Infravesical Outflow Obstruction Research Articles

Revisted Blocksom vesicostomy: Operative steps

Posterior urethral valves (PUVs) are the most common cause of infravesical outflow obstruction in boys. Vesicostomy is considered in selective cases of PUV as an initial temporary procedure. The most commonly followed procedure is the one described by Blocksom. The procedure is simple and easy to perform. We revisited this procedure and describe the operative steps.

Changes in the Function and Expression of T-Type and N-Type Calcium Channels in the Rat Bladder after Bladder Outlet Obstruction

We evaluated possible changes in the function and expression of T-type and N-type Ca(2+) channels in the bladder of rats with bladder outlet obstruction. Female Sprague Dawley® rats were divided into a group with bladder outlet obstruction created by partial urethral ligation and a sham operated group. Six weeks postoperatively we determined the mRNA expression of T-type and N-type Ca(2+) channels in the bladder, dorsal root ganglion and spinal cord. We also cystometrically investigated expression by intravenous administration of the T-Ca blocker RQ-00311610 or the N-type Ca(2+) channel blocker ω-conotoxin GVIA. We then performed in vitro functional studies of detrusor strips using these blockers. mRNA expression of T-type Ca(2+) channels in the bladder detrusor and mucosa layers, and the spinal cord dorsal horn, and N-type Ca(2+) channels in the whole bladder and detrusor layer, and the spinal cord dorsal horn was greater in the obstructed group than the sham operated group. In obstructed rats bladder capacity and voided volume increased after RQ-00311610 administration but the number of nonvoiding contractions decreased after ω-conotoxin GVIA administration. Detrusor strips from obstructed rats showed weaker contractile responses to electrical field stimulation, particularly in regard to the purinergic component. ω-Conotoxin GVIA suppressed electrical field stimulation induced contractions only in the detrusor of obstructed rats, especially the cholinergic component. Blocking T-type Ca(2+) channels increased bladder capacity while N-type Ca(2+) channel blockade inhibited nonvoiding contractions in rats with bladder outlet obstruction. Decreased bladder efferent neurotransmission occurred after bladder outlet obstruction, predominantly in its purinergic component and detrusor contractions via cholinergic neurotransmission were activated in a compensatory manner, probably via N-type Ca(2+) channel up-regulation.

Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats

We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.

Simulated Bladder Pressure Stimulates Human Bladder Smooth Muscle Cell Proliferation via the PI3K/SGK1 Signaling Pathway

A mechanical stimulus on detrusor tissue is critical to bladder outlet obstruction progression and functional bladder tissue engineering. A hypothesis is that mechanical stimulus triggers human bladder smooth muscle cell proliferation. To help better understand this relationship of bladder function to growth at the cellular level we used a novel method of applying cyclic hydrodynamic pressure that simulates the bladder cycle to cell cultures. We detected the proliferation response of human bladder smooth muscle cells (4310, ScienCell™) to different pressures as well as the signal transduction mechanism of this process. Human bladder smooth muscle cells cultured in scaffolds underwent 4 pressures (0, 100, 200 and 300 cm H(2)O) for 24 hours, as controlled by a BioDynamic® bioreactor. We then used flow cytometry to examine cell cycle distribution, and polymerase chain reaction and immunoblot to quantify SGK1 and AKT expression and activation in each group. SGK1 was silenced in human bladder smooth muscle cells using small interfering RNA to validate the role of SGK1 in mediating pressure induced cell proliferation. Compared with the 0 cm H(2)O control group, human bladder smooth muscle cells in the 200 and 300 cm H(2)O groups showed increased cell proliferation. SGK1 expression and activity were also increased while AKT, another downstream signal of PI3K, did not change significantly. SGK1 silencing abolished the increases in cell proliferation induced by pressure. To our knowledge we provide the first report of cyclic hydrodynamic pressure stimulating the proliferation of human bladder smooth muscle cells cultured in scaffolds. The signal transduction mechanism for this process is involved with the PI3K/SGK1 and not the PI3K/AKT signaling pathway.

Cannabinor, a Selective Cannabinoid-2 Receptor Agonist, Improves Bladder Emptying in Rats With Partial Urethral Obstruction

