Abstract: OBJECTIVE: To examine the expression of ubiquitin hydrolase (UH), an enzyme which is part of the ubiquitin-proteasome system involved in the regulation of cell growth and differentiation, to gain an insight into the cell types and processes underlying the tissue remodelling that occur after bladder neck damage. MATERIALS AND METHODS: Three groups of male guinea pigs were used, comprising controls (not operated, four), sham (five) and obstructed (six). The bladder outlet was obstructed by implanting a silver ring around the urethra, which was left in situ for 2-4 weeks. Sham-operated guinea pigs had the same operative procedure but no ring was implanted. The bladders were removed and incubated in Krebs' solution at 36 degrees C, gassed with 95% O2 and 5% CO2, Tissues were then fixed in 4% depolymerized paraformaldehyde and processed for immunohistochemistry. We used antibodies raised against UH, cyclooxygenase type I and vimentin. Specific antibody binding was visualized using the appropriate secondary antibodies. RESULTS: Staining with an antibody to UH showed the presence of both sensory and motor nerves in control, sham and obstructed bladders. In the control bladders this was the predominant staining pattern. In the sham and obstructed bladders UH staining revealed additional positive cell types; cells associated with the outermost layers of the urothelium (the umbrella cells), in the lamina propria (the lamina propria interstitial cells (lp-ICs), on the surface of the muscle bundles (surface muscle, sm-ICs) and on the serosal surface (muscle coat, mc-ICs). All ICs stained with vimentin. The ICs within the muscle bundles (intramuscular, im-ICs) did not stain with UH. The number and density of the UH-positive cells was greater in the obstructed than in the sham bladders, suggesting a change in relation to the severity of damage to the bladder neck. CONCLUSION: The expression of UH implies the re-targeting of proteins marked for degradation in the proteasome. Increased expression of UH in the lp-ICs and sm-ICs shows that these cells are active in the early and late stages of the tissue remodelling resulting from obstruction. These results show a further subset of ICs that might be involved in the increased deposition of extracellular material and tissue remodelling.
Abstract: AIMS: Reactive nitrogen and oxygen species (RNOS) likely play a role in the development of bladder dysfunction related to bladder outlet obstruction. Antioxidants protect against these free radicals. The aim of our study was to investigate the effect of bladder outlet obstruction on the endogenous antioxidant status of the bladder and to correlate this to bladder structure and function. METHODS: In 16 guinea pigs either a partial outlet obstruction or a sham operation was induced. The contractile responses of detrusor strips to electrical field stimulation (EFS), acetylcholine, potassium, and ATP were monitored 4 weeks after the operation. The nerve density in bladder tissue was determined by using the non-specific nerve marker PGP 9.5. Separate antioxidants and the total antioxidant status were assessed using the trolox equivalent antioxidant capacity (TEAC) test. RESULTS: Contractile responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation. The nerve-mediated responses in strips from obstructed bladders were lower compared to the sham group. Obstructed bladders showed a patchy denervation and the nerve density was significantly lower compared to the sham group. The total antioxidant capacity, the glutathione and the glutathione reductase (GR) levels significantly decreased in obstructed bladders compared to the sham group. CONCLUSION: This study demonstrates that the antioxidant status of guinea pig bladders exposed to outlet obstruction decreased which might be associated with the observed reduction in nerve density. The results strengthen the hypothesis that oxidative stress is involved in the pathophysiology of bladder dysfunction related to obstructed bladders. Neurourol. Urodynam. 28:461-467, 2009. (c) 2008 Wiley-Liss, Inc.
Abstract: OBJECTIVES To study the additional diagnostic value of ambulatory urodynamic measurements/monitoring (AUM) in patients with lower urinary tract symptoms (LUTS). PATIENTS AND METHODS We reviewed the urodynamic data, collected at the urology department of our University Hospital between 2002 and 2007. During this period, 2393 urodynamic investigations were conducted. In 108 patients both conventional urodynamic measurements (CUM) and AUM were conducted. RESULTS In 25 patients an AUM was conducted for bladder evacuation problems due to absent bladder contractility, seen on CUM. In 21 cases, AUM showed the presence of contractility of the bladder under normal conditions at home. Their symptoms were due to other factors such as a concomitant non-relaxation of the urinary sphincter or pelvic floor, psychological reasons or obstruction, for all of which treatment could be initiated. In 32 cases, the indication for AUM was an inconclusive CUM. Of these patients 16 had clear overactive contractions on AUM. CONCLUSION AUM has a more important place in the second-line diagnostic evaluation of patients with LUTS than generally considered. In half of the cases (16 of 32) in which CUM could not provide a diagnosis, AUM helped us to diagnose overactive bladder. Moreover, in the absence of AUM, many patients would have been misdiagnosed with an acontractile bladder based on their CUM results, which would most probably have resulted in life-time clean intermittent self-catheterization.
Abstract: OBJECTIVE: To identify the cells expressing the M(3) muscarinic receptor subtype in the lamina propria of the bladder. MATERIALS AND METHODS: The bladders from five normal guinea pigs were isolated and fixed in 4% paraformaldehyde. Tissues sections (10 microm) were then cut and stained with antibodies to the type 3 muscarinic receptor (M(3)), the interstitial cell marker vimentin and the nonspecific nerve marker PGP 9.5. The specificity of the antibody to the M(3) receptor was established using the complementary blocking peptide and Western blot analysis of human embryonic kidney (HEK) cells transfected to express the M(3) receptor protein. RESULTS The M(3) antibody pre-incubated with its blocking peptide showed no immunohistochemical staining. Investigating this antibody using HEK cells transfected to express the M(3) receptor protein and control HEK cells showed a single band in the transfected cells and no band in the control cells. M(3) receptor immunoreactivity (M(3)-IR) was detected primarily on a dense network of vimentin-positive (vim(+)) cells lying immediately below the urothelium, i.e. the suburothelial interstitial cells (Su-ICs). The M(3)-IR was punctate and appeared to be located on the cell surface. The diffuse network of cells in the remaining regions of the lamina propria showed no M(3)-IR. Few nerve fibres were associated with the M(3)-IR Su-ICs. The M(3)-IR Su-ICs were most numerous and prominent in the lateral wall. The number of M(3)-IR/vim(+) cells diminished towards the bladder base and were absent in the bladder urethral junction. In the base and urethral junction there were vim(+) cells that were not M(3)-IR. A population of umbrella cells in the lateral wall also showed weak punctate M(3)-IR. CONCLUSIONS Using a well-characterized M(3) antibody, these results show for the first time that the M(3) muscarinic receptor in the lamina propria is located specifically on the Su-ICs. The physiological role of these cells is unknown and consequently the significance of what appears to be a cholinergic signalling system is unclear. Previously published data showed that these cells respond to nitric oxide and atrial natriuretic peptide with an increase in cGMP and possibly prostaglandin. All of these observations, taken together, suggest that the Su-ICs receive multiple inputs and that they must be part of a complex signalling system in this region of the bladder wall.
