Clinical Outcomes in Early Cervical Cancer Patients Treated with Nerve Plane-sparing Laparoscopic Radical Hysterectomy.

STUDY OBJECTIVE: To explore the feasibility of nerve plane-sparing laparoscopic radical hysterectomy (NPS-LRH) as a simplified C1-type surgery for cervical cancer patients and to compare this technique with laparoscopic radical hysterectomy (LRH). DESIGN: A retrospective comparative study. SETTING: An academic tertiary hospital affiliated with the Chinese National Cancer Center. PATIENTS: Six hundred fifteen patients with Fédération Internationale de Gynécologie et d'Obstétrique stage Ib and IIa cervical cancer who underwent laparoscopic radical hysterectomy between January 2010 and December 2017 were enrolled. Among them, 263 patients underwent the NPS-LRH surgery, and 352 patients underwent the LRH surgery. Intraoperative data and postoperative outcomes were compared between the 2 groups. INTERVENTIONS: NPS-LRH is a simplified type C1 procedure that preserves the ureteral mesentery and its nerve plane, whereas LRH is a type C2 procedure in the Querleu-Morrow surgical classification system. MEASUREMENTS AND MAIN RESULTS: There were no statistically significant differences in age, body mass index, Fédération Internationale de Gynécologie et d'Obstétrique stage, tumor differentiation, pathological type, depth of invasion, lymphovascular space invasion, parametrial tissue invasion, lymphatic metastasis, neoadjuvant chemotherapy, or postoperative adjuvant radiotherapy and chemotherapy between the 2 groups. Compared with the LRH group, the NPS-LRH group had a shorter length of operation (238.7 ± 53.9 minutes vs 259.8 ± 56.6 minutes, p < .01), less intraoperative bleeding (p < .01), more resected lymph nodes (p = .028), shorter duration of urinary catheterization (p < .01), lower incidences of postoperative hydronephrosis (p = .044), less long-term frequent urination (p < .01), less acute urinary incontinence (p < .01), poor bladder sensation (p = .028), and constipation (p = .029). There were no statistically significant differences in the disease-free survival and overall survival between the 2 groups (p = .769 and .973, respectively). CONCLUSION: NPS-LRH is a simplified, safe, and feasible type C1 operation that had a shorter length of operation, less intraoperative bleeding, more resected lymph nodes, and better postoperative bladder function compared with the LRH group. Further studies are required to assess its benefits on rectal function and long-term prognosis.

Precise characterization of urinary tract innervation using three-dimensional reconstruction: A contemporary review. / Caracterización precisa de la inervación del tracto urinario mediante reconstrucción tridimensional: una revisión contemporánea.

A precise understanding of the autonomic innervation of the urinary tract is crucial to successful management of urologic disease given the important role that neurophysiology plays in genitourinary pathology. Recent studies using a combination of contemporary histopathology and imaging technologies have furthered our understanding of the spatial nerve distribution in the kidneys, ureters, and bladder. The findings of these recent studies may have important clinical applications in expanding our knowledge of the etiology and treatment of disease processes affecting the urinary tract. In this narrative review, our goal is to provide an overview of the autonomic innervation of the urinary tract. Specifically, we aim to provide a three-dimensional gender-specific description of renal, ureteral and vesical innervation. We also highlight some possible opportunities for clinical and investigational application of this new knowledge.

Gross and Histologic Anatomy of the Pelvic Ureter: Clinical Applications to Pelvic Surgery.

