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Lack of promotion of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in mice by rat cancer promoters.

The effects of dietary exposure to sodium L-ascorbate (Na-AsA), butylated hydroxyanisole (BHA), and diphenyl on the development of urinary bladder tumors in a mouse two-stage carcinogenesis model were examined. Male B6C3F1 mice received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 4 weeks and were then treated with 5% Na-AsA, 1% BHA, or 1% diphenyl for 32 weeks. None of these chemicals enhanced the development of either preneoplastic or neoplastic lesions in the urinary bladder. Furthermore, DNA synthesis levels of urinary bladder epithelium in mice treated with each substance alone for 8 weeks were not elevated significantly, although Na-AsA was associated with a significant increase in the urinary pH value and Na+ concentration. The results indicate that Na-AsA, BHA, and diphenyl do not exert an enhancing influence on mouse bladder carcinogenesis, in clear contrast to the case in the rat.

Animals↗

Effect of several bicyclic peptide and cyclic pseudopeptide tachykinin NK2 receptor antagonists in the human isolated urinary bladder.

1. We have studied several tachykinin NK2 receptor antagonists, bearing a monocyclic pseudopeptide (MEN 10,508, MEN 10,573, MEN 10,581, MEN 10,612, MEN 10,619 and MEN 10,677), or bicyclic peptide (MEN 10,627, MEN 10,692, MEN 10,771, MEN 10,882 and MEN 10,993) structure, on the human isolated urinary bladder detrusor muscle against neurokinin A as an agonist, and compared their affinities in this preparation with those for NK2 receptors expressed in the rabbit isolated pulmonary artery and hamster isolated trachea. 2. In the human bladder, all the antagonists tested produced a concentration-dependent and competitive antagonism of neurokinin A-mediated contractions: among the cyclic pseudopeptides MEN 10,677 (pKB = 8.0) was the most potent antagonist, while among the bicyclic analogues it was MEN 10,993 (pKB = 8.8). 3. In general, the bicyclic peptide antagonists tested were more potent than the monocyclic pseudopeptide compounds, either in the human urinary bladder or in the rabbit pulmonary artery or hamster trachea, showing a nanomolar affinity for the human NK2 receptor. 4. A highly significant correlation was found between the estimated pKB values of all the antagonists tested in the human urinary bladder and rabbit pulmonary artery (r2 = 0.94, n = 12, P < 0.01), whereas no linear correlation was found between pKB values measured in the human urinary bladder and hamster trachea (r2 = 0.52, n = 12, P > 0.05): these observations provide further pharmacological evidence for receptor homology between the human and rabbit NK2 receptor. 5. The present results point out the class of NK2 receptor antagonists bearing a bicyclic peptide structure, like MEN 10,627, as candidates for testing in pathological conditions, such as bladder hyperactivity, for which preclinical evidence indicates that a therapeutic effect could result from the block of the tachykinin NK2 receptor.

Aged↗

Restoration of micturition using microelectric current in experimentally induced spastic urinary bladder in rabbits.

The 29 rabbits used in this study were divided into three groups, A (A1 and A2), B, and C. In subgroup A1, 4 animals were used in order to verify whether the contact of an electrode to the sacral nerves results in some abnormality of voiding reflex. In subgroups A1 and A2 (4 animals each) we further studied the micturition function using three parameters: (i) urinary bladder fluoroscopy and radiography, (ii) cystomanometry, and (iii) electromyography of the pelvic floor muscles (external sphinter). In group B (9 rabbits) spastic paraplegia and micturition disturbances resulted from spinal cord compression that was induced by inserting a balloon catheter into the T11-T12 intervertebral foramen. In this group the parameters studied revealed a spastic urinary bladder in all animals. Finally, the 12 animals of group C were rendered paraplegic as described in group B, and microelectrodes were placed over the sacral nerves as in subgroup A1. By applying a specific sequence of sacral nerve stimulation we succeeded in satisfactory urinary bladder emptying as confirmed by the micturition parameters studied: The urinary bladder pressure decreased from 65 +/- 3 to 28 +/- 3 mm Hg. The pelvic floor muscle amplitude was lowered from 130 +/- 7 to 20 +/- 3 microV, and finally the radiological bladder size also decreased from 38 cm2 before voiding to 18 +/- 3 cm2 after voiding. These results indicate that microelectric current stimulation of the sacral nerves, when applied under a specific sequence, could rather satisfactorily restore micturition disturbances, at least in this experimental animal.