Abstract: For many people a recurrent strong desire to void, sometimes with incontinence, diminishes their quality of life. At present there are few insights into what underlies these problems. The condition is described as the 'overactive bladder symptom complex' but this definition is proving to be unhelpful. It focuses on overt bladder contractions rather than the main problem, which is altered and heightened sensation. Also, current approaches that describe bladder sensations as episodic and leading to voiding as 'first and second sensation to void' might also be misleading if they are taken too literally and used to suggest mechanisms. Current research is beginning to focus on the mechanisms that generate afferent information from the bladder and how it can become altered. As these views develop it is crucial that we appreciate the diversity of the bladder afferent system and distinguish between afferent and sensory information; in this review we explore this underlying complexity. The central nervous system (CNS) receives vast amounts of information from the bladder, which arises from different locations, uses different fibre types and involves different methods. The CNS is continually being bombarded with 'afferent noise'. The challenge now is to understand the nature and components of this 'afferent noise' and which components are essential to sensation. The emerging picture is complex, but this complexity must not be negated or oversimplified. It must be embraced and incorporated it into thinking when designing experiments, analysing data, diagnosing patients and evaluating treatment.
Abstract: INTRODUCTION: In patients with minor lower urinary tract symptoms (LUTS), elevated prostate-specific antigen (PSA) levels and (multiple) negative multi-site biopsies, therapy decision is complex. Long-term outcome of a diagnostic transurethral resection of the prostate (TURP) in these patients needs to be determined. METHODS: We retrospectively evaluated patients with minor LUTS, elevated PSA levels (>or=4 ng/ml) and no signs of prostate cancer. Patients with bladder outlet obstruction (BOO) underwent TURP. When TURP showed no malignancy, patients were annually evaluated by PSA testing and the International Prostate Symptom Score (IPSS). RESULTS: The study included 82 consecutive patients satisfying the inclusion criteria. All patients underwent TURP. No malignancy was encountered in 74 patients (90.2%). Of this group, 36 patients were followed >3 years (mean 62.1 months). One patient (2.8%) showed a persistently rising PSA level with positive extended multi-site biopsies 4 years after TURP, implying further treatment. 35 patients (97.2%) had a permanent complete normalization of PSA levels (<4 ng/ml) together with normalized IPSS. CONCLUSIONS: We consider an elevated PSA level in patients with minor LUTS and (multiple) negative multi-site biopsies as a sign of BOO. If these patients receive a diagnostic TURP, long-term outcome is excellent.
Abstract: Patients with elevated and/or rising prostate-specific antigen (PSA), minor lower urinary tract symptoms (LUTS), and no evidence for prostate cancer on (multiple) extended prostate biopsies are a regularly encountered problem in urological practice. Even now, patients are seen with no objective explanation of this persistent elevated and/or rising PSA. So far, many strategic proposals have been elaborated and published to deal with this specific population including the use of different PSA derivates; applying different biopsy schemes-strategies-biopsy target imaging; diagnostic use of prostate cancer genes; and many more. In this review, we propose a new algorithm in which an urodynamic evaluation should be included since bladder outlet obstruction (BOO) can be expected. Once BOO is confirmed, a transurethral resection of the prostate (TURP) can be offered to these patients. This procedure will result in subjective and biochemical improvement and allows extensive histological examination. Current literature was reviewed with regard to this specific population. This research was performed using the commercially available Medline online search tools and applying the following search terms: "diagnostic TURP"; "elevated PSA"; and "prostate biopsy". Furthermore, subsequent reference search was executed on retrieved articles.
Abstract: OBJECTIVES: Bladder outlet obstruction is correlated with an increased peroxidation of lipids. The aldehyde 4-hydroxynonenal (HNE) is produced in relative large amounts during lipid peroxidation. The aim of this study was to investigate the effect of HNE on excitation-contraction coupling of detrusor smooth muscle. METHODS: We used smooth muscle strips from pig urinary bladder. Contractile responses to electrical field stimulation (EFS) (4 to 32 Hz), carbachol (10(-8) to 3.10(-5) M), and potassium (65.3 mM) were monitored before and after the addition of HNE. We investigated the effect of the synthetic thiol inactivator N-ethylmaleimide (NEM) on the stimulation pathways and compared it with the HNE-mediated effect. RESULTS: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. HNE (100 microM) diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration response curve did not decrease after exposure to HNE. The maximal effect obtained with carbachol was significantly reduced after 100 microM HNE treatment. Contractions induced by potassium were affected in a similar degree by HNE compared with EFS- and carbachol-induced responses of comparable amplitude. Incubation of bladder strips with NEM had similar effects on pharmacological responses compared with HNE exposure. CONCLUSIONS: 4-Hydroxynonenal affects pig bladder contractility. L-type calcium channels and or the contractile system of the bladder muscle are susceptible to HNE-mediated damage. The cholinergic nerves and the muscarinic receptor signaling system remain largely unaffected. The effects of HNE are most likely mediated via alkylation of sulfhydryl groups.