OBJECTIVE: To further evaluate relationships of the pelvic ureter to clinically relevant structures and to characterize the anatomy, histology, and nerve density of the distal ureter. METHODS: In this observational cadaveric study, 35 female cadavers were examined, 30 by gross dissections and five microscopically. Ureter length and segments of pelvic ureter were measured. Closest distances between the ureter and clinically relevant points were recorded. The distal pelvic ureter and surrounding parametrium were evaluated microscopically. Nerve density was analyzed using automated quantification of peripheral nerve immunostaining. Average measurements of nerve density in the anterior and posterior quadrants surrounding the ureter were statistically compared using a two-tailed t test. Descriptive statistics were used for analyses with distances reported as mean±SD (range). RESULTS: Gross dissections revealed ureter length of 26.3±1.4 (range 24-29) cm (right), 27.6±1.6 (25-30.5) cm (left). Lengths of ureter from pelvic brim to uterine artery crossover were 8.2±1.9 (4.4-11.5) cm (right), 8.5±1.5 (4.5-11.5) cm (left) and from crossover to bladder wall 3.3±0.7 (2.4-5.8) cm (right), 3.2±0.4 (2.6-4.1) cm (left). Intramural ureter length was 1.5±0.3 (1-2.2) cm (right) and 1.7±1.2 (0.8-2.5) cm (left). Distances from the ureter to uterine isthmus: median 1.7 (range 1-3.0) cm (right) and 1.7 (1.0-2.9) cm (left); lateral anterior vaginal fornix 1.5 (1.0-3.1) cm (right) and 1.7 (0.8-3.2) cm (left); lateral vaginal apex 1.3 (1.0-2.6) cm (right) and 1.2 (1.1-2.2) cm (left) were recorded. Microscopy demonstrated denser fibrovascularity posteromedial to the ureter. Peripheral nerve immunostaining revealed greater nerve density posterior to the distal ureter. CONCLUSION: Proximity of the ureter to the uterine isthmus and lateral anterior vagina mandates careful surgical technique and identification. The intricacy of tissue surrounding the distal ureter within the parametrium and the increased nerve density along the posterior distal ureter emphasizes the importance of avoiding extensive ureterolysis in this region.

Origin and nature of pelvic ureter innervation.

AIMS: Innervation of the pelvic ureter traditionally comes from the pelvic plexus. This innervation is independent: adrenergic and cholinergic. The purpose of this study was to describe more precisely the origin and nature of its innervation (adrenergic, cholinergic, nitrergic, and somatic). METHODS: Six specimens of normal human fetal pelvis (four male and two female) from 20 to 30 weeks gestation were studied. The sections of these fetuses, carried out every 5 µm without interval, were treated with Hematoxylin Eosin (HE), with Masson's trichrome (TriM), immunolabeling of smooth muscle cells with smooth anti-actin, of nerves with anti-S100 protein, anti-tyrosine hydroxylase, anti-VAChT, anti-nNOS, and with anti- peripheral myelin protein 22 (PMP 22). The slides were scanned and two-dimensional images reconstructed in 3D, and analyzed. RESULTS: The terminal pelvic ureter travels above and inside the inferior hypogastric plexus (IHP). The nerve fibers that innervate the ureterovesical junction come mainly from the superior hypogastric plexus (SHP) which gives off the hypogastric nerves and pelvic branches of the sacral plexus that form the IHP. Most nerve fibers meet below the ureter, behind the bladder to form an ascending bundle, which innervates the pelvic ureter. Immunohistochemical analysis shows that the nerves of the pelvic ureter consist of adrenergic, cholinergic, and nitrergic fibers. CONCLUSION: The innervation of the distal ureter depends mainly on the SHP. This innervation is adrenergic, cholinergic, and nitrergic. It innervates the pelvic ureter in an ascending manner. This anatomical information can change rectal resection and ureteral reimplantation techniques and drug treatments for pelvic ureter stones. Neurourol. Urodynam. 36:271-279, 2017. © 2015 Wiley Periodicals, Inc.

[Anatomic application of the genitofemoral nerve in uroandrological surgery].

The genitofemoral nerve (GFN) has its unique anatomic characteristics of location, run and function in the male urinary system and its relationship with the ureter, deferens and inguinal region is apt to be ignored in clinical anatomic application. Clinical studies show that GFN is closely correlated with postoperative ureteral complications and pain in the inguinal region after spermatic cord or hernia repair. GFN transplantation can be used in the management of erectile dysfunction caused by cavernous nerve injury. Therefore, GFN played an important role in the clinical application of uroandrology. This review summarizes the advances in the studies of GFN in relation to different diseases in uroandrology.

Precise Characterization and 3-Dimensional Reconstruction of the Autonomic Nerve Distribution of the Human Ureter.

