The concept of bladder work: work and power in bladder emptying.
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Animals↗
Biomedical subjects
P A Longhurst
Publications and source records attributed to P A Longhurst.
Etiology of bladder dysfunction secondary to partial outlet obstruction. Calcium disregulation in bladder power generation and the ability to perform work.
Similar to all smooth muscle, contraction of urinary bladder smooth muscle depends upon a rise in intracellular free calcium, which results from both calcium influx from extracellular spaces and calcium release from intracellular stores (calcium-induced calcium release [CICR]). Recent studies from our laboratory demonstrate that one of the major dysfunctions induced by partial outlet obstruction is a marked reduction in the participation of CICR (from IP3-sensitive and IP3-insensitive sites on the sarcoplasmic reticulum [SR]) during stimulation by both field stimulation (neurotransmitter release) and by direct muscarinic stimulation (bethanechol). Experimentally, rabbit urinary bladder function can be evaluated using an isolated whole bladder model. The current study utilizes the isolated whole bladder model to compare the effects of partial outlet obstruction on the responses to field stimulation and bethanechol with the responses of normal bladders following inhibition of CICR with the combination of thapsigargin+ryanodine. The parameters measured include the magnitude of pressure generation, rate of pressure generation, time to maximal pressure generation, percent volume emptied, rate of emptying, power generation, and work performed (both total work and work per ml emptied). Partial outlet obstruction resulted in virtually identical alterations in the responses of the bladder to stimulation (field stimulation and bethanechol) to that of inhibition of CICR by thapsigargin+ryanodine. Thus, these studies provide strong support for our hypothesis that the contractile dysfunctions secondary to partial outlet obstruction are directly related to a marked inhibition of the CICR component of the response to both field stimulation and bethanechol.
Animals↗
The human P2x1 receptor: molecular cloning, tissue distribution, and localization to chromosome 17.
A human urinary bladder cDNA library was screened with a rat P2x purinoceptor probe. A full-length cDNA was isolated, and like its rat homologue, the deduced protein consists of 399 amino acids (M(r) = 44980 Da), contains two hydrophobic, putative transmembrane, domains flanking a large presumed extracellular loop, and represents the P2x1 subtype of this multigene family (approximately 89% amino acid sequence identity to rat P2x1, but only 40-50% identity to rat P2x2-4). Expression of the P2x1 gene in human bladder was confirmed by Northern analysis, which demonstrated a major transcript of approximately 2.9 kb. Transcripts were also found in a variety of other tissues including adult peripheral leukocytes, pancreas, spleen, prostate, small intestine, colon, testis, and ovary, and in fetal liver. The gene encoding the human P2x1 receptor was localized to chromosome 17 by Southern analysis of DNAs isolated from a panel of somatic cell hybrids. The results support a role for P2x purinoceptors in the regulation of human bladder function.
Adult↗
Effects of glucose deprivation on the contractile response of the rabbit bladder to repetitive stimulation.
The urinary bladder requires an adequate energy supply to maintain contractile function. The primary metabolic fuel is glucose. Through glycolysis and oxidative phosphorylation, high energy phosphates are generated, which in turn supply the metabolic energy for the contractile activities of the urinary bladder. The aim of this study was to determine the effects of glucose deprivation and recovery from glucose deprivation on the phasic and tonic components of the contractile responses of rabbit bladder strips to field stimulation, bethanechol, and KCl. The results can be summarized as follow: In response to glucose deprivation, (1) the tonic responses to field stimulation, bethanechol, and KCl all decreased at a significantly greater rate than the phasic responses; (2) the phasic and tonic responses to field stimulation were both reduced to less than 10% of control within 70 minutes of initiating glucose deprivation; (3) the tonic responses to bethanechol and KCI were reduced to approximately 10% of control within 180 minutes whereas the phasic responses remained stable at 40 and 30%, respectively; and (4) glucose replacement stimulated a rapid and nearly complete recovery of the phasic and tonic components of the responses to field stimulation, bethanechol, and KCI. These results indicate that the tonic responses to all forms of stimulation are more sensitive to glucose deprivation than the phasic responses.
Animals↗
Effects of partial outlet obstruction on bladder-strip sensitivity to glucose deprivation: an in vitro study in the rat.
