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Biomedical subjects

R M Levin

Publications and source records attributed to R M Levin.

At least 73 records · Page 4Linked to original sources
PubMed1998

Effects of atropine, isoproterenol and propranolol on the rabbit bladder contraction induced by intra-arterial administration of acetylcholine and ATP.

INTRODUCTION: In the rabbit, both cholinergic and purinergic nerves mediate bladder contraction. Acetylcholine is the neurohumoral transmitter for the cholinergic nerves, and ATP is the neurohumoral transmitter for purinergic innervation. Beta-adrenergic stimulation mediates relaxation of the bladder. In the current study, we investigated the effects of atropine, isoproterenol and propranolol on the bladder contraction induced by intra-arterial administration of acetylcholine and ATP. METHODS: Mature male New Zealand White rabbits were used in this study. A polyethylene catheter with an outer diameter of 0.043 inches was inserted through the rabbit's right femoral artery until it reached the lower abdominal aorta. An 8 F catheter was inserted through the urethral orifice into the bladder and secured by tying a 2-0 silk ligature around the bladder neck. The catheter was connected to an infusion pump and a pressure transducer by a 3-way valve. After 15 ml. of saline was infused into the bladder, an intra-arterial administration of acetylcholine and ATP was infused and the change of intravesical pressure was quantitated and recorded with a Grass model 7D polygraph. The procedure was repeated after a 5-minute pretreatment with atropine, isoproterenol or propranolol. RESULTS: The results are summarized as follows: 1) Baseline intravesical pressure was not altered by pretreatment with atropine. Pretreatment with atropine shifted the dose-response curve of acetylcholine to the right and the maximal response was reduced by 9%, 49% and 77% respectively with pretreatment with atropine 10(-8), 10(-7) and 10(-6) mole/kg. The dose-response curve of ATP was not significantly affected by pretreatment with atropine. 2) Baseline intravesical pressure was lowered by pretreatment with isoproterenol. Pretreatment with isoproterenol shifted both dose-response curves of acetylcholine and ATP rightward. The maximal response of acetylcholine was reduced by 10%, 26% and 37% respectively, and the maximal response of ATP was reduced by 6%, 31% and 43% respectively by pretreatment with isoproterenol 10(-8), 10(-7) and 10(-6) mole/kg. 3) Baseline intravesical pressure was not changed by pretreatment with propranolol. Both dose-response curves of acetylcholine and ATP were not significantly affected by pretreatment with propranolol. SUMMARY: In conclusion, pretreatment with atropine inhibited acetylcholine-induced bladder contraction, but had no effect on ATP-induced contraction. Pretreatment with isoproterenol significantly inhibited both contractile stimulation by acetylcholine and ATP. Pretreatment with beta-adrenergic antagonist had no effect on the bladder contraction induced either by acetylcholine or by ATP. Thus, although beta-adrenergic stimulation is capable of significantly inhibiting the contractile responses to both cholinergic and purinergic stimulation, under normal conditions, sympathetic nerves do not modulate either cholinergic or purinergic stimulation.

Acetylcholine↗
PubMed1997

Compliance of the obstructed fetal rabbit bladder.

We evaluated compliance in the developing bladder using a newly developed animal model of posterior urethral valves: partial infravesical obstruction in the fetal rabbit bladder. Partial bladder outlet obstruction was created in fetal rabbits at day 23 of a 31 to 32-day gestation period. An in vitro whole bladder preparation provided data on compliance and an isolated bladder strip preparation provided data on the mechanical properties of the bladder wall. In addition, the influence of calcium on both preparations was evaluated. Partial bladder outlet obstruction in the fetal rabbit resulted in a markedly larger bladder weight (246.4 +/- 22.3 mg, n = 14) than control bladders (90.2 +/- 5.7 mg, n = 13). Isolated smooth muscle strips from obstructed and normal bladders revealed identical stretch-stress patterns. In contrast, obstructed bladders had significantly increased compliance in the whole bladder preparation. Since the increase in compliance was not correlated to mechanical properties of the isolated bladder strips, it must therefore result from the pattern of mass increase of the whole bladder wall. During filling, both the control and obstructed bladders had the same slow, large amplitude spontaneous contractions. In addition, both had rapid contractions: those in the obstructed bladders had significantly lower frequency and higher amplitude than the ones in the control bladders. Removing the calcium from the organ bath eliminated the spontaneous contractions but did not change the baseline pressure or force values, indicating that the compliance of these fetal rabbit bladders is a function of the passive properties of the bladder wall. Three main patterns occur in cystometrograms of patients with posterior urethral valves: myogenic failure, hyperreflexic bladders, and low compliance bladders. Using our model of partial outlet obstruction in the fetal rabbit bladder, we could not imitate the group with low compliance. We therefore hypothesize that the different patterns of bladder dysfunction associated with posterior urethral valves are due to infravesical obstruction occurring with different severities or at different ages of gestation.