PURPOSE: We sought to characterize and 3-dimensionally reconstruct the distribution of the autonomic innervation of the human ureter. MATERIALS AND METHODS: Three male and 3 female pairs of ureters were evaluated at 2 mm serial transverse sections along the entire length of the ureter. The location of nerve tissue was immunohistochemically identified using the neuronal marker, S100 protein. ImageJ software was used to calculate nerve count and density in the adventitia and smooth muscle. Blender® graphics software was used to create a 3-dimensional reconstruction of autonomic nerve distribution. RESULTS: Within the adventitia nerve density was highest in the mid and distal ureter (females 2.87 and 2.71 nerves per mm2, and males 1.68 and 1.69 nerves per mm2) relative to the proximal ureter (females and males 1.94 and 1.22 nerves per mm2, respectively, p >0.0005). Females had significantly higher nerve density throughout the adventitia, especially in the distal ureter (2.87 vs 1.68 nerves per mm2, p <0.0005). In smooth muscle the nerve density progressively increased from the proximal to the distal ureter (p >0.0005). Smooth muscle nerve density was similar in the 2 genders (p = 0.928). However, in females nerve density was significantly higher in the first 2 cm of the distal ureter relative to the second 2 cm (3.6 vs 1.5 nerves per mm2, p <0.001) but not in males (3.0 vs 2.1 nerves per mm2, p = 0.126). CONCLUSIONS: Nerve density was highly concentrated at the distal ureter in the adventitia and smooth muscle of the male and female human ureters. The female ureter had greater nerve density in the adventitia, and in smooth muscle nerves were significantly concentrated at the ureteral orifice and the ureteral tunnel.

Current concepts and practical techniques of nerve-sparing laparoscopic radical hysterectomy.

Laparoscopic radical hysterectomy has been widely performed for patients with early-stage cervical cancer. The operative techniques for nerve-sparing to avoid bladder dysfunction have been established during the past three decades in abdominal radical hysterectomy, but how these techniques can be applied to laparoscopic surgery has not been fully discussed. Prolonged operation time or decreased radicality due to less accessibility via a limited number of trocars may be a disadvantage of the laparoscopic approach, but the magnified visual field in laparoscopy may enable fine manipulation, especially for preserving autonomic nerve tracts. The present review article introduces the practical techniques for sparing bladder branches of pelvic nerves in laparoscopic radical hysterectomy based on understanding of the pelvic anatomy, clearly focusing on the differences from the techniques in abdominal hysterectomy.

Careful Dissection of the Distal Ureter Is Highly Important in Nerve-sparing Radical Pelvic Surgery: A 3D Reconstruction and Immunohistochemical Characterization of the Vesical Plexus.

OBJECTIVE: Radical hysterectomy with pelvic lymphadenectomy (RHL) is the preferred treatment for early-stage cervical cancer. Although oncological outcome is good with regard to recurrence and survival rates, it is well known that RHL might result in postoperative bladder impairments due to autonomic nerve disruption. The pelvic autonomic network has been extensively studied, but the anatomy of nerve fibers branching off the inferior hypogastric plexus to innervate the bladder is less known. Besides, the pathogenesis of bladder dysfunction after RHL is multifactorial but remains unclear. We studied the 3-dimensional anatomy and neuroanatomical composition of the vesical plexus and describe implications for RHL. MATERIALS AND METHODS: Six female adult cadaveric pelvises were macroscopically dissected. Additionally, a series of 10 female fetal pelvises (embryonic age, 10-22 weeks) was studied. Paraffin-embedded blocks were transversely sliced in 8-µm sections. (Immuno) histological analysis was performed with hematoxylin and eosin, azan, and antibodies against S-100 (Schwann cells), tyrosine hydroxylase (postganglionic sympathetic fibers), and vasoactive intestinal peptide (postganglionic parasympathetic fibers). The results were 3-dimensionally visualized. RESULTS: The vesical plexus formed a group of nerve fibers branching off the ventral part of the inferior hypogastric plexus to innervate the bladder. In all adult and fetal specimens, the vesical plexus was closely related to the distal ureter and located in both the superficial and deep layers of the vesicouterine ligament. Efferent nerve fibers belonging to the vesical plexus predominantly expressed tyrosine hydroxylase and little vasoactive intestinal peptide. CONCLUSIONS: The vesical plexus is located in both layers of the vesicouterine ligament and has a very close relationship with the distal ureter. Complete mobilization of the ureter in RHL might cause bladder dysfunction due to sympathetic and parasympathetic denervation. Hence, the distal ureter should be regarded as a risk zone in which the vesical plexus can be damaged.

IDENTIFICATION AND THE RELATIONSHIP OF DIFFERENT TYPES OF SPONTANEOUS ACTIVITY IN THE RAT URINARY TRACT: URETER, URINARY BLADDER.