Partial outlet obstruction has been shown to result in contractile and metabolic dysfunctions. Specifically, there is a greater reduction in the response to field stimulation (FS) in comparison with the responses to bethanechol and KCl, a greater reduction in the tonic response to stimulation in comparison with the phasic response, and a reduction in oxidative metabolism of glucose accompanied by an increase in the glycolytic metabolism of glucose. The specific aim of the current study was to correlate the effects of partial outlet obstruction on the contractile responses of isolated strips of bladder smooth muscle to repetitive stimulation in the presence and absence of glucose. Adult male Sprague-Dawley rats were subjected to partial outlet obstruction by the surgical placement of silk ligatures around the urethra. After 2 weeks, each rate was anesthetized, the bladder was excised, and isolated strip studies were performed. These studies demonstrated that the maximal phasic response to FS was significantly decreased in the obstructed strips as compared with controls, with no difference being noted for responses to bethanechol or KCl; the tonic responses to all forms of stimulation were significantly decreased after obstruction, with the tonic response to FS being decreased to a greater degree than were the tonic responses to bethanechol and KCl; and in the absence of glucose, the tonic responses of control strips to all forms of stimulation were reduced to a greater degree than were the phasic responses. These studies demonstrate that the tonic response to FS is extremely sensitive to fatigue induced by repetitive stimulation.
Analysis of Variance↗
Effects of diuresis on micturition.
Micturition can be characterized experimentally by monitoring both the frequency and volume of micturition. Previous studies demonstrated that the functional capacity of the rat and rabbit bladder, as determined by cystometry, is approximately equal to the maximal single micturition volume as recorded over a 24 hour period. Studies in many laboratories have demonstrated that chronic increases in diuresis induce increases in micturition frequency and capacity, and an increase in bladder mass. The current study compares the temporal relationship among these parameters in three models of diuresis: streptozotocin-induced diabetes in rats, sucrose-induced diuresis in rats, and furosemide-induced diuresis in rabbits. In both sucrose diuresis in rats and furosemide diuresis in rabbits there were immediate increases in both the frequency and volume of micturition. The magnitude of the increases in micturition frequency and micturition volume paralleled the increase in the total volume of urine excreted. Bladder mass increased progressively over the time course of the study. Streptozotocin-induced diabetes resulted in a more gradual (but parallel) increase in micturition frequency and volume, and again a more gradual increase in bladder mass. These studies demonstrate that functional bladder capacity is increased immediately upon the initiation of diuresis with sucrose or furosemide, as is the frequency of micturition. This indicates that functional bladder capacity is probably under neuronal regulation and the change in capacity is not a function of the increased bladder mass which occurs at a later time period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Contractile proteins and their response to bladder outlet obstruction.
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Actins↗
Influence of strip size and location on contractile responses of rat urinary bladder body strips.
1. We investigated the influence of strip length and dorsal or ventral location of rat urinary bladder strips on contractile responsiveness. 2. No differences occurred in the contractile responses of 0.5, 1.0 and 2.0 cm strips to field stimulation, carbachol, ATP, substance P or to KCl when the data were expressed as either absolute tension or as tension per cross-sectional area. However, correction for strip mass resulted in significant decreases in the contractile responses of the 2.0-cm strips compared with the 0.5-cm strips. 3. No differences occurred in length-tension curves for ventral and dorsal bladder strips, even though the strips from the dorsal surface appeared thinner than those from the ventral surface. 4. Strips from the ventral surface exhibited more variability in response to field stimulation and were less sensitive to atropine pre-treatment than were those from the dorsal surface. They were also less sensitive to the contractile effects of carbachol than dorsal strips. Dorsal and ventral strips were equally responsive to ATP, substance P and KCl. 5. Our data indicate that the contractile responsiveness of rat urinary bladder strips is independent of strip length. Although there are some differences between the cholinergic responsiveness of strips from the ventral and dorsal surfaces of the bladder, the differences are so small that for most studies they will probably have no influence on data interpretation.
Adenosine Triphosphate↗
Characterization of the functional muscarinic receptors in the rat urinary bladder.