Animals↗
PubMed1997

Effect of partial outlet obstruction on 14C-adenine incorporation in the rabbit urinary bladder.

Bladder outlet obstruction induces severe changes in urinary bladder function and metabolism. These changes are characterized by significant reductions in the ability of the in vitro whole bladder to generate pressure and to empty. Metabolically, partial outlet obstruction induces a shift from oxidative to anaerobic metabolism. The decreased oxidative metabolism is mediated in part by significant decreases in mitochondrial substrate metabolism, which in turn is correlated with decreased activity of 2 important mitochondrial enzymes: citrate synthase and malate dehydrogenase. The present study was designed to evaluate mitochondrial function by studying the incorporation of 14C-adenine into high-energy phosphates (ATP, AMP, and ADP). Mild partial outlet obstructions were created by surgically placing silk ligatures loosely around the bladder neck. The results of these studies demonstrate that after 60 min incubation in oxygenated medium containing glucose + 1uCi14C-adenine, 1) There was no significant differences in the total AMP, ADP, and ATP concentrations measured in bladders taken from controls, 7- and 14-day obstructed rabbits; 2) there was no effect of obstruction on either the concentration of 14C-AMP in the tissue or in the ratio of hot to cold AMP; and 3) there was a 50% decrease in the concentration of 14C-ADP and a 70% decrease in the concentration of 14C-ATP in the bladder smooth muscle obtained from obstructed tissue (from both 7- and 14-day obstructions) compared to concentration in the control bladder smooth muscle. These results confirm the previous finding that obstruction did not reduce the rate of incorporation of adenine to AMP within the obstructed bladder smooth muscle and extends these studies to identify a significant reduction in the synthesis of both ADP and ATP. These results support the hypothesis that partial outlet obstruction induce a major dysfunction in mitochondrial function, both in the ability to oxidize substrates and in the ability to generate ATP.

Adenine↗
PubMed1997

Beneficial effects of Tadenan therapy after two weeks of partial obstruction in the rabbit.

Tadenan (Debat Laboratories, France) is a plant extract used in Europe for the treatment of micturition disorders associated with benign prostatic hypertrophy (BPH). Prior studies demonstrated that pretreatment of rabbits with Tadenan significantly reduced the contractile dysfunction observed after 2 weeks of partial outlet obstruction. The specific aim of the present study was to determine the effect of Tadenan therapy following the creation of partial outlet obstruction. Two sets of experiments were performed: one with mild and the other with severe outlet obstruction. For both sets of experiments, male New Zealand rabbits (3-5 kg) were separated into 3 groups of 5 rabbits each. Each rabbit in groups 1 and 2 was obstructed using standard methodology. Rabbits in group 3 served as controls and did not receive any surgery. After 2 weeks, each rabbit in group 1 received Tadenan orally at 100 mg/kg/day for 3 weeks; each rabbit in group 2 received vehicle (peanut oil). After 3 weeks of treatment (5 weeks after partial outlet obstruction), rabbits were anesthetized and cystometries were performed. Immediately after cystometry, the rabbits were euthanized, the bladder rapidly removed, and 4 longitudinal strips prepared and mounted in individual baths for contractile studies. The contractile responses to field stimulation, carbachol, adenosine-5'-triphosphate (ATP), and potassium chloride (KCl) were determined, as follows: (1) Bladder mass approximately doubled in the mildly obstructed groups. Bladder mass increased significantly (3-5-fold) in the severely obstructed groups. (2) Cystometrograms from the mildly obstructed rabbits treated with peanut oil showed low compliance, whereas those of the mildly obstructed rabbits treated with Tadenan showed normal compliance. The cystometrograms of all severely obstructed rabbits showed low compliance. (3) Mild obstruction caused small but significant decreases in the contractile response to field stimulation that were reversed by Tadenan treatment. No changes were noted in response to bethanechol, ATP, and KCl stimulation. (4) Severe obstruction caused significant decreases in the response of bladder strips to field stimulation and bethanechol. Following Tadenan therapy, there was a significant improvement in the response to high-frequency field stimulation and a substantial improvement in the response to bethanechol (response equal to control). No changes were noted in response to ATP and KCl stimulation. In conclusion, Tadenan treatment reversed the bladder dysfunctions induced by mild partial outlet obstruction, and resulted in improved bladder function in the severe model of outlet obstruction. These studies are consistent with previous studies showing that Tadenan pretreatment protects the bladder against the development of contractile dysfunctions.