Animals↗

Pharmacological characterization of muscarinic receptors in rabbit isolated iris sphincter muscle and urinary bladder smooth muscle.

1. The pharmacological characteristics of muscarinic receptors in the rabbit iris sphincter muscle were studied and compared to M3 receptors in rabbit urinary bladder smooth muscle. 2. (+/-)-Cis-dioxolane induced concentration-dependent contractions of the iris sphincter muscle (pEC50 = 6.41+/-0.10, Emax = 181+/-17 mg, n = 38) and urinary bladder smooth muscle (pEC50 = 6.97+/-0.04, Emax = 4.28+/-0.25 g, n = 54). These contractions were competitively antagonized by a range of muscarinic receptor antagonists (pK(B) values are given for the iris sphincter muscle and the bladder smooth muscle, respectively): atropine (9.30+/-0.07 and 9.40+/-0.04), AQ-RA 741 (6.35+/-0.04 and 6.88+/-0.03), darifenacin (9.56+/-0.05 and 9.12+/-0.05), methoctramine (5.75+/-0.07 and 5.81+/-0.06), oxybutynin (8.10+/-0.09 and 8.59+/-0.06), pirenzepine (6.79+/-0.05 and 6.89+/-0.04), secoverine (7.54+/-0.05 and 7.66+/-0.05), p-F-HHSiD (7.55+/-0.09 and 7.50+/-0.05) and zamifenacin (8.69+/-0.10 and 8.36+/-0.06). A significant correlation between the pK(B) values in the bladder and the pK(B) values in the iris was obtained. 3. In both tissues, the pK(B) values correlated most favorably with pKi values for these compounds at human recombinant muscarinic m3 receptors. A reasonable correlation was also noted at human recombinant muscarinic m5 receptors given the poor discriminative ability of ligands between m3 and m5 receptors. 4. Overall, the data from this study suggest that the muscarinic receptors mediating contraction of the rabbit iris sphincter muscle and urinary bladder smooth muscle are similar and equate most closely with the pharmacologically-defined muscarinic M3 receptor.

Animals↗

Multistage carcinogenesis in the urinary bladder.

The induction of cancer of the urinary bladder is a multi-stage process involving multiple exogenous and endogenous factors. Based on the classical initiation-promotion model, we have used N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as initiator and sodium saccharin (SAC) or tryptophan as promoters. These latter chemicals have the properties expected of promoters: induction of hyperplasia, reversibility and nonmutagenicity. Also, tumors were induced whether the promoter was administered immediately after FANFT or beginning 6 weeks after FANFT was discontinued, but no tumors resulted if either promoter was given without initiation with FANFT. Factor(s) present in normal urine also are involved in the promotion process, in addition to the role of urine as a carrier of carcinogens. However, administration of SAC to animals with a rapidly proliferating bladder mucosa, induced by ulceration, pellet insertion, or in utero, resulted in bladder tumor induction, even without prior initiation with FANFT. To better understand the complex interaction of the multiple variables in bladder carcinogenesis, a stochastic computer model has been formulated based on long-term carcinogenicity and tissue kinetic studies in vivo. This model indicates the importance of cell proliferation and the development of hyperplasia in carcinogenesis.

Animals↗

Squamous carcinoma of urinary bladder.

The clinical course of 56 patients with squamous cell carcinoma of the urinary bladder and poorly differentiated transitional cell carcinoma with squamous metaplasia were compared. Survival was evaluated to compare treatments and biologic potentials of these neoplasms. Squamous cell carcinoma of the urinary bladder behaves as poorly differentiated transitional cell carcinoma with squamous metaplasia, and survival is significantly poorer than in poorly differentiated transitional cell carcinoma. While survivals are limited, only radical, surgical extirpation can be associated with significant patient salvage.

Aged↗

Number of fibres and fibre diameter distributions of nerves innervating the urinary bladder in humans. Acceptor nerve analysis. II.(IV).