1. Muscarinic receptors mediating contraction of the rat urinary bladder were characterized functionally in vitro by use of atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP methiodide), 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (4-DAMP mustard), hexahydro-sila-diphenidol hydrochloride (HHSiD), the p-fluoro analogue of hexahydro-sila-diphenidol hydrochloride (p-F-HHSiD), methoctramine, and pirenzepine. 2. (+)-cis-Dioxolane contracted bladder strips in a concentration-dependent manner with an EC50 of 0.169 +/- 0.018 microM and an Emax of 7.84 +/- 0.67 g. 3. Concentration-effect curves to (+)-cis-dioxolane were shifted to the right in the presence of the antagonists in a concentration-dependent manner. The rank order of antagonist affinities against the (+)-cis-dioxolane response was (pA2 values in the parentheses) atropine (9.28) > or = 4-DAMP methiodide (9.04) > HHSiD (8.01) > p-F-HHSiD (7.28) = pirenzepine (7.12) > or = methoctramine (6.77, 7.25). The profile resembles that associated with the M3 receptor subtype. 4. Atropine, 4-DAMP methiodide, pirenzepine, and methoctramine had no effects on the contractile response to 120 mM KCl. However, HHSiD and p-F-HHSiD decreased the response to KCl, and 4-DAMP mustard increased it. 5. Contractile responses to electrical field stimulation (1-32 Hz, 0.05 ms pulse duration) were biphasic in nature. The tonic response was suppressed more than the phasic response by all antagonists except methoctramine. The suppression was not always concentration-dependent, and did not seem to be related to antagonism of any one receptor subtype. 6. Our findings are consistent with the minority M3 receptors mediating the contractile response to muscarinic stimulation by (+)-cis-dioxolane in the rat bladder.
Animals↗
The role of the mucosa in the in vitro changes in guinea pig bladder function which occur after sensitization with ovalbumin.
Bladder strips from sensitized guinea pigs respond to ovalbumin challenge with a contraction accompanied by release of histamine, prostaglandin, and leukotriene. Histamine and prostaglandin release occurs preferentially from the bladder mucosa, while leukotrienes are released by the smooth muscle. This study investigated the effects of removal of the bladder mucosa on contractile responses of strips from control and sensitized guinea pigs to electrical stimulation and to contractile agonists. Removal of the mucosa potentiated the contractile response to electrical stimulation at low voltages and pulse durations. The presence of ovalbumin had no effects on the response to electrical stimulation. Removal of the mucosa had no effect on the contractile responses of bladder strips to bethanechol, histamine, KCl, or ovalbumin, although after correction for the decreased strip mass after mucosa removal there was a tendency for the responses to increase. We conclude that the responsiveness of bladder strips from sensitized guinea pigs to ovalbumin challenge results primarily from effects which occur within the smooth muscle.
Animals↗
Effects of the peptide leukotriene receptor antagonist ICI 198,615 on the in vivo and in vitro changes in guinea pig bladder function which occur after sensitization with ovalbumin.
PURPOSE: The present studies were designed to determine the effects of in vivo and in vitro administration of ICI 198,615 (ICI), a leukotriene receptor antagonist, on the inflammatory changes that occur in the bladder after sensitization with ovalbumin. MATERIALS AND METHODS: The effect of intravenous administration of ICI on urodynamic changes after instillation of ovalbumin to sensitized guinea pigs was evaluated by in vivo cystometry. Responses of in vitro bladder muscle strips to contractile stimuli and ovalbumin were also evaluated in the presence of ICI. RESULTS: In sensitized guinea pigs, in vivo cystometry with ovalbumin induced a marked decrease in bladder capacity and increase in intravesical pressure. Pretreatment with ICI prior to cystometry prevented the ovalbumin-induced changes in capacity and intravesical pressure. There were no significant differences between control and sensitized animals in the responses of in vitro bladder muscle strips to field stimulation or bethanechol. However, maximal contractile responses to ovalbumin were significantly greater in the strips from sensitized animals than in controls. Preincubation with ICI, indomethacin, or pyrilamine alone was unable to inhibit the contractile responses to ovalbumin. However, combined administration of ICI, indomethacin and pyrilamine completely blocked the responses. CONCLUSIONS: In vivo administration of the leukotriene receptor antagonist ICI 198,615 reversed the urodynamic changes induced by ovalbumin challenge in sensitized guinea pigs. These results indicate that leukotrienes are primarily responsible for the changes in in vivo bladder function associated with sensitization.