Abstract: OBJECTIVE: To identify and characterize possible structural specialisations in the wall of the lower urinary tract (LUT) in the region of the bladder urethral junction (BUJ), with the specific objective of identifying regional variations in sensory nerve fibres and interstitial cells (ICs). MATERIALS AND METHODS: The bladder base and urethra was removed from five male guinea pigs killed by cervical dislocation. Tissue pieces were incubated in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2), fixed in 4% paraformaldehyde and processed for immunohistochemistry. The nonspecific marker vimentin and the general neuronal marker protein gene product (PGP) 9.5 were used to identify ICs and nerve fibres, respectively. Specific antibody binding was visualized using the appropriate secondary antibodies. RESULTS: The wall of the LUT in the region immediately between the bladder base and the urethra, the BUJ, differed in its cellular composition relative to the adjacent areas. PGP-positive (PGP(+)) nerve fibres, presumptive afferent fibres, lay within the urothelium running between the epithelial cells. There were two general nerve patterns: branching fibres with no varicosities, and complex fibres with varicosities. Fibre collaterals with varicosities exited the urothelium and occupied the space under the urothelium adjacent to the layer of suburothelial ICs. The latter, lamina propria and around the muscle bundles were identified using vimentin (vim(+)). In the base a few vim(+) cells were also PGP(+). In the region of the BUJ there was a decrease in the amount of smooth muscle. In this region, below the lamina propria, there was an area densely populated with vim(+)/PGP(+) ICs. Nerve fibres ran between the cells in this region. CONCLUSION: These structural specialisations within the urothelium and deeper layers of the BUJ suggest that they might be associated with specific functions. The localized highly branched network of the putative afferent nerves suggests the presence of a local axonal reflexes involving possible cross-talk between the urothelium and suburothelial layer. The function of the specialized region of ICs is not known and must await further information on the functional properties of this novel cell type. These observations show further the cellular heterogeneity of the cells in the LUT and the complexity of the structures. One of the major current challenges in functional urology is to understand the relationships between these novel structures and overall bladder and urethral function.
Abstract: BACKGROUND: Deciding on strategy for patients with minor lower urinary tract symptoms (LUTS), elevated prostate-specific antigen (PSA) levels, unsuspicious digital rectal examination (DRE) and/or transrectal ultrasound (TRUS), and multiple negative extended prostate biopsies is complex. OBJECTIVES: To define the role and clinical significance of transurethral resection of the prostate (TURP) in these patients. DESIGN, SETTINGS, AND PARTICIPANTS: Thirty-three patients with elevated PSA; minor LUTS, as assessed by the International Prostate Symptoms Score (IPSS); no suspicion for prostate cancer on DRE and/or TRUS; and negative extended prostate biopsies were prospectively enrolled in a cohort study at a tertiary care institution. INTERVENTION: After full urodynamic investigation showing all patients to be bladder outlet obstructed, TURP was performed. MEASUREMENTS: Resected tissue was histologically examined for presence of prostate cancer. Within 6 mo after TURP, patients were clinically reevaluated by means of IPSS and PSA level. RESULTS AND LIMITATIONS: Preoperatively, mean PSA and IPSS values were 8.2ng/ml and 6.8, respectively. Mean detrusor pressure at maximum flow was 80.3cm H(2)O. Histological examination after TURP revealed benign prostate hyperplasia in 81.8% (subgroup 1) and aggressive prostate cancer in 6.1% of patients (subgroup 2). In 12.1% of patients, only a few chips of nonaggressive prostate cancer (T1a) were detected. In patients without signs of aggressive prostate cancer (93.9%=12.1%+81.8%, subgroup 3), mean postoperative PSA and IPSS values were 0.6ng/ml and 2.4, respectively, while these values were 0.6ng/ml and 2.5ng/ml in subgroup 1 (p<0.0001). This study is limited in sample size, requiring more research to confirm these results. CONCLUSIONS: This prospective study shows that, in patients with minor LUTS and no suspicion for prostate cancer, bladder outlet obstruction can result in elevated PSA levels. These patients will benefit from TURP regarding symptomatology and supernormalisation of PSA levels. Moreover, albeit in few cases, histological examination will reveal aggressive prostate cancer.
Abstract: Localised phasic contractions in the bladder wall (autonomous activity) have been hypothesized to be an integral part of a motor/sensory system contributing to bladder sensation. The sites responsible for generating this activity, the mechanisms involved in its propagation and modulation remain unknown. This phasic motor activity is modulated by exogenous prostaglandins. Therefore, analysis of the sites of prostaglandin production and action within the bladder wall may shed light on the mechanisms of generation and modulation of this phasic activity. In this paper we report the localization of immuno-reactivity indicative of the expression of cyclo-oxygenase enzyme type I (COX I-IR) within the bladder wall. Basically, three types of COX I-IR cell were identified: epithelial cells in the basal and intermediate layers of the urothelium, complex vimentin-positive and COX I-IR cells in the lamina propria and vimentin-negative COX I-IR cells in the lamina propria and on the surface of the inner muscle bundles. These vimentin-negative/COX I-IR cells appear to be in close apposition to a continuous network of vimentin-positive cells which extends from the lamina propria into the inner muscle layers and subsequently into the outer muscle layers. However, the interstitial cells in this region might form a distinctly different subtype. Firstly, the interstitial cells in this region differ from those in the inner layer by their responsiveness to NO with a rise in cGMP. Two subtypes have been identified: cells on the surface of the muscle bundles and within the muscle bundles. Secondly, COX I-IR cells are not associated with the interstitial cells in the outer layers. The physiological significance for these apparent differences in the interstitial cell network is not clear. However, such differences are likely to reflect differences in the processes involved in their activation, modulation and control.
Abstract: OBJECTIVES: To determine the clinical relevance of transurethral resection of the prostate (TURP) in patients with minor lower urinary tract symptoms (LUTS) but elevated prostate-specific antigen (PSA) levels. METHODS: We retrospectively included 82 patients, aged 50.2-78.2 yr, with minor LUTS, elevated PSA (> or =4 ng/ml), and no signs of prostate cancer (PCa) after (multiple) negative multisite biopsies who underwent TURP after they were diagnosed by urodynamics with bladder outlet obstruction (BOO). We evaluated the clinical benefit of TURP by assessing its effect on International Prostate Symptom Score (IPSS) and PSA and the diagnostic value of histologic examination of the resected tissue for the presence of PCa. RESULTS: After TURP, histologic analysis of the resected specimen revealed that eight patients (9.8%) had PCa; seven of these patients had a tumour that needed further treatment. The remaining 74 patients (90.2%) were diagnosed with BOO due to benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE). In this group, the mean PSA level decreased from 8.8 ng/ml before TURP to 1.1 ng/ml in the first year and 1.3 ng/ml in the second year after TURP; the mean IPSS decreased from 8.8 to 1.5 in the first year after TURP. CONCLUSIONS: The current data suggest that patients with minor LUTS and elevated PSA without evidence of PCa are very likely to have BOO due to BPH/BPE and may benefit from TURP if obstruction is proved. However, a prospective trial is warranted to assess the impact of these results on clinical practice.