Simultaneous recording of spontaneous electrical activity was conducted from the ending areas of the ureter (the zone bordered with pyeloureteral anastomosis and bladder, respectively), as well as of the proximal part of the bladder. Normally the activity of the distal ureter zone is a propagating from the perirenal area action potentials with increased amplitude (100 microV). In these conditions from the bladder were recorded action potentials with relatively lower values of amplitude and frequency rhythm (31.9 microV and 17 min(-1), respectively). Isolation of investigating ureter areas from each other and from the bladder leads to the emergence of spike activity in the peribladder area different from that in norm: in the background of oscillating waves arises the action potential. Isolation of the ureter from the bladder also affects the nature of the initial activity. Of all analyzed parameters of activity change (decrease) only the amplitude and the frequency of action potentials reaching respectively 24.5 microV and 14.2 min(-1). The results indicate the presence of different types of autonomous spontaneous activity in the extreme zones of the ureter and bladder. The adjustment of these activity parameters in the areas can be provided by their relationship with each other.

[CHARACTERISTICS OF THE URETER CONTRACTIONS IN CHILDREN WITH CHRONIC PYELONEPHRITIS].

The article presents results of electrophysiological study of the function of the ureter in the frequency range of 0.6-35 Hz, conducted in 100 children aged 5 to 13 years with chronic pyelonephritis. Data of 35 healthy people were used as a control. It was shown that the features of ureter contractions were significantly different in the two groups. Marked decrease of amplitudes of signal harmonics was found at a frequency of 1.4 Hz in patients with pyelonephritis compared to controls. Myostimulation in pyelonephritis group has led to an approximation of harmonic amplitudes to the values of the control group.

Ureteral relaxation through calcitonin gene-related peptide release from sensory nerve terminals by hypotonic solution.

OBJECTIVES: To evaluate the influence of hypotonic solutions on ureteral relaxation mediated by the release of calcitonin gene-related peptide from intramural sensory nerve endings. METHODS: Urine osmolarity of Sprague-Dawley rats drinking water low in salt content (Fiuggi water) or a reference water for 7 days was measured. Release of calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter and urinary bladder by hypotonic solutions was assessed by an immunometric assay. The mechanism through which hypotonic solutions inhibit neurokinin A-induced phasic contractions of isolated rat ureters was evaluated by organ bath studies. RESULTS: A 7-day consumption of Fiuggi water in rats reduced urine osmolarity by ~40%. Exposure to hypotonic solutions released calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter. This response was abated in a calcium-free medium, after capsaicin desensitization, and in the presence of the unselective transient receptor potential channel antagonist, ruthenium red. Exposure of isolated rat ureteral preparations to a hypotonic solution inhibited neurokinin A-evoked phasic contraction. This response was attenuated by capsaicin desensitization and in the presence of the calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide8-37 . Transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4 antagonists did not affect the neurogenic and calcitonin gene-related peptide-dependent relaxation. CONCLUSION: Present data show that hypotonic solution evokes calcitonin gene-related peptide release from capsaicin-sensitive intramural sensory nerves, thus inhibiting ureteral contractility, through a transient receptor potential-dependent mechanism. However, this mechanism does not involve transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4. Future studies with appropriate in vivo models should investigate the hypothesis that hypostenuric urine diffusing into the ureteral tissue might favor ureteral relaxation through this novel mechanism.

Lymphatic and nerve distribution throughout the parametrium.

BACKGROUND: Our objective was to concomitantly assess distribution of lymphatic and nerve structures in the parametrium. METHODS: Twenty hemipelvises from ten fresh cadavers were dissected to differentiate between, three different parts of the parametrium: the lateral parametrium, the proximal and the distal part of the posterior parametrium. Histologic and immunofluorescence analyses of nerve and lymphatic structures were performed using NSE and LYVE-1 staining, respectively. The percentage of structures was independently scored as 0 (0%), 1 (1-20%), 2 (20-50%), 3 (50-80%), 4 (>80%). RESULTS: The lateral parametrium and the proximal part of the posterior parametrium contained both nerve (scored 2.25 and 2.50, respectively) and lymphatic (scored 2.50 and 2.00, respectively) structures. The distal part of the posterior parametrium also contained numerous nerve structures (scored 2.00) but lymphatic structures were rare (scored 0.88). No difference in nerve distribution was found according to the parts of parametrium while a significantly lower distribution of lymphatic vessels was observed in the distal part of the posterior parametrium (p=0.03). CONCLUSION: The distal part of the posterior parametrium is of high nerve density and low lymphatic density raising the issue as to whether it should be removed during radical hysterectomy.

Ureterovesical junction obstruction causes increment in smooth muscle contractility, and cholinergic and adrenergic activity in distal ureter of rabbits.