Animals↗
Temporal changes in micturition and bladder contractility after sucrose diuresis and streptozotocin-induced diabetes mellitus in rats.
Studies were done to compare the acute effects of streptozotocin-induced diabetes and sucrose consumption on micturition, bladder mass and contractile responses of bladder strips to field stimulation and contractile agonists. Micturition changes occurred gradually in diabetic rats, reached maximal values within 7 to 14 days, and were accompanied by significant increases in bladder mass after 7 days. Bladder strips from diabetics responded to field stimulation, carbachol and KCl with significantly greater contractions than did those from controls within 7 days. Sucrose-drinking rats had maximal increases in fluid consumption and micturition frequency on the first night after starting treatment. Increases in micturition volumes were slower to develop than in diabetics. Bladder mass was significantly increased 30 and 60 days after starting sucrose treatment. Bladder strips from sucrose-drinking rats responded to field stimulation and carbachol with significantly greater contractions than did those from controls only after 60 days. Monitoring of drinking and micturition patterns established that diabetic rats drink and urinate during both the dark and light cycles. In contrast, control and sucrose-drinking rats drink and urinate principally at night. The results demonstrate that differences in bladder function between diabetic and sucrose drinking rats are apparent during the first month after treatment begins. The data suggest that the effects of diabetes and sucrose consumption on contractile bladder function are related to the diuresis-induced increases in bladder mass.
Animals↗
Factors that modulate the initiation of micturition.
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Animals↗
3H-thymidine uptake by the rat urinary bladder after partial outflow obstruction.
Partial outflow obstruction induces marked changes in detrusor contractile function and morphology. One common finding in all experimental animal models of outflow obstruction is a significant increase in bladder mass. It is not clear which tissue compartments undergo hypertrophy, hyperplasia, or both. The present study was designed to evaluate the time-related changes in 3H-thymidine uptake and distribution within each tissue compartment induced by partial outflow obstruction using autoradiography. Partial outlet obstruction in rats induced a mild 2-fold increase in mass over a 14 day period. DNA synthesis increased significantly at 1 day following surgery, and remained increased through 7 days. DNA synthesis returned to control levels by 14 days. Distribution studies (using autoradiography) demonstrated a marked increase in the number of labelled urothelium cells at 1 and 3 days after obstruction. Sham surgery also initiated an increase in the number of labelled cells in the urothelium at 1 day. Although both sham and obstructive surgeries induced substantial increases in the labelling of cells within the connective tissue components, the magnitude of the increase in labelled connective tissue cells of the obstructed bladders was greater than that of the sham group. The number of labelled smooth muscle cells of the obstructed bladder increased significantly at 3, 5, and 7 days. However, there were no changes in smooth muscle incorporation of 3H-thymidine by the sham groups. In conclusion, partial outflow obstruction induced time-dependent increases in bladder wall proliferation. The urothelium and connective tissue were the compartments first affected, followed by smooth muscle.
Animals↗
Rabbit as a model of urinary bladder function.
Micturition is a complex neuromuscular process. Although control mechanisms have been identified at several levels of the central nervous system and spinal cord, the final pathway in the control of micturition is the autonomic innervation of the urinary bladder and related structures. Following this line of reasoning further, micturition is ultimately dependent on the ability of the urinary bladder to both contract and generate intravesical pressure, and to modify its shape in such a way as to efficiently expel its contents without leaving a high residual volume. In order to understand the various elements of micturition, a wide variety of both in vivo and in vitro animal models has been developed. In many cases, animal models have been utilized to describe the effect of specific experimental pathologies on the lower urinary tract. The current review of the use of the rabbit in urological research is not meant to be a comprehensive treatise on the topic, but should provide a rational description of the how this species can be utilized to study both normal and pathological function.
Aging↗
Update on bladder smooth-muscle physiology.