Abstract: AIMS: Several pathophysiological conditions in the urinary bladder, for example, ischemia/reperfusion and inflammation are characterized by the formation of reactive oxygen species (ROS). The ROS are highly toxic because they can destroy proteins, DNA, and lipids. The aim of this study was to investigate the effect of oxidative stress on excitation-contraction coupling of detrusor smooth muscle. MATERIALS AND METHODS: Smooth muscle strips were dissected from pig urinary bladder and mounted in organ baths. Oxidative stress was mimicked by the addition of Cumene hydroperoxide (CHP), a lipophilic hydroperoxide, to the organ baths. Contractile responses to electrical field stimulation (EFS: 4-32 Hz), carbachol (10(-8)-3 x 10(-5) M), potassium (65.3 mM), and ATP (1 mM) were monitored before and after the addition of CHP. RESULTS: Responses of detrusor strips to EFS were for the greater part based on neurogenic stimulation and the release of acetylcholine. CHP diminished contractile responses to EFS and carbachol to the same extent. The pD(2) value of the carbachol concentration-response curve decreased significantly after exposure to 0.1 mM, 0.4 mM, 0.8 mM CHP. Furthermore the maximal effect obtained with carbachol was significantly reduced after 0.1 mM, 0.4 mM, and 0.8 mM CHP treatment. Contractions induced by potassium and ATP were significantly less affected by oxidative stress compared to EFS- and carbachol-induced responses of comparable amplitude. CONCLUSIONS: The results of our study demonstrate that oxidative stress induced by CHP affects pig bladder contractility. The muscarinic receptor signaling system is severely damaged. L-type calcium channels and the contractile system are less affected and cholinergic nerves remain largely unaffected.
Abstract: OBJECTIVES: To determine the role of pressure flowmetry in patients without bothersome lower urinary tract symptoms (LUTS), rising prostate-specific antigen (PSA) levels and diagnosed as having clinical benign prostatic hyperplasia (BPH) after negative (multiple) extended multi-site biopsy. METHODS: The study enrolled patients with minor LUTS who were referred to our urological practice by their general practitioner because of a rising PSA level (>/=4 ng/ml). After exclusion of clinical prostatic carcinoma by digital rectal examination and transrectal ultrasound, all patients underwent at least one set of extended multi-site biopsies to exclude T1c prostate cancer. Patients with negative biopsies (clinical BPH) were subjected to pressure flowmetry whereafter those with bladder outlet obstruction underwent TURP. RESULTS: The study included 82 patients, with a mean age of 64.8 years (50.2-78.2 years), satisfying the inclusion criteria. Urodynamic analysis showed that all patients had bladder outlet obstruction. After TURP, eight patients (9.8%) were diagnosed as having histologically proven prostate cancer; 74 patients (90.2%) were diagnosed as having BPH. Patients of the BPH group had a mean preoperative PSA level of 8.8 ng/ml (4.3-25.8 ng/ml) and a mean international prostate symptom score of 8.8 (2-18). The mean detrusor pressure at maximum flow in BPH patients was 89.5 cmH(2)O (20-200 cmH(2)O). CONCLUSIONS: An increased PSA in patients with minor or no LUTS, clinical BPH and negative extended multi-site prostate biopsy is strongly correlated to bladder outlet obstruction. Therefore, patients with these characteristics should be treated with TURP.
Abstract: OBJECTIVES: To establish the functional consequences of exposing the isolated whole bladder preparation to exogenous prostaglandins (PGE(1), PGE(2), PGF(2alpha)) and to determine which cells express cyclooxygenase (COX) types I and II, to generate PG to effect these changes in vivo. MATERIALS AND METHODS: Fifteen female guinea pigs (270-350 g) were used, i.e. seven for structural studies and eight for physiological measurement. For the structural study pieces of the lateral wall were incubated separately in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2) with 1 mm isobutyl-methyl-xanthene. Individual pieces were then exposed to 100 microm of the nitric oxide (NO) donor NONOate for 10 min; control tissues remained in Krebs' solution. Tissues were then fixed in 4% paraformaldehyde. For the physiological experiments bladders were isolated and a cannula inserted into the urethra to monitor intravesical pressure. The bladders were suspended in a chamber containing carboxygenated physiological solution at 33-36 degrees C. All drugs were added to the abluminal bladder surface. RESULTS: In the resting bladder there were small spontaneous transient rises in pressure, i.e. autonomous activity. Exposure to PGE(2) (3-300 nM) resulted in an increase in basal pressure on which were superimposed autonomous activity, which was increased both in amplitude and frequency. The changes in the amplitude and frequency depended on the concentration of PGE(2). After a brief exposure (240 s) to PGE(2) the augmentation of the autonomous activity continued for >60 min despite regular washing. The responses were similar with PGE(1) but the responses to PGF(2alpha) and arachidonic acid were reduced. The augmented activity was reduced by the EP1/EP2 receptor blocking agent AH6809 (10 microm). Using an antibody to the 70 kDa constitutive form (COX I), COX I immunoreactivity (COX I-IR) was located in cells in the basal urothelium, in lamina propria and cells on the surface of the inner muscle bundles. There were few COX I-IR cells associated with the outer muscle bundles. The COX I-IR cells lying within the lamina propria were distinct from the suburothelial cells which respond to NO with an increase in cGMP. The lamina propria COX I-IR cells appeared to form a network surrounding muscle trabeculae within the inner muscle layer. COX II-IR was associated with the nuclei of cells in the urothelium, lamina propria and muscle. CONCLUSIONS: These data show that PGs regulate autonomous activity. Potential sources of endogenous PG were identified. It is unclear how the PGs produced by these cells alter autonomous activity. There might be a direct activation of the muscle by PGs released by the network of superficial muscle interstitial cells, or PG released from the urothelium might influence phasic contractile activity via networks of COX I-IR interstitial cells. The possible roles and importance of this mechanism for bladder physiology and pathology are discussed.