1. The nerves innervating the urinary bladder were analysed morphometrically for their nerve fibre number and their nerve fibre group composition. 2. The nervi pelvini contained about 4000 myelinated nerve fibres, the nervi rectales inferiores and perineales 1700 and the nervus hypogastricus 2000 fibres. 3. An upper limit for somatic sphincteric alpha 2-motoneurons was 30 in the nervi rectales inferiores and perineales. The nervi pelvini contained about 400 fibres with diameters between 7 and 15 microns and myelin sheath thicknesses between 1.8 and 2.3 microns. Some of these thick nerve fibres could innervate the external urethral sphincter. It is estimated that the number of efferent parasympathetic fibres in the nervi pelvini on one side was about 800, which makes about 20% of all the myelinated fibres of the nervi pelvini. 4. It is discussed that efferent fibres to the external bladder sphincter may lead through the nervi pelvini or a direct branch instead of leading through the pudendal nerve. 5. In the Clinical Implications it is summarized that one intercostal nerve (9000 afferents, 1000 efferents) with its dissectable skin (3000 aff), muscle (300 aff, 300 eff) and mixed branches (2500 aff, 1500 eff) contains enough myelinated fibres for a reinnervation of the detrusor (3200 aff, 800 eff), the external anal and bladder sphincters (30 aff, 30 eff), the mucosa of the urethra, trigonum vesicae and anal canal (200 aff) and the lower sacral skin (6000 aff) on one side if one intends to restorate urinary bladder function in paraplegia by a nerve anastomosis. Reasons for a loss of plasticity of the injured spinal cord are given.

Adult↗

Effects of hormonal and electrical stimulation of sodium transport on metabolism of toad urinary bladder.

The carbon dioxide produced by toad urinary bladders bathed on their mucosal surfaces by sodium Ringer solution and on their serosal surfaces by modified Leibovitz tissue culture medium was analysed by multiple regression on both sodium transport and time. The fractions contributed by metabolism related to transport and by basal metabolism were assessed, and the extent to which these might vary with time was determined. This analytical method, which improves the accuracy with which suprabasal metabolism is estimated, was used to examine the effects on metabolism of vasopressin, aldosterone, and mucosa-positive voltage-clamping. Vasopressin (0.05 u./ml), which on average increased sodium transport 2.9 times and concurrently increased the rate of carbon dioxide production in these transporting tissues, also altered the carbon dioxide production of non-transporting, amiloride-treated control hemibladders. For each hemibladder the ratio of sodium transported to suprabasal carbon dioxide produced after vasopressin was compared with that observed before vasopressin. Differences between the ratios were much reduced when the carbon dioxide productions of the paired transporting hemibladders were corrected for the effects of vasopressin on basal carbon dioxide production. With such analysis, it was confirmed that vasopressin did not alter the stoichiometry of sodium transport. A 30 mV, mucosa-positive voltage clamp, applied near the peak of the response to vasopressin, further increased both sodium transport and carbon dioxide production. No alterations of the ratio of sodium to suprabasal carbon dioxide were seen under these conditions where the maximal rate of active sodium transport in this tissue must have been approached. Active sodium transport was more than doubled some 4 h after adding aldosterone (10(-7) M). However, the related increase in suprabasal carbon dioxide production was greater than threefold. Therefore, whereas the stimulation resulting from vasopressin and voltage clamping had no effect on the ratio of sodium transported to suprabasal carbon dioxide produced, this ratio was reduced significantly by aldosterone. When the sodium transport of aldosterone-treated bladders was increased further by voltage clamping, the ratio of sodium transported to suprabasal carbon dioxide production remained at the reduced value. Sodium transport was increased by approximately 35% more when aldosterone-treated hemibladders were voltage clamped after vasopressin, the control paired hemibladders being exposed to vasopressin and voltage clamping alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldosterone↗

Hepatoid adenocarcinoma of the urinary bladder.