The urinary bladder responds to distension induced by a number of different stresses with rapid and substantial increases in bladder mass and concomitant alterations in the contractile responses to neuronal stimulation, pharmacological simulation by autonomic agonists, and membrane depolarization. Furosemide, sucrose, or diabetes-induced diuresis, as well as outlet obstruction and overdistension all produce similar effects on the bladder. Accompanying the increases in bladder mass and contractile changes are increases in DNA synthesis and [3H]-thymidine uptake. Autoradiographic studies have localized the increased DNA synthesis following bladder distension initially to the urothelium, followed by slower increases in labelling of the lamina propria and extramural connective tissue. The net result of these compartmental differences in DNA synthesis is a reorganization of the structural relationships between smooth-muscle cells, the connective-tissue matrix, and the extrinsic connective-tissue lamina. This may contribute to the functional changes which occur after severe overdistension. Increases in the expression of heat-shock protein-70, basic fibroblast growth factor, N-ras, and c-myc, and decreases in transforming growth factor-beta occurred acutely after obstruction, suggesting that these changes may play a role in obstruction-induced bladder hypertrophy. Removal of the obstruction induces apoptosis of urothelial and connective tissue elements in the bladder, accompanied by increases in transforming growth factor-beta and decreases in basic fibroblast growth factor genes, and a reversal of the bladder dysfunction. Therefore the bladder hyperplasia after outlet obstruction and the regression following removal of the obstruction seem to be directly opposing processes governed by gene expression.
Animals↗
A novel canine model of partial outlet obstruction secondary to prostatic hypertrophy.
Benign prostatic hyperplasia (BPH) is a major medical problem in the United States. The primary medical complication of BPH is progressive obstruction of the urethra and a subsequent in reduction the ability or the bladder to empty efficiently. The urodynamic characteristics associated with BPH include hyperreflexia, increased bladder capacity, increased frequency, decreased flow rate, and increased residual volume. Although there currently are individual animal models of prostate enlargement and animal models of partial outlet obstruction, there is no model of progressive obstruction secondary to prostate enlargement. The primary objective of the current study was to develop a canine model of BPH that would secondarily result in partial urethral obstruction and impaired urodynamics. Our model consists of encapsulating the prostate in a nylon mesh to prevent the growth of the prostate into the peritoneal cavity and then treating the dog with steroids to induce prostate growth and subsequently produce urethral constriction. The results demonstrate that encapsulation of the dog prostate and administration of steroids results in an increase in prostate mass simultaneously with an increase in urethral pressure and in changes in bladder contraction consistent with the presence of partial outlet obstruction. This preliminary study demonstrates that by preventing the outward growth of the steroid-stimulated prostate, urethral obstruction resembling BPH can be produced.
Animals↗
Regulation of actomyosin and contraction in smooth muscle.
Unlike striated muscle cells, smooth muscle cells do not have an organized sarcomeric structure. However, all smooth muscle cells contain the contractile proteins, myosin, actin, and tropomyosin. Polymorphism of the myosin heavy chain exists in smooth muscle cells. Two myosin heavy chain (MHC) isoforms, SM1 (204 kDa) and SM2 (200 kDa), are present in smooth muscle cells; however, their ratios vary in smooth muscles from different sources. The hypertrophy of the urinary bladder induced by partial outlet obstruction in rabbits is associated with an alteration of the SM1-to-SM2 ratio from 1:3 to 1:1. Both heavy chains react with polyclonal antibody against smooth muscle myosin; however, antibody prepared against a peptide from the C-terminal region of the SM2 heavy chain cross-reacts only with the SM2 heavy chain. Removal of the obstruction reverses the bladder to normal mass with a concomitant change in the SM1-to-SM2 ratio back to 1:3. The expression of the SM1 mRNA is increased in response to obstruction-induced hypertrophy, and it also returns to normal upon removal of the obstruction. Urinary bladder smooth muscle contains predominantly gamma-actin. Obstruction-induced hypertrophy of the bladder smooth muscle is associated with an increase in the gamma-actin at both protein and mRNA levels. The beta-non-muscle actin is decreased and the alpha-smooth muscle actin is unchanged in response to obstruction-induced bladder hypertrophy. Contraction of all smooth muscles involves similar mechanisms. This review describes our current understanding of the mechanisms regulating contraction of the smooth muscle of the urinary bladder.
Actomyosin↗