Abstract: OBJECTIVE: To identify and describe changes to the motor component of the motor/sensory system, which contributes to sensation during the filling phase of the micturition cycle, as a result of surgically induced bladder pathology, i.e. damage to the bladder neck and outlet obstruction. MATERIALS AND METHODS: Adult male guinea pigs (294-454 g) were assigned initially into three groups: (i) normal guinea pigs with no surgical intervention (control, seven); (ii) guinea pigs which, with full surgical anaesthesia, had a silver ring implanted around the bladder neck (obstructed, 13); and (iii) guinea pigs operated to expose the bladder neck but with no implantation of a ring (sham, six). At 2-4 weeks after surgery the bladders were isolated, weighed and the pressure recordings used to identify autonomous activity. RESULTS: The bladder weights in all operated groups, including the sham, were greater than controls. Bladder weights in the obstructed guinea pigs varied considerably, reflecting the degree of pathological change. Consequently, bladders from this group were divided into those with high (OBH) and those with low bladder weight (OBL). The mean (sd) amplitudes of the autonomous contractions were 1.1 (0.1), 10.8 (1.8), 11.4 (2.5) and 17.1 (4.0) cmH(2)O in control, sham, OBL and OBH bladders, respectively, indicating a progressive alteration in function with the pathology. The changes in the sham group suggested that the pathological changes were not the result of obstruction but damage to the bladder neck, the implantation of the silver rings exacerbating the damage. There were episodes of rapid phasic activity (bursts) in 10 of 13 of the ring-implanted bladders, and in two of six in the sham group, but never in controls. Neither the autonomous activity nor the bursts were affected by tetrodotoxin (1 microm) or atropine (3 microm) but they were abolished by noradrenaline (3 microm). In control bladders, adding the muscarinic agonist arecaidine produced a transient acceleration of phasic activity and increased the amplitude of the contractions. There was a similar acceleration of activity in all the operated groups but the concentrations needed to achieve an increase in frequency were significantly lower, the relative sensitivity to arecaidine being OBH >/= OBL > sham > control. CONCLUSION: The mechanism involved in controlling the frequency of the motor component of the motor/sensory system, the 'pacemaker', appears to become progressively 'supersensitive' to cholinergic stimulation with the development of pathology. These observations are discussed in relation to the motor/sensory system and the origins of sensation in the bladder. The argument is proposed that damage to the bladder neck, not obstruction per se, results in altered nonmicturition activity which contributes to increased afferent output. In turn this contributes to the increased sensations of urge associated with bladder dysfunction. The cholinergic regulation of this altered 'pacemaker' might be the target for one of the therapeutic actions of anticholinergic drugs.
Abstract: Interstitial cells (ICs) play a role in regulating normal bladder activity. This study explores the possibility that the sub-urothelial and muscle networks of NO/cGMP-responsive ICs are altered in animals with surgically induced outflow obstruction. In sham-operated animals, the urothelium comprised NO-stimulated cGMP-positive (cGMP(+)) umbrella cells, an intermediate layer and a basal layer that stained for nNOS. cGMP(+) sub-urothelial interstitial cells (su-ICs) were found below the urothelium. cGMP(+) cells were also associated with the outer muscle layers: on the serosal surface, on the surface of the muscle bundles and within the muscle bundles. Several differences were noted in tissues from obstructed animals: (1) the number of cGMP(+) umbrella cells and intensity of staining was reduced; (2) the intermediate layer of the urothelium consisted of multiple cell layers; (3) the su-IC layer was increased, with cells dispersed being throughout the lamina propria; (4) cGMP(+) cells were found within the inner muscle layer forming nodes between the muscle bundles; (5) the number of cells forming the muscle coat (serosa) was increased; (6) an extensive network of cGMP(+) cells penetrated the muscle bundles; (7) cGMP(+) cells surrounded the muscle bundles and nodes of ICs were apparent, these nodes being associated with nerve fibres; (8) nerves were found in the lamina propria but rarely associated with the urothelium. Thus, changes occur in the networks of ICs following bladder outflow obstruction. These changes must have functional consequences, some of which are discussed.
Abstract: AIMS: Flavonoids comprise a large group of natural polyphenolic compounds, which possess a wide spectrum of physiological and pharmacological effects. Recently, the flavonoid galangin was found to modulate smooth muscle contractility. The aim of the present study was to investigate the mechanism of actions of galangin on pig bladder smooth muscle and to characterize its potential as an alternative inhibitor of bladder smooth muscle contraction. MATERIALS AND METHODS: Strips of pig detrusor muscle were mounted in separate 6-ml organ baths containing Krebs solution. The contractile response to carbachol (10(-8)-10(-4)M), potassium (2x10(-2)-10(-1)M), and electrical field stimulation-EFS (2-32 Hz) were determined before and after the addition of galangin (3x10(-5)M). The contractile responses to carbachol in calcium-free Krebs' solution plus EGTA and L-type channel blocker were determined in the absence and presence of the flavonoid. Furthermore, the effect of galangin was also evaluated after the administration in the bath of a number of antagonists/inhibitors including a combination of propranolol, phentolamine, capsazepine, and verapamil. Student's t-test and one factor ANOVA were used to determine the statistical significance of the effects. RESULTS: Galangin inhibited the maximal contractile response to carbachol and potassium by 57.41% (P<0.01) and 33.52% (P<0.05), respectively. The maximum force of the carbachol-evoked contractions in calcium-free solution after incubation with galangin was 32% of the maximum initial force (Emax.initial: 5.8387+/-0.72 mN, Emax.Galangin: 1.9157+/-0.30 mN, P<0.01). The maximal contractile responses to EFS at 2, 4, 8, 16, and 32 Hz were reduced, compared to control, by 91.61% (P<0.01), 79.46% (P<0.01), 70.54% (P<0.01), 61.10% (P<0.01), and 9.8% (P>0.05), respectively. The inhibitory effect of galangin was unaffected by a combination of propranolol, phentolamine, and capsazepine (P>0.05). However, when verapamil was added to the medium, the inhibitory effects of galangin were partially blocked. CONCLUSIONS: Galangin, at high concentrations, exerts an inhibitory effect on pig bladder smooth muscle contractility through the inhibition of calcium influx and the modulation of intracellular calcium movement. Furthermore, we have demonstrated that the inhibitory effect of galangin involves, at least in part, L-type calcium channels pathways.
Abstract: There is increasing evidence that the generation of free radicals plays a role in the development of bladder dysfunction. Flavonoids are a group of polyphenolic compounds with broad pharmacological activity. In the present study, the protective effects of the flavonoid galangin on the progressive decrease of bladder smooth muscle contractile responses during repetitive field stimulation (RFS; a model for muscular fatigue) were demonstrated. Pig detrusor strips were mounted for tension recording in organ baths aand were subjected to RFS for 90 min at 32 Hz for 15 s every 5 min. The strips were then washed four times with fresh buffer and allowed a period of recovery for 90 min. The 90 min of RFS caused a progressive decrease in maximal contractile response to electrical field stimulation and to muscarinic agonist-induced contractions (34% and 46% decrease, respectively). Galangin (10(-7) M) prevented the decrease in contractile smooth muscle response of strips to electrical field stimulation during RFS compared with untreated tissues. The antioxidant activity of galangin was assessed by measuring its ability to inhibit the lipid peroxidation induced by iron and ascorbate in rat liver microsomes (IC50 1.7+0.12x10(-6) M). If the data are confirmed in-vivo, exogenously administered galangin may be a new approach in the prevention and/or treatment of bladder dysfunction.