Animals↗
PubMed1997

Ability of obstructed bladders to empty is dependent on method of stimulation.

PURPOSE: To correlate pharmacologic changes that occur in the bladder after a partial outlet obstruction with the bladder's ability to perform work and empty. METHODS: After 2 weeks of partial outlet obstruction, rabbit bladders were stimulated in vitro both isovolumetrically [field stimulation (FS)] and to empty (FS, bethanechol, and KCl). RESULTS: The obstructed bladders were separated into two groups according to their ability to empty when stimulated with FS. Compensated bladders were those that could empty as much as controls. Decompensated bladders emptied significantly less than controls. With FS and bethanechol, the compensated obstructed bladders showed no difference from the control bladders in their ability to empty. In contrast, with KCl, the compensated bladders generated significantly less pressure, performed less work, and emptied less than controls. When the decompensated bladders were stimulated with all three types of stimulation, all parameters, including emptying ability, were significantly decreased. CONCLUSIONS: The reduction in the response of compensated bladders to KCl stimulation suggested that the initial defects to the bladder after an outlet obstruction involved the interaction of smooth muscle proteins with calcium and ATP. In contrast, the response of decompensated bladders to all three forms of stimulation was equally reduced, suggesting that the degenerative processes were directly related to significant cellular damage to metabolic processes involved in energy synthesis, storage, and utilization.

Animals↗
PubMed1997

Correlation of ischemia/reperfusion or partial outlet obstruction-induced spectrin proteolysis by calpain with contractile dysfunction in rabbit bladder.

OBJECTIVES: In the rabbit, both experimental ischemia and partial outlet obstruction of the urinary bladder induce similar dysfunctions with regard to the contractile responses to both field (neuronal) stimulation and postsynaptic receptor stimulation. Circumstantial evidence indicates that the pathologic response to both conditions is related to two connected processes-tissue ischemia and reperfusion injury-that result in a marked increase in intracellular calcium ([Ca2+]i), followed by the activation of the Ca(2+)-dependent neutral protease calpain. Calpain activation results in the proteolysis of specific membrane proteins, including those of neuronal membranes (resulting in progressive denervation of the detrusor) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), resulting in the previously reported decrease in SERCA. The current study is designed to generate direct support for the theory that both ischemia and partial outlet obstruction result in the activation of calpain. METHODS: Separate sets of rabbits were subjected to 1 or 2 hours of ischemia, followed by reperfusion for different lengths of time, or partial outlet obstruction for different lengths of time. We determined the state of calpain activation by quantitating tissue proteolysis of alpha-spectrin by Western blot analysis. Correlative organ bath studies were conducted to observe the contractile responses of bladder strips to field stimulation and bethanechol administration. RESULTS: (1) Sixty minutes of ischemia followed by 30 minutes of reperfusion resulted in (a) a reduction in the contractile responses to field stimulation and bethanechol (89% and 57%, respectively), and (b) a 72% decrease in native alpha-spectrin, with a concomitant 300% increase in its breakdown products (BDPs). Neither alpha-spectrin nor its BDPs had returned to control levels after 72 hours of reperfusion. (2) Twenty-four hours after the creation of a partial obstruction, alpha-spectrin BDP levels were increased 330%, then gradually fell to 130% of control levels by 14 days after obstruction. Concomitantly, the native alpha-spectrin level was decreased 74% 24 hours after obstruction and remained low through 7 days after obstruction. At 14 days after obstruction, the alpha-spectrin levels had recovered to 75% of control levels. CONCLUSIONS: These findings suggest that Ca(2+)-dependent proteolysis of the preferred calpain substrate alpha-spectrin in urinary bladder tissues is increased significantly by both ischemia/reperfusion and partial outlet obstruction. Temporally, proteolysis precedes the reduced muscle function resulting from these pathologic conditions.