We studied the effects of chronic treatment with the novel selective cannabinoid 2 receptor agonist cannabinor (Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) on bladder function in conscious rats with partial urethral obstruction and on the functional properties of isolated detrusor muscle. A total of 24 female Sprague-Dawley® rats with surgically created partial urethral obstruction received daily intraperitoneal injections of 3 mg/kg cannabinor (12) or saline as controls (12) for 2 weeks. Cystometry was done, the rats were sacrificed and the bladders were prepared for in vitro studies. Mean ± SEM bladder weight was 0.97 ± 0.15 gm in controls and 0.53 ± 0.08 gm in cannabinor treated rats (p <0.05). There was no difference between the groups in the mean micturition interval, or mean baseline, threshold, flow or maximum pressure. In controls and cannabinor treated rats mean post-void residual volume was 0.28 ± 0.07 and 0.06 ± 0.02 ml, mean micturition compliance was 0.032 ± 0.006 and 0.069 ± 0.016 ml/cm H(2)O, and mean bladder wall force at the start of flow was 950 ± 280 and 1,647 ± 325 mN/gm, respectively (each p <0.05). Nonvoiding contractions were significantly less frequent in cannabinor treated rats than in controls. We noted no difference in carbachol (Sigma®) half maximum concentration between the groups but the carbachol maximum response in detrusor strips from cannabinor treated rats was significantly higher than that in control strips. In rats with partial urethral obstruction treated daily for 14 days with cannabinor bladder weight was lower, the ability to empty the bladder was preserved and nonvoiding contraction frequency was low compared to those in controls. Detrusor preparations from cannabinor treated rats showed a higher response to nerve stimulation than those from controls. Selective cannabinoid 2 receptor activation may be a novel principle to enable improved bladder function after partial urethral obstruction.

NOCTURNAL BLADDER EMPTYING:: A SIMPLE TECHNIQUE FOR REVERSING URINARY TRACT DETERIORATION IN CHILDREN WITH NEUROGENIC BLADDER

In this preliminary study we sought to determine the effect of instituting nocturnal bladder emptying (NBE) in children with neurogenic (NGB) or nonneurogenic neurogenic bladder (NNGNGB) in whom urinary tract deterioration developed despite optimal daytime clean intermittent catheterization (CIC) and urotropic medications. We hypothesize that a syndrome of nocturnal overdistention of the bladder (SNOB) can cause urinary tract deterioration through increased nighttime storage pressures manifested by recurrent urinary tract infection (UTI), worsening incontinence, hydronephrosis and/or decreasing bladder compliance and capacity, and may be reversed by NBE. A total of 19 children with NGB (17) or NNGNGB (2) who displayed urinary tract deterioration while on CIC and urotropic medications were started on NBE. Of the patients 15 used a continuously draining nighttime catheter while 4 had scheduled awakenings during the night to perform CIC. The primary indications for NBE were recurrent symptomatic UTI in 5, new or progressive hydronephrosis in 7, and decreasing bladder capacity and compliance in 7. At a mean followup of 23 months 15 (79%) patients showed improvement or complete resolution of 1 or more signs or symptoms of hydronephrosis (7), increase in bladder capacity (5), recurrent UTI (6) and worsening incontinence (3). The remaining 4 patients had no response to NBE. No adverse effects were observed with 10 hours or less of nightly indwelling catheter time. Patients with NGB or NNGNGB on idealized daytime programs of CIC and urotropic drugs may have high intravesical pressures and experience urological deterioration because of an unrecognized SNOB. NBE is a simple technique for treating this condition and reversing the pathophysiological changes. The observation that NBE alone may increase bladder compliance and capacity sufficient to avoid bladder augmentation suggests that development of decreased bladder compliance and capacity in children with NGB may not simply represent normal progression of NGB disease. These changes may be avoidable consequences of untreated SNOB. Early institution of NBE may prevent urinary tract deterioration from developing in this population.

ROLE OF SLING INTEGRITY IN THE RESTORATION OF LEAK POINT PRESSURE IN THE RAT VAGINAL SLING MODEL

We tested the hypothesis that cutting the sling at its suburethral section does not cancel its anti-incontinence effect. We also examined the long-term effects of the sling on bladder function in a recently validated rat model of vaginal sling. Stress urinary incontinence was created in 60 female Sprague-Dawley rats by the previously established method of bilateral pudendal nerve transection. Under anesthesia 20 animals received a vaginal sling, 20 received a vaginal sling in which the suburethral portion of the sling was cut immediately after placement and 20 received a sham vaginal sling. Six weeks after the procedures leak point pressure was determined and a cystometrogram was done using anesthesia in each animal via a previously implanted suprapubic catheter. Kruskal-Wallis and pairwise separate rank multiple comparison tests were performed with a significance level of 0.05. The cut and intact slings increased leak point pressure similarly and these values were significantly higher than that of the sham sling (24.9 and 27.9 cm H2O, respectively, vs 20.7, p <0.0001). Peak micturition pressure was not significantly different among the 3 groups, indicating absent bladder outlet obstruction in the sling groups. Bladder compliance was significantly decreased 6 weeks after placement of a cut or intact sling compared with the sham sling (p = 0.007 and 0.05, respectively). An intact suburethral portion is not a requirement for sling effectiveness in the rat model of stress urinary incontinence. However, the sling procedure decreases bladder compliance. This may explain the observed voiding dysfunction associated with sling procedures.

Expression of CD44 and E-cadherin cell adhesion molecules in hypertrophied bladders during chronic partial urethral obstruction and after release of