Abstract: The present study was designed to examine the effect of the flavonoid galangin on the muscarinic receptor mediating a carbachol-induced contraction and to investigate the effect of the flavonoid on Ca (2+) release from intracellular stores in the urinary bladder of the pig. Galangin (10(-7) -10(-4)M) produced a concentration-dependent inhibition of the contractile responses to electrical field stimulation (EFS) and carbachol (10(-5)M). Galangin (3 x 10(-5)M) reduced muscle contractions evoked by carbachol (10(-5)M) in calcium-containing solution as well as contractions evoked by carbachol and caffeine (2 x 10(-2)M) in Ca(2+)-free solutions significantly. The flavonoid had a stronger effect on the maximal force of the contractions induced by caffeine, compared to contractions induced by carbachol. These results suggest that galangin has an important effect on the intracellular calcium mobilization, which might be attributed predominantly to its influence on ryanodine-receptors.
Abstract: OBJECTIVES: To test the capability of the flavonoid galangin to protect pig urinary bladder from damage due to a period of repetitive field stimulation as well as a period of anoxia/glucopenia and reperfusion. METHODS: Smooth muscle strips of the pig bladder were mounted for tension recording in small organ baths and the strips underwent either 1.5 hours of repetitive field stimulation at 32 Hz for 15 seconds every 5 minutes or under anoxia/glucopenia and reperfusion conditions. Galangin, at different concentrations, was added to the reperfusion Krebs solution to check the effect of this flavonoid compared with untreated strips under the same conditions. A group of experiments was performed to examine its possible underlying mechanisms. RESULTS: Repetitive field stimulation for 1.5 hours caused a progressive decrease in the maximal contractile response to electrical field stimulation (34% decrease). Galangin (10(-7) M) partially prevented the progressive decrease in the contractile response. This effect was significantly reduced when verapamil was added to the solution. Galangin significantly improved the response of strips to electrical field stimulation under anoxia/glucopenia and reperfusion conditions compared with untreated tissues. CONCLUSIONS: Galangin has a protective effect on bladder contractility by an action that at least, in part, depends on l-type calcium channels. Furthermore, galangin protects detrusor nerves against the anoxia/glucopenic and reperfusion damage.
Abstract: The precise effect of low estrogen levels on urinary bladder contractility remains controversial. The present study was designed to analyze the effect of 17beta-estradiol in bladder smooth muscle contractility and the involvement of specific estrogen receptor stimulation in this effect. Castrated male and female pig detrusor strips were mounted for tension recording in an organ bath, superfused with Krebs solution at 37 degrees C and stimulated electrically and pharmacologically. In order to verify the acute effect of 17beta-estradiol on muscle contractility, the strips were incubated with different concentrations of the hormone. Muscle contractions were induced by potassium chloride, acetylcholine chloride and electrical field stimulation. The involvement of the estrogen receptor in the effects of 17beta-estradiol was assessed by incubation of some strips with the selective estrogen receptor antagonist ICI 182.780 before estradiol was applied. Estradiol at a dose of 30 micromol/l elicited a lower amplitude of contractions induced by EFS, Ach and KCl in female as well as in castrated male pig bladder smooth muscle strips. The effects of 17beta-estradiol were stronger in contractions induced by potassium chloride than those induced by other forms of stimulation. Pre-treatment with the pure estrogen receptor antagonist had no effect on 17beta-estradiol-induced inhibition of muscle contractility. These observations suggest that 17beta-estradiol induces lower amplitude of contraction of female as well as castrated male pig detrusor which is not mediated by the classic estrogen receptor. Furthermore, we can conclude that estradiol has a stronger inhibitory effect on the depolarization of muscle cell membrane compared to a muscarinic receptor-induced contraction.
Abstract: OBJECTIVES: Standard urodynamic investigations showed no correlation between the efficacy of sacral neuromodulation (SNS) and urodynamic data. Ambulant urodynamic investigations (ACM) are presented as more sensitive and reliable in detecting and quantifying bladder overactivity. In this study we looked at the correlation and results of ambulant urodynamic data and the clinical effects of SNS. METHODS: Data of patients with bladder overactivity, who underwent an ACM before and during SNS were investigated. Blind analyses of the ACM were performed and the detrusor activity index (DAI) was calculated as the degree of bladder overactivity of the detrusor. The ACM parameters, before and during SNS, were analyzed and correlated to the clinical effect of SNS. RESULTS: In 22 of the 34 patients a DAI before and during stimulation could be calculated because of quality aspects. In all other patients, the other ambulatory urodynamic parameters could be analyzed and a significant reduction was found in bladder overactivity. A significant correlation (p = 0.03) was found in DAI reduction of the ACM before and during SNS as compared to the clinical improvement in overactive bladder symptoms. CONCLUSIONS: The objective and subjective results show a decrease in bladder overactivity during SNS. During SNS bladder instabilities are still present, which is in accordance with the published literature. The reduction of the DAI during SNS as compared to before SNS correlates significantly to the clinical effect of SNS.
Abstract: The objective of this study was to investigate the predictive validity of the Dutch translation of the Golombok Rust Inventory of Sexual Satisfaction (GRISS) for the presence of clinically relevant sexual dysfunctions and patient's need of help. A total of 57 male urological outpatients (age 50.7+/-13.2 y; range 27-77 y) completed the GRISS, a 28-item self-report questionnaire assessing sexual dysfunctions and sexual satisfaction in heterosexual relationships. GRISS subscales were found to differentiate multivariately between men with and without sexual dysfunctions. The erectile dysfunction (In the original English version of the GRISS, the term 'impotence' was used instead of 'erectile dysfunction'), dissatisfaction, and infrequency subscales also differentiated univariately between these groups. The predictive validity for the presence of sexual dysfunctions and for the patients' need for professional help was investigated. Prediction models, derived by means of logistic regression analysis, were tested in a crossvalidation sample. Sensitivity and specificity for the presence of sexual dysfunctions, as well as the predictive values positive and negative were found to be satisfactory. The predictive validity of the GRISS was found equally satisfactory for the patients' need for professional help. The discriminant and predictive validity of the GRISS in men with and without sexual dysfunctions appeared satisfactory. Routine use of the GRISS appears warranted for the screening of sexual dysfunctions in new urological patients.