Animals↗
PubMed1997

Contractile responses and calcium mobilization induced by muscarinic agonists in the rat urinary bladder: effects of age.

In the current study, the contractile responses to muscarinic stimulation of urinary bladder strips from young rats and aged rats were compared. 1. The EC50 values of the two groups in response to bethanechol were similar. 2. The magnitude and the velocity of tension generation was significantly lower in strips from the aged group. 3. The magnitude as well as the velocity of tension generation in response to high K+ solution of the two models were similar. 4. The time to peak [Ca2+]i in response to bethanechol was prolonged in strips from the aged group as compared with the young group. 5. 45Ca2+ influx in response to bethanechol was significantly reduced in the aged group as compared with the young group. It is concluded that the reduced contractile response to muscarinic stimulation of isolated urinary bladder strips from aged rats is mediated at least in part by a decreased rate of Ca2+ entry.

Age Factors↗
PubMed1997

Effect of age and outlet resistance on rabbit urinary bladder emptying.

PURPOSE: To investigate the influence of age and effect of increased outlet resistance on the ability of rabbit bladders to empty in response to various methods of stimulation. MATERIALS AND METHODS: Bladders from six-month-old (young) and three-year-old rabbits (aged) were mounted in an in vitro whole organ bath system and filled with 15 ml. saline. The ability of the bladders to empty against low outlet resistance (LOR) and high outlet resistance (HOR) in response to field stimulation, bethanechol, and KCl was measured. The following parameters were measured: intravesical pressure and volume emptied. From these, flow rate, power, and external mechanical work were calculated. RESULTS: Maximum isometric pressure did not change with age. All bladders emptied with increased pressure and decreased flow rate at HOR. The young bladders generated a greater maximum power in response to bethanechol and KCl than the aged bladders at both outlet resistances, and maximum power did not change with increased resistance. The aged bladders did less work and emptied significantly less than the young bladders at the HOR. CONCLUSIONS: The aged rabbit bladders were unable to maintain the bladder contraction long enough to empty completely through an increased outlet resistance. Because maximum power remained constant when the outlet resistance was increased, it might be useful clinically to determine the emptying ability of the urinary bladder, independent of changes in outlet resistance. In addition, bladder work could be used to evaluate bladder function if the volume emptied is also taken into consideration.

Aging↗
PubMed1997

Partial bladder outlet obstruction in the fetal rabbit.

PURPOSE: We developed and tested an animal model of bladder dysfunction due to posterior urethral valves using partial outlet obstruction of the fetal rabbit bladder. MATERIALS AND METHODS: Partial bladder outlet obstruction of fetal rabbit bladders was created on day 23 of gestation. Of the litter of 8 to 10 fetuses half was obstructed and the remainder served as controls. The doe and fetuses were sacrificed on day 30 of gestation (full term 31 to 32 days) and the fetal bladders were removed. Bladders that had doubled in weight from the average bladder weight of the control littermates were deemed sufficiently obstructed. Hematoxylin and eosin staining was performed and bladder strip response to 32 Hz. field stimulation, 200 microM. bethanechol and 200 mM. potassium chloride was measured. RESULTS: Average body weight did not differ between the control and obstructed fetuses, indicating that surgery did not hinder fetal development. Hematoxylin and eosin staining confirmed smooth muscle cell hypertrophy and increased connective tissue in the obstructed bladders. Obstructed bladder strips responded significantly less to field stimulation, and significantly more to bethanechol and potassium chloride (mean plus or minus standard deviation 5.18 +/- 1.52, 6.29 +/- 1.3 and 10.15 +/- 2.18 x force per/100 mg. tissue, respectively)than control bladder strips (9.0 +/- 1.19, 3.5 +/- 0.46 and 6.16 +/- 1.33 x force per/100 mg. tissue, respectively) suggesting that denervation supersensitivity may have resulted from obstruction. CONCLUSIONS: Partial outlet obstruction of the fetal rabbit bladder results in bladder hypertrophy and dysfunction but these changes are markedly different from those in the adult rabbit. Since rabbit fetal development is delayed compared to human fetal development, this model can be used to assess the consequences of posterior urethral valves.

Animals↗
PubMed1997

Subcellular distribution of SERCA and calcium-activated ATPase in rabbit and human urinary bladder smooth muscle.