Hepatoid adenocarcinoma is rare in the urinary bladder with only three well-illustrated previously reported cases. Pathological diagnosis is based on a combination of histological features resembling hepatocellular carcinoma and the positive immunostaining for alpha-fetoprotein. We present the clinicopathological features of four additional cases. The patients were males 66, 85, 61 and 68 years old. Hematuria was the initial symptom in all four patients. Two cases were treated by cystoprostatectomy and the remaining two by transurethral resection of the bladder. On histology, the cases showed a mixture of cells growing in a solid fashion and sheets or anastomosing trabeculae of hepatoid cells merging focally with a secondary glandular pattern of adenocarcinoma. Intracytoplasmic hyaline globules in all and bile production in three of the cases also supported the impression of hepatocytic differentiation. Immunoreactivity for alpha-fetoprotein, low molecular weight cytokeratin, alpha-1-antitrypsin, albumin, epithelial membrane antigen and a striking canalicular pattern when stained against polyclonal carcinoembryonic antigen (CEA), all indicate hepatocellular differentiation. The hepatic nature of the cells was further assessed by detecting the recently incorporated marker hepatocyte paraffin 1, by means of immunohistochemistry and albumin gene mRNA non-isotopic in situ hybridization, both of which had positive signals in all four cases. Three patients died 12, 14 and 19 months after diagnosis. The fourth patient was alive with disease at 26 months of follow-up. In conclusion, hepatoid adenocarcinoma seems to be an aggressive malignant neoplasm that is rare in the bladder whose correct diagnosis may need appropriate immunohistochemical and in situ hybridization means in addition to a complete patient clinical and pathological evaluation. The exact histogenesis and classification of these tumors remains to be established.

Adenocarcinoma↗

Basic science research on the urinary bladder and interstitial cystitis: new genetic approaches.

This article summarizes recent genetic research that promises to advance understanding of the functioning of the urinary bladder and further our knowledge about interstitial cystitis. Results reported at the Tenth International Research Symposium on Interstitial Cystitis and Bladder Research and in the current literature are presented. Three specific areas of genetic research are summarized: gene expression via DNA arrays, development of new animal models through transgenic or gene knockout approaches, and gene therapy. Advances in genetic research (specifically in gene therapy; development of new, genetically engineered mouse models; and study of gene expression using DNA array assays) will contribute to further understanding the functioning of the urinary bladder in health and disease.

Animals↗

Hemangiopericytoma arising from the wall of the urinary bladder.

Hemangiopericytoma (HPC) arising from within the urinary bladder is exceptionally rare. A 45-year-old man having the symptoms of left groin pain, vague suprapubic discomfort and frequency was admitted to our clinic. Pelvic tomography revealed a tumor in the bladder wall measuring 4 x 3 cm and was not clearly distinct from the lower abdominal wall. Partial cystectomy was performed and the histopathological examination confirmed the hemangiopericytoma. Three thousand rad exterior beam irradiation was performed after operation. Partial cystectomy and adjuvant radiotherapy may be a simple and effective alternative operation for the patient with HPC.

Cystectomy↗

Aldosterone-Induced Membrane Phospholipid Fatty Acid Metabolism in the Toad Urinary Bladder.

Aldosterone action in the isolated toad urinary bladder has been studied by incubation of the tissue with several specifically labeled lipogenic precursors. Within 30 min after hormone addition phospholipid synthesis is stimulated; the metabolism of oleic acid is particularly enhanced. Additionally, during this time interval a phospholipid deacylation-reacylation cycle is stimulated by aldosterone.

Acetates↗

Hyperthermic irrigation of urinary bladder tumor in rabbits.

Hyperthermic treatment for bladder tumor in the rabbit was investigated by the irrigation with hot saline through cystostomy after the transplantation of V2 carcinoma cells. When the bladder was irrigated with 42-44 degrees C saline, the inhibitory effect on transplanted tumor growth in the urinary bladder was significant in comparison with control groups. Antitumor effect on the survival and changes in body weight were also significant. Histological study showed the tumor cells were more susceptible to heat than normal mucosal layer. The results suggest that the hyperthermic irrigation of the urinary bladder was effective in preventing the tumor growth with minimum damage on the normal bladder mucosa. Moreover, this malignant bladder tumor of rabbit seems especially suitable for the purpose of studying the new method for transurethral hyperthermic treatment of the urinary bladder cancer.

Animals↗

Metabolic abnormalities associated with rupture of the urinary bladder in neonatal foals.

Rupture of the urinary bladder was diagnosed in 4 neonatal male foals. Marked hyponatremia, hypochloremia, and hyperkalemia developed in all 4 cases, and the electrolyte abnormalities were considered to be of potential diagnostic value. Blood urea nitrogen concentration was normal or only slightly higher than normal in 3 of 4 cases and therefore was not a reliable diagnostic test.

Animals↗

Inflammatory pseudotumor of the urinary bladder with an aberrant expression of cytokeratin.