Abstract: OBJECTIVE: To examine whether erectile functioning after termination of sildenafil intake in men with psychogenic ED (erectile dysfunction) can be predicted with psychological measures. METHOD: The subjects in a nonrandomized controlled trial were 65 heterosexual men with acquired psychogenic ED, aged 54.2 +/- 11 years. Sildenafil medication was taken as required before sexual activity, up to two times per week. Response to a global end point question ("Did the treatment you took during the study improve your physical response during sexual activity in the last 4 weeks?") was recorded after 6 weeks of sildenafil use and, subsequently, 6 weeks without medication. Other measures of sexual functioning and cognitive predictor measures were also administered. RESULTS: Of the 65 participants who commenced sildenafil treatment, 37% withdrew from the study before follow-up assessment. At posttreatment, 89% of participants reported that treatment had improved or cured their erectile functioning. At follow-up, 66% of participants had maintained posttreatment gains. Response at follow-up could be predicted (p <.001) with 96% sensitivity and 50% specificity by entering changes in sexual self-confidence and the participant's rating of his partner's wish to continue treatment in a logistic regression model. Higher odds for recovery of erectile functioning were found in participants reporting increased sexual self-confidence and the estimation that their partner wanted them to continue sildenafil use. High pretreatment sexual desire was found to further increase the odds for positive responding at follow-up. CONCLUSIONS: The present results indicate that continued improvement of erectile functioning is possible after discontinuation of sildenafil use in men with psychogenic ED. Maintenance of gains can be predicted from cognitive changes before medication is withdrawn.
Abstract: OBJECTIVE: To assess the long-term efficacy and safety of two-stage sacral neuromodulation with an implantable pulse generator (IPG) in patients treated for urinary urge incontinence (UI) and/or urinary retention (UR). PATIENTS AND METHODS: The two-stage technique is used if patients have a good response during the acute phase of the percutaneous nerve evaluation (PNE) test, but have a poor response during the following 4-7 days (subchronic phase). In the first stage only the permanent electrode was implanted and connected to a temporary external stimulator, allowing patients to be assessed for longer. If the main symptoms improved by more than half the patient proceeded to the second stage, the insertion of the IPG. We reviewed all patients who underwent two-stage implantation; all had signed an informed consent and were asked to complete voiding diaries and a questionnaire to assess the subjective effects of the therapy. Safety was assessed from relevant medical events, management, and relative to the thera-py and resolution. Residual urine was assessed by self-catheterization. The long-term voiding diary results were compared with baseline estimates and analysed statistically using the two-sided Student's t-test. RESULTS: Between 1991 and 1998, 15 patients (13 women and two men, mean age 53 years, range 44-66) underwent the two-stage technique; the mean (median, range) follow-up was 4.9 (5.2, 2.5-7.5) years. Seven patients had UI and seven had UR, with one having both. The mean (range) number of PNEs undertaken in each patient was 2.1 (1-4) and these all failed in the subchronic phase. All patients underwent a first- and second-stage implant after a mean (range) screening period of 12.2 (2-29) days. One patient was explanted after implantation of only the first stage, and two others explanted in a later phase because the IPG was ineffective during the follow-up. The voiding diary results of the remaining 12 patients showed improvement in all the main variables, and in the subjective assessment 11 reported an improvement and were satisfied with the therapy. There were 17 adverse events, 14 of which were resolved and seven of which required surgical intervention. CONCLUSION: The long-term results of the two-stage implantation show clinically and statistically significant improvements, probably because the implantation of the lead (first stage) more closely resembles the final therapy. If a temporary PNE test is not optimal (lead migration, longer testing needed), the two-stage technique can offer a good and safe alternative of comparable efficacy in the long-term. If the two-stage technique had not been available to these 12 patients they would not have been offered neuromodulation.
Abstract: OBJECTIVE: In the standard operation procedure for sacral neuromodulation, the implantable pulse generator (IPG) is implanted in a subcutaneous pocket at the lower part of the anterior abdominal wall. This procedure requires a long operation time and three incisions. With the IPG in the abdominal wall, some patients complain of displacement or pain at the IPG site postoperatively. By modifying the technique of placement of the IPG, these disadvantages are overcome. METHODS: Between August 1999 and July 2000, 39 patients underwent a buttock implant of the IPG. In 2 of these patients the position of the IPG was changed from abdominal region to the buttock. During follow-up, complications concerning the operation and location of the IPG were compared to the published literature. RESULTS: Operation time is reduced in all patients by approximately 1 h. No repositioning of the patient is required during surgery. Only a short subcutaneous tunnel is required to connect the lead to the IPG. Pain at the level of the IPG was noted in 10% of the patients, which needed no further treatment. No infections were seen and the IPG did not displace postoperatively. CONCLUSION: Buttock placement of the IPG in sacral nerve stimulation leads to shorter operation time; only two incisions are needed instead of three and a shorter subcutaneous tunnel is needed. Using this technique there are less complications and a lower re-operation rate.
Abstract: It is unknown whether changes in bladder function due to urethral obstruction follow a specific sequence. To answer this, we adapted a small animal model to allow repeated complete pressure-flow studies, enabling individual follow-up of changes in bladder function on urethral obstruction. Obstruction was induced in guinea pigs by placing a silver ring around the urethra. Urodynamic studies were repeated under anesthesia with ketamine/xylazine. Bladders were filled and bladder pressure measured through a single suprapubic catheter. Urine flow rate was measured using an ultrasound probe around the penis. Accurate measurements of bladder pressure and urine flow rates were obtained at 1-week intervals for 11 weeks in individual guinea pigs. In the control animals, the urodynamic parameters did not show significant changes. In the obstructed group, urethral resistance (P(low,ave)) increased from 20 to 35 cm H(2)O after 4 weeks and remained at that level. The maximum flow rate (Q(max)) increased from 0.17 to 0.24 mL/s after 2 to 3 weeks. After this peak, it gradually decreased to lower than the starting value after 10 to 11 weeks. The pressure at maximum flow rate (p(Qmax)) increased from 24 to 47 cm H(2)O after 6 to 7 weeks and thereafter declined. During weeks 1 through 4 of obstruction, unstable contractions were seen. All animals followed a similar sequence of patterns but at variable rates. Our animal model allows complete urodynamic follow-up of individual animals with urethral obstruction. We observed a specific sequence of changes in urodynamic patterns and parameters of bladder function.