Previous studies have demonstrated that calcium storage and release from IP-3-dependent sites in the sarcoplasmic reticulum play an important role in the contractile response of the rabbit urinary bladder to both field stimulation (mediated via neurotransmitter release) and bethanechol (direct muscarinic stimulation). In view of the importance of SERCA in urinary bladder smooth muscle function, we studied the distribution of SERCA by two methods: using Western blotting to quantitate the protein concentration and by enzyme analysis using thapsigargin to specifically inhibit SERCA. Rabbit and human samples of urinary bladder smooth muscle were homogenized and the homogenate separated into three particulate fractions by differential centrifugation: nuclear-cell wall, mitochondrial, and microsomal. The protein concentration of these three particulate fractions was determined and the SERCA protein level quantitated by Western blotting using SERCA-2 antibodies. The calcium-ATPase activity was quantitated using standard enzymatic analysis and the thapsigargin sensitivity determined. The results demonstrated that: (1) the concentration of SERCA was significantly greater in the microsomal fraction than in either of the other fractions for both rabbit and human bladder smooth muscle; (2) the enzymatic activities of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase were evenly divided among the three fractions, and (3) the enzymatic activity of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase of the rabbit exceeded that of the human. In conclusion, the distribution of SERCA and calcium-ATPase of the rabbit bladder smooth muscle was similar to that in the human bladder smooth muscle, although activities in rabbit were significantly greater than those of human tissue.

Animals↗
PubMed1997

Subcellular distribution of SERCA and calcium-activated ATPase in rabbit and human urinary bladder smooth muscle.

Previous studies have demonstrated that calcium storage and release from IP3-dependent sites in the sarcoplasmic reticulum play an important role in the contractile response of the rabbit urinary bladder to both field stimulation (mediated via neurotransmitter release) and bethanechol (direct muscarinic stimulation). In view of the importance of SERCA (see text) in urinary bladder smooth muscle function, we studied the distribution of SERCA by two methods; using Western blotting to quantitate the protein concentration and by enzyme analysis using thapsigargin to specifically inhibit SERCA. Rabbit and human samples of urinary bladder smooth muscle were homogenized and the homogenate separate into three particulate fractions by different centrifugation: the cell wall-nuclear, mitochondrial, and microsomal. The protein concentration of these three particulate fractions was determined and the SERCA protein level quantitated by Western blotting using SERCA-2 antibodies. The calcium ATPase activity was quantitated using standard enzymatic analysis and the thapsigargin sensitivity determined. The results demonstrated that (1) the concentration of SERCA was significantly greater in the microsomal fraction than in either of the other fractions for both rabbit and human bladder smooth muscle; (2) the enzymatic activities of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase were evenly divided among the three fractions, and (3) the enzymatic activity of both total calcium-activated ATPase and thapsigargin-sensitive calcium ATPase of the rabbit exceeded that of the human. In conclusion, the distribution of SERCA and calcium ATPase of the rabbit bladder smooth muscle was similar to that in the human bladder smooth muscle, although activities in rabbit were significantly greater than those of human tissue.

Adenosine Triphosphatases↗
PubMed1997

Calcium regulation of urinary bladder function.

PURPOSE: To investigate the effect of independently inhibiting calcium influx from extracellular sources and calcium release from intracellular stores on the ability of the urinary bladder to generate pressure and empty. MATERIALS AND METHODS: Rabbit bladders were mounted in an in vitro whole organ bath and filled with 15 ml. saline. Each bladder was incubated separately in Tyrode's solution, with diltiazem (10 microM), to block extracellular calcium influx, or with thapsigargin (40 microM) and ryanodine (80 microM), to block the uptake and release of calcium from the sarcoplasmic reticulum. The bladder was then stimulated isometrically with field stimulation (32 Hz), and to empty with field stimulation and with bethanechol (250 microM), independently. During stimulation, transmural pressure and volume emptied were measured. From these, flow rate, power, and external mechanical work were calculated. RESULTS: In the presence of diltiazem, the time to maximal pressure decreased while the rate of pressure generation increased. This results from increased participation of intracellular calcium release, which occurs rapidly and near the smooth muscle filaments, decreasing the diffusion time. In the presence of thapsigargin and ryanodine the maximal rate of pressure generation was decreased, due to the increased diffusion time required for calcium to move to the muscle filaments from extracellular sites. CONCLUSIONS: The current study demonstrates that bladder pressure generation and emptying are dependent upon both an influx of calcium through L-type calcium channels (inhibited by diltiazem) and the stimulated release of calcium from the SR (inhibited by thapsigargin and ryanodine).