A case of inflammatory pseudotumor of the urinary bladder in a 47 year old Japanese male patient is presented. Inflammatory pseudotumor of the urinary bladder is a benign but rare proliferative lesion of the submucosal stroma, easily mistaken for a malignant neoplasm. Based on the clinical diagnosis of bladder cancer by cystoscopy and magnetic resonance imaging (MRI), urologists started chemotherapy before results of the histological report were available which described inflammatory pseudotumor on the biopsy. Biopsied materials showed marked proliferation of irregularly bundled spindle cells, varied in size and shape and separated in severe loose myxoid stroma with moderate infiltration of the inflammatory cells and capillary proliferations. At a glance, these findings resemble the sarcomatous pattern. However neither severe nuclear atypism nor atypical mitoses were present. Immunohistochemically, these spindle cells, which were positive for vimentin and alpha-smooth muscle actin, showed a diffuse aberrant expression of cytokeratin. Some of them were positive for phosphotungstic acid hematoxylin. Electron microscopy revealed only the fibroblasts. No recurrence has been observed for 10 months. These findings indicate that inflammatory pseudotumor is a benign mesenchymal lesion that must be discriminated from true sarcoma to avoid subjecting the patient to unnecessary therapy. Only careful histological examination can enable a successful diagnosis.

Granuloma, Plasma Cell↗

Effects of polymyxin B on mammalian urinary bladder.

Previous reports have demonstrated that large cationic polypeptides (of molecular mass 5,000 daltons or greater) cause an increase in the apical membrane conductance of the rabbit urinary bladder epithelium. This report investigates the effects of the small cationic molecule polymyxin B (PX: a 1,400 dalton antibiotic) on the permeability of the rabbit urinary bladder. The addition of micromolar concentrations of polymyxin B to the luminal solution of the rabbit urinary bladder resulted in an increase in the transepithelial conductance of the bladder. The magnitude of the increase in the conductance was dependent upon the concentration of PX, and the polarity and magnitude of the apical membrane potential. As the apical membrane potential was made more cell interior negative, the larger was the increase in the membrane conductance. This voltage-dependent increase in conductance was an exponential function of the applied voltage, with a negligible increase in conductance occurring when the membrane potential was cell interior positive. Upon changing the membrane voltage from cell interior positive to negative, there was a delay before there was a measurable change in the membrane conductance. The longer the apical membrane was exposed to PX, the more poorly reversible was its effect on the transepithelial conductance, suggesting a toxic effect of PX on this epithelium.

Animals↗

Biochemical and functional evidence for nerve sprouting in the decentralized, hypertrophied rat urinary bladder.

The preganglionic nerves of the rat urinary bladder were cut. The decentralized bladders gained markedly in weight. Both one and four weeks post-operatively, transmural nerve stimulation evoked contractile responses of the muscle strips of the decentralized bladders, that were of the same magnitude as those of the control bladders. However, four weeks post-operatively, the atropine resistant fraction of the response was decreased; consequently, the atropine sensitive (cholinergic) fraction was increased. The activity of the acetylcholine synthesizing enzyme, choline acetyltransferase, was increased at the late time of observation. The present biochemical and functional findings may suggest outgrowth of branches from the decentralized post-ganglionic cholinergic nerves.

Animals↗

Hypertonic media produce Ca(2+)-dependent release of calcitonin gene-related peptide from capsaicin-sensitive nerve fibres in the rat urinary bladder.

Superfusion of slices of the rat urinary bladder with hypertonic NaCl produced a remarkable and concentration-dependent (150-280 mM) increase in the outflow of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI). This effect was completely abolished by pre-exposure of the tissue to capsaicin (10 microM for 20 min) or by superfusion with a Ca(2+)-free medium. Capsaicin (10 microM) was still able to release a consistent amount of CGRP-LI from tissue pre-exposed (20 min) to 280 mM NaCl. Similarly, hypertonic sucrose (160 mM added to the physiological salt solution) induced a consistent release of CGRP-LI that was abolished by capsaicin-pretreatment or in a Ca(2+)-free medium. The experiments demonstrate that hypertonic solutions activate the efferent function of capsaicin-sensitive neurons and suggest that this event may have some relevance in pathophysiological conditions of the lower urinary tract in which hypertonic urine may diffuse to submucosal layers.

Animals↗