value of Systematic Biopsy Methods in the Investigation of Prostate Cancer

This article summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract. The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. The neural control of micturition is organized as a hierarchical system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brain stem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brain stem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary micturition, leading to urinary incontinence. Neuroplasticity underlying these developmental and pathological changes in voiding function is discussed.

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Neural Control of the Lower Urinary Tract

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as alpha(3)-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.

Muscarinic receptor antagonists for overactive bladder

Preservation, sterilization and de-epithelialization of human amniotic membrane for use in ocular surface reconstruction.

Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve.

Although gastrointestinal segments have been widely used for bladder reconstruction, they are not ideal because of the possible complications. Searches have therefore continued for an alternative material for augmentation. Here, we performed bladder augmentation in rats using human amniotic membrane (hAM). Morphologically, the hAM-augmented bladder revealed regeneration of urothelium, detrusor smooth muscle, and nerve fibers within 3 months post-operatively. In our functional evaluation of bladder strips, we compared hAM-augmented bladders with bladders augmented using small intestinal submucosa (SIS). For example, at 6 months post-operatively, contractions of the following size (as a percentage of the responses in the control-bladder group) were obtained in response to high potassium, carbachol, and electrical field stimulation, respectively: hAM 22% vs SIS 15%, hAM 15% vs SIS 7%, hAM 5.3% vs SIS 1.3% (no significant differences, hAM vs SIS). Both hAM- and SIS-augmented bladders displayed adequate capacity and compliance. The present results indicate that, for bladder augmentation, hAM can be used as a scaffold and is comparable in this respect with SIS. hAM can be more easily obtained than SIS and requires little preparation, and its use raises few ethical questions. Hence, hAM may represent a new therapeutic alternative for urological reconstructions.

Transplantation of preserved human amniotic membrane for bladder augmentation in rats.

Aims

Previous studies have suggested that ATP has a role in mechano-afferent transduction, at least partly mediated by nerves other than capsaicin (Cap)-sensitive nerves. We investigated the direct effect of ATP on single fiber activity (SFA) of the primary bladder afferent nerves and its relationship with Cap-sensitivity.



Methods

Female Sprague–Dawley rats were used. On the basis of conduction velocities, SFA was grouped as Aδ- or C-fibers. First, SFA and intravesical pressure were measured during filling as the baseline. Then, Cap (10−5 M) was instilled intravesically and the SFA response was monitored. To desensitize Cap-sensitive nerves, resiniferatoxin (RTX) (10−6 M) was administered intravesically, and then Cap was again administered to confirm the desensitization effect. Thereafter, ATP (10−3 M) or its vehicle was instilled intravesically and another filling cycles recorded.



Results

Thirty-two single afferent fibers were discriminated. Aδ-fibers did not respond to intravesical instillation of Cap, RTX or ATP. Based on Cap-sensitivity, C-fibers could be divided into two subtypes: Cap-sensitive (n = 8) and Cap-insensitive (n = 16). In the Cap-sensitive C-fibers, the response to bladder filling mostly disappeared after RTX desensitization, no matter if the bladder was filled with vehicle or ATP. On the other hand, in the Cap-insensitive C-fibers, even after RTX-treatment, the response was preserved and more enhanced when the bladder was filled with ATP compared to vehicle.



Conclusions

Mechanosensitive bladder afferents can be classified as (1) Aδ-fibers, (2) Cap-insensitive, and (3) Cap-sensitive C-fibers. The activation of the bladder afferents induced by intravesical application of ATP is mediated mainly through Cap-insensitive C-fibers. Neurourol. Urodyn. 30:163–168, 2011. © 2010 Wiley-Liss, Inc.

Effects of intravesical instillation of ATP on rat bladder primary afferent activity and its relationship with capsaicin‐sensitivity

Mechanosensitive primary bladder afferent activity in rats with and without spinal cord transection.

Hypothesis / aims of study Recent findings have suggested that during the storage phase, there is an ongoing release of acetylcholine from nerves and/or urothelium acting on muscarinic receptors. Acetylcholine may act directly on afferent nerves to initiate the micturition reflex and contribute to the symptoms of OAB. Previous studies have revealed that intravesical administration of oxybutynin has a temporary anesthetic effect on pelvic afferent C fibers without any effect on Aδ fibers (1), whereas parenteral administration of oxybutynin decreases activity in both C and Aδ fibers (2). However oxybutynin is an anticholinergic agent with mixed actions, so theoretically the observed effects can be due to the anticholinergic, direct muscle relaxant or local anesthetic actions. To evaluate the effect of muscarinic receptor blocking during the storage phase, a pure antimuscarinic drug has to be studied. This study aims to evaluate the efficacy of solifenacin, on bladder afferent activity. Study design, materials and methods Eight female Sprague-Dawley rats were used for the experiments. After urethane anesthesia, the left pelvic nerve was identified and put on an electrode for electrical stimulation. A catheter was inserted into the bladder dome for filling and emptying. The lumbosacral spinal cord was exposed by laminectomy and the both L6 dorsal roots were cut. The dorsal skin was tied up to make a pool and the spinal cord was covered with body warm paraffin oil. Fine filaments were dissected from the left L6 dorsal root and placed on recording electrodes. Afferent fibers originating from the bladder were identified by electrical stimulation of the pelvic nerve and by bladder filling. Those with a conduction velocity <2.5 m/sec were considered to correspond with C fibers and those with a CV >2.5 m/sec with Aδ fibers (3). Afferent activity was studied during constant flow cystometry at 0.08 ml/min until an intravesical pressure of 35 cm water was reached. The effect of intravenous solifenacin (1mg/kg) on bladder afferent fibers was evaluated. After a baseline bladder filling, solifenacin was administered and the afferent activity was again assessed during cystometry every 30 minutes up to 180 minutes after administration. Afferent activity after solifenacin is expressed as a percentage of baseline activity, integrated for the whole filling phase. Results Twelve single unit afferent fibers were isolated in 8 rats. Eight units corresponded to criteria for C fibers (CV: 1.327 ±0.1268 m/sec), and four for Aδ fibers (CV: 4.005 ±0.9722 m/sec). Six fibers out of eight C fibers and three out of four Aδ fibers showed a decrease in activity after solifenacin administration, with the remainder showing either inconsistent and small effect or no change. Only the 10 fibers that exhibited a response after drug administration were included for further analysis. For the Aδ fibers, afferent sensitivity 30 min after solifenacin was 59 % (P>0.05) of the baseline sensitivity, 28 % after 60 min (P<0.001), 31 % after 90 min (P<0.01), 31 % after 120 min (P<0.01), 32 % after 150 min (P<0.01), and 52 % after 180 min (P < 0.05). For the C fibers, afferent sensitivity respectively was 64 % (30min, P < 0.05), 63 % (60min, P < 0.05), 58 % (90min, P<0.01), 53 % (120min, P<0.01), 40 % (150min, P<0.001), and 47 % (180min, P<0.001) compared with baseline activity. No difference was found between effect on Aδ and C fibers after solifenacin.

Kazuyoshi Iijima

Papers

Effects of the M3 receptor selective muscarinic antagonist darifenacin on bladder afferent activity of the rat pelvic nerve.

Transplantation of preserved human amniotic membrane for bladder augmentation in rats.

Effects of intravesical instillation of ATP on rat bladder primary afferent activity and its relationship with capsaicin‐sensitivity

Mechanosensitive primary bladder afferent activity in rats with and without spinal cord transection.

Effects of the Muscarinic Antagonist, Solifenacin, on Bladder Afferent Activity of the Rat Pelvic Nerve