Animals↗
PubMed1997

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↗
PubMed1997

Cellular and molecular aspects of bladder hypertrophy.

Bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction associated with ageing. As the disease slowly progresses, the bladder changes from a state of compensation to decompensation, in which there are severe, irreversible alterations in bladder function. Using a rabbit model of partial outlet obstruction we have identified three major cellular changes in the bladder which result from such obstruction. These include progressive denervation, mitochondrial dysfunction and disturbances of calcium storage and release from the sarcoplasmic reticulum. Our hypothesis is that outlet obstruction results in bladder hypertrophy which induces ischaemia. This leads to a release of intracellular calcium, leading to activation of specific enzymes and generation of free radicals. These then attack the membranes of nerves, sarcoplasmic reticulum and mitochondria. We have demonstrated that pretreatment of rabbits with Pygeum africanum extract (Tadenan) significantly reduced the severity of both the contractile and metabolic dysfunctions induced by partial outlet obstruction. Our current hypothesis is that Tadenan may either prevent the activation of degradative enzymes (or generation of free radicals), or protect the intracellular membranes against the destructive effects of free radicals or degredative enzymes. In conclusion, identifying cellular mechanisms responsible for bladder dysfunction induced by partial outlet obstruction provides new possibilities for non-surgical treatment of BPH. Our studies on Tadenan support this concept that the bladder provides a novel target for therapeutic intervention.

Aging↗
PubMed1997

Animal models of bladder outlet obstruction and molecular insights into the basis for the development of bladder dysfunction.

In humans, chronic bladder outlet obstruction resulting from benign prostatic hypertrophy (BPH) can induce severe and irreversible upper urinary tract changes, especially in the bladder. BPH can be mimicked in rabbits by artificially creating a partial obstruction of the bladder outlet. The structural and functional changes initiated eventually elicit a pathology and symptomology similar to human BPH. The rabbit bladder responds to partial outlet obstruction in three characteristic stages: hypertrophy, compensation and decompensation Basic fibroblast growth factor, epidermal growth factor and transforming growth factor-beta appear to be involved in the hypertrophy phase. During this initial phase normal bladder function is maintained but in the later phases, it is drastically impaired. We propose that the various stages of bladder remodelling subsequent to partial outlet obstruction are essentially driven by reduction in blood flow to the bladder (ischaemia). Initially this ischaemia might stimulate a compensatory response enabling the bladder to deal with the stress outlet obstruction. However, the long-term reduction in blood flow resulting from cyclical filling of the obstructed bladder, ultimately induces the degenerative changes that impede bladder function. These findings have important implications for the development of novel therapies to prevent or reverse bladder dysfunction resulting from BPH.

Animals↗
PubMed1997

Transcription of mitochondrial and mitochondria-related nuclear genes in rabbit bladder following partial outlet obstruction.

Using the rabbit model, we showed that partial outlet obstruction of the urinary bladder causes significant changes in the status and expression of the mitochondrial (mt) genetic system in bladder smooth muscle immediately after obstruction is initiated. Here we investigate quantitatively the severity of the mt genetic response to partial outlet obstruction in both short- and long-term obstructed rabbits. Based on previous functional studies, bladders with mass < 6 fold greater than control were considered compensated; bladders with mass > 6 fold that of control were considered decompensated. Analyses of DNA from compensated rabbit bladders showed that relative mt genome copy number decreased to 30% of control values. Transcript analyses for these samples showed that mt RNA levels increased 3 fold to compensate for lower template copy number. Analysis of decompensated bladders demonstrated that mt genome copy number increased to approximately 90% of control levels; mt transcripts progressively decreased in these samples by as much as 30 fold. In contrast, transcription of a mt-related nuclear gene decreased 3-9 fold in compensated bladders but increased 10-30 fold in decompensated bladders. Activity for the cytochrome oxidase complex, and for the mt enzyme citrate synthase, decreased steadily with increasing bladder hypertrophy. These data suggest that bladder dysfunction following partial outlet obstruction is mediated partly by a significant loss in mt and mt-related nuclear gene coordination.

Animals↗
PubMed1996

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↗