Abstract: Photolysis of caged calcium (Nitr5, Calbiochem) can be used to study calcium dependent processes such as excitation-contraction coupling and muscular mechanics. Expensive high energy light sources are routinely used for UV light exposure, but this study describes an alternative low cost xenon flash unit constructed in our laboratory. A 300 J short arc xenon flash lamp (Heimann) was mounted in an elliptical reflector and driven by a modified Metz 60 CT 4 photoflash unit up to 240 J input energy and 4 ms flash duration. A 20 microliters cuvette containing a test solution was placed in a complementary elliptical reflector. An ion selective calcium electrode was used to measure the free calcium concentration [Ca2+] before and after flash in test solutions containing 1.00 mM Nitr5 in combination with different added [Ca2+]s. Using this technique we estimated that 1 flash on 1.00 mM Nitr5 increased the free [Ca2+] from 10(-7) to 1.1 x 10(-5) M. When the added [Ca2+] was less than 2.3 x 10(-4) M, the used Nitr5 behaved as a strong calcium chelator because 23% of it was unloaded with calcium. It is concluded that a physiologically relevant change in free [Ca2+] can be evoked by photolysis of Nitr5 using a low cost (approximately $1500) xenon flash unit, and that ion selective Ca electrodes can be adequately used to monitor the resulting changes in [Ca2+].
Abstract: The guinea pig has become an excellent model for the study of mechanical and electrical mechanisms regulating bladder function in the normal and obstructed state. Much preliminary work has been done on the in vitro behavior of the detrusor smooth muscle. The tissue has permitted electrophysiological studies by sucrose gap, microelectrode, and patch clamp technique. Excellent urodynamic studies can be performed under anesthesia. A recent model of bladder obstruction has resulted in a source of tissue which is suitable for electrophysiological analysis of the muscle. Low-cost and simple animal care requirements permit large-scale studies correlating urodynamic, structural, biochemical, contractile, and electrophysiological changes in response to obstruction.
Abstract: The parameters P(isv) (active isovolumetric detrusor pressure) and Vmax (maximum shortening velocity), which characterize the contractility of the detrusor muscle, were determined in guinea pigs. To this end it was necessary to develop a method of measuring flow rates in these small animals. The values found were used to calculate the contractility parameter Wmax. Thirteen animals were used. The results found for P(isv) and Vmax were 43.0 +/- 3.7 cm. H2O and 20.2 +/- 3.7 mm. per second, respectively. The latter corresponded to about 0.38 muscle lengths per second, which is similar to values reported for bladder strips from other species. Previous work showed that in vitro P(isv) decreased with increasing bladder volume over a wide range of volumes. In vivo P(isv) seemed to be independent of bladder volume. This suggests that neurogenic stimulation intensifies as volume increases. Vmax also was independent of volume. Wmax appeared to be suitable for detecting differences in the contractility of the bladders of different animals. Values were not significantly different in isovolumetric and nonisovolumetric contractions. Normalized to the size of the bladder, the Wmax values indicated that the power generated by the guinea pig bladder is similar to the power generated by the human bladder.
Abstract: We created gradual partial urethral obstruction in 20 guinea pigs using silver jeweler's jump rings. After 4 or 8 weeks obstruction all animals underwent cystometry and were assigned to one of five urodynamic categories: normal, high pressure voiding, unstable, low compliance, or decompensated. After sacrifice, the contractile responses of bladder strips to electrical field stimulation of intramural nerves, direct electrical muscle stimulation, 0.1 mM carbachol, and high K+ solution were sampled by computer for phase plot analysis. Following 8 weeks obstruction, the value of the phase plot parameter Fiso, indicative of the number of contractile muscle units, was reduced to 60% of the control response to nerve stimulation (P < 0.05) and to 77% of the control response to carbachol stimulation (P < 0.05). Parameter C, the slope of the phase plot (indicative of unit recruitment during force development), was unchanged for all forms of stimulation. Although in the latter case not statistically significant, obstruction affected responses to nerve and muscle stimulation similarly suggesting that muscle change may possibly be a common denominator of dysfunction. In view of the reduction in Fiso and the increase in bladder weight, instability may represent a more advanced form of dysfunction due to obstruction than high pressure voiding.
Abstract: To study the relative importance of neurogenic factors in detrusor contractility, active bladder wall stress values were compared in situ and in vitro. Eight male guinea pigs were used. The active stress in the bladder wall in spontaneous micturition contractions was calculated from the results of urodynamic examinations and compared with the active stress developed in response to optimum electrical stimulation in full-thickness bladder wall strips taken from the same bladders. The results indicated that, in normal micturition, the detrusor muscle is not fully stimulated, and the rate of pressure development is not determined by mechanical factors. To identify topological variations of detrusor contractility, the strips were taken from three different locations. It was found that strips from the posterior wall contracted more forcefully than those from the anterior wall.
Abstract: We developed a new model of partial urethral obstruction using the guinea pig. We placed jeweler's jump rings loosely around the proximal urethra of immature guinea pigs and allowed the obstruction to develop gradually as the animal grew. After four or eight weeks of obstruction, we studied the filling and emptying characteristics of the bladder during continuous repetitive cycling under urethane anesthesia. Following this examination, bladders were removed and weighed. Wet weight was compared to urodynamic findings. We identified four abnormal urodynamic patterns: high pressure voiding, instability, poor compliance and decompensation. All obstructed bladders showed weight gain associated with muscle hypertrophy, but the degree of weight gain was different for each of the various urodynamic categories. High pressure voiding was associated with the least weight gain, whereas instability and decompensation showed the most weight gain. The results are consistent with a thesis that partial urethral outlet obstruction in the guinea pig gives rise to several distinct forms of abnormal voiding characterized by high pressure in the early stages, and progressing to more advanced forms of dysfunction characterized by instability and decompensation in the later stages.
Abstract: Excitatory pathways in the smooth muscle of the pig urinary bladder were investigated using phase-plot analysis of isometric contractions. The phase plots, plots of the rate of change of the force as a function of the force itself, were dominated by a straight line described by the horizontal intercept (Fiso) and the vertical intercept (U). The quotient Fiso/U is a time constant that characterizes the rate-limiting step in isometric force development in the muscle. Bladder strips of 1 mm diameter were activated by electrical field stimuli, acetylcholine, potassium, and ATP in combination with selective pathway inhibitors such as verapamil, atropine, or a calcium-free solution containing ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. When pathways that depended significantly on depolarization or intracellular calcium release were selected, the time constant was significantly smaller, indicating a faster process. The results indicated that the rate-limiting step in force development was determined by the influx of extracellular calcium.