BACKGROUND/PURPOSE: The controversy in management of primary obstructed megaureter necessitates further elucidation of the underlying pathophysiology. We evaluated smooth muscle contractility, and cholinergic, adrenergic and serotonergic activity of rabbit distal ureters after ureterovesical junction (UVJ) obstruction. METHODS: Sham (SH) operation, partial obstruction (PO) and complete obstruction (CO) of the right UVJ were performed in rabbits. Three weeks later, distal ureters were isolated; spontaneous contractions (SC), contractile responses to electrical field stimulation (EFS), high KCl, carbachol, phenylephrine and serotonin were recorded. RESULTS: SC amplitudes increased in CO compared to PO and SH (p<0.001). SC frequency was higher in CO (p<0.05). EFS-induced contraction amplitudes were greater in CO than other groups (p<0.05). High KCl-induced contractions were greater in CO (p<0.001) and PO (p<0.01). Carbachol-induced contractility was enhanced in CO and PO (p<0.05). Contractile response to phenylephrine was greater in CO than other groups (p<0.05). Serotonin induced contractile responses in CO and PO, greater in CO (p<0.05). UVJ obstruction also increased spontaneous contractility in contralateral PO and CO ureters. CONCLUSIONS: UVJ obstruction increased spontaneous and neurotransmitter-induced contractions in an obstruction grade-dependent manner. Obstruction also altered contractility of the contralateral ureters. Our findings may serve to provide further understanding of the pathophysiology of megaureter.

Expression and functional role of ß3 -adrenoceptors in the human ureter.

OBJECTIVES: To investigate the presence of ß-adrenoceptor subtypes in the human ureter, and to examine whether ß(3) -adrenoceptors modulate relaxation of the human ureter. METHODS: Expression of messenger ribonucleic acid of ß-adrenoceptors in the human ureter was determined by reverse transcription polymerase chain reaction, and distribution of ß-adrenoceptors was examined by immunohistochemistry. In functional studies, the relaxant effects of isoproterenol, procaterol, TRK-380, salbutamol and BRL 37344 on KCl-induced contraction of the human ureter were evaluated, and the inhibitory effects of isoproterenol, procaterol and TRK-380 on electrical field stimulation-induced contractions were determined. RESULTS: Expression of ß(1) -, ß(2) - and ß(3) -adrenoceptor messenger ribonucleic acid in the human ureter was confirmed by reverse transcription polymerase chain reaction. Positive staining for ß(1) -, ß(2) - and ß(3) -adrenoceptor was identified not only in smooth muscle, but also in the urothelium of the human ureter. All ß-adrenoceptor agonists decreased the tone of KCl-induced contractions of the human ureter with a rank order of relaxant effects of isoproterenol > procaterol > TRK-380 > salbutamol > BRL 37344. Furthermore, isoproterenol, procaterol and TRK-380 significantly decreased the amplitude of electrical field stimulation-induced contractions with a rank order of inhibitory effects of isoproterenol > procaterol > TRK-380. CONCLUSIONS: Human ureteral relaxation is mediated by both ß(2) - and ß(3) -adrenoceptor stimulation. ß(3) -Adrenoceptor agonists have the potential to relax the human ureter, and their clinical application in the treatment of ureteral stones is expected.

Purinergic signalling in the lower urinary tract.

The aim of this review is to describe the conceptual steps contributing to our current knowledge of purinergic signalling and to consider its involvement in the physiology and pathophysiology of the lower urinary tract. The voiding reflex involves ATP released as a cotransmitter with acetylcholine from parasympathetic nerves supplying the bladder and ATP released from urothelial cells during bladder distension to initiate the voiding reflex via P2X3 receptors on suburothelial low threshold sensory nerve fibres. This mechanosensory transduction pathway also participates, via high threshold sensory nerve fibres, in the initiation of pain in bladder and ureter. Treatment of prostate and bladder cancer with ATP is effective against the primary tumours in animal models and human cell lines, via P2X5 and P2X7 receptors, and also improves the systemic symptoms associated with advanced malignancy. Acupuncture is widely used for the treatment of urinary disorders, and a purinergic hypothesis is discussed for the underlying mechanism.

Is the pelviureteric junction an anatomical entity?

OBJECTIVE: The concept of the pelviureteric junction has existed for more than a century and yet there is no clear anatomical definition of this junction. This systematic review addresses the question of whether the human pelviureteric junction is a discrete anatomical entity. METHODS: A systematic literature review was undertaken to investigate the normal gross and microscopic anatomy of the pelviureteric junction using the electronic databases MEDLINE, PubMed, Cochrane Library and Google Scholar. RESULTS: In most individuals there is a gradual transition between the renal pelvis and ureter with no external features indicating the presence of a discrete pelviureteric 'junction'. Internally, however, luminal mucosal folds are prominent in this region. There is no consensus on the arrangement of muscle fibers at the pelviureteric junction (which may be age-dependent) although some studies suggest a focal thickening in the muscle wall consistent with physiological observations suggesting a high pressure zone capable of regulating urine flow. Studies of innervation have shown no evidence of specialization at this site. CONCLUSIONS: There is some evidence that a pelviureteric region can be delineated anatomically and physiologically. However, although it may be a useful clinical concept, there is no sound anatomical basis for an actual pelviureteric junction.

Is pelvic plexus nerve documentation feasible during robotic assisted laparoscopic ureteral reimplantation with extravesical approach?

PURPOSE: Urinary retention is a known complication of using an extravesical approach for ureteral reimplantation, especially in bilateral cases. The etiology may be secondary damage to pelvic nerves during ureteral dissection. Recent literature suggests that it is possible to visually identify these nerves during a robotic assisted laparoscopic approach. We performed an exploratory study to identify and document them in pediatric patients by means of electrophysiologic recordings. MATERIAL AND METHODS: Seven consecutive patients undergoing robotic assisted laparoscopic ureteral reimplantation with extravesical approach were prospectively enrolled in the study. Following dissection of the ureter below the level of vas deferens in male and the uterine artery in female, staying close to the adventitia and approaching the ureterovesical junction, the fibers as described in human cadaveric studies were identified dorsomedial to the ureter and preserved. Stimulating and recording electrodes were passed through to record post-synaptic compound muscle action potentials of the bladder. RESULTS: Even though the nerve fibers were visually identified, we were unable to consistently and reproducibly record compound muscle action potentials after stimulation of putative pelvic plexus fibers at the distal ureter, despite modulation in stimulation intensity, pulse characteristics, signal recording sensitivity and stimulator probe variation. CONCLUSIONS: In this pilot study, the inconsistent findings raise questions about the exact location of the neurovascular bundle, nature of bladder smooth muscle electrophysiology and the appropriate methodology of evaluation. This may provide a reason to reexamine the intraoperatively expected location of pelvic plexus nerve fibers.

Modeling the urinary tract-computational, physical, and biological methods.

Models of the lower urinary tract are used to understand better the physiological and pathological functions of the tract and to gain insight into the relative importance of different components. The key requirement of a model is described, namely: to involve a continuous iteration with experiment; whereby experiments provide parameters and validation for components of the model, which is then used to generate hypotheses, which are tested experimentally. Different types of models are described: computational models that describe mathematically the whole urinary tract or components; physical models useful especially in testing medical devices; and tissue-engineered models. The purpose of modeling is first described in terms of the ability of models to predict the properties of the system of interest, using components that have a physiological interpretation, and to gain insight into the relative importance of different components. Examples are used to illustrate the use of modeling the urinary tract with reference to the different categories listed above.

Muscarinic acetylcholine receptors in the urinary tract.

Muscarinic receptors comprise five cloned subtypes, encoded by five distinct genes, which correspond to pharmacologically defined receptors (M(1)-M(5)). They belong to the family of G-protein-coupled receptors and couple differentially to the G-proteins. Preferentially, the inhibitory muscarinic M(2) and M(4) receptors couple to G(i/o), whereas the excitatory muscarinic M(1), M(3), and M(5) receptors preferentially couple to G(q/11). In general, muscarinic M(1), M(3), and M(5) receptors increase intracellular calcium by mobilizing phosphoinositides that generate inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol (DAG), whereas M(2) and M(4) receptors are negatively coupled to adenylyl cyclase. Muscarinic receptors are distributed to all parts of the lower urinary tract. The clinical use of antimuscarinic drugs in the treatment of detrusor overactivity and the overactive bladder syndrome has focused interest on the muscarinic receptors not only of the detrusor, but also of other components of the bladder wall, and these have been widely studied. However, the muscarinic receptors in the urethra, prostate, and ureter, and the effects they mediate in the normal state and in different urinary tract pathologies, have so far not been well characterized. In this review, the expression of and the functional effects mediated by muscarinic receptors in the bladder, urethra, prostate, and ureters, under normal conditions and in different pathologies, are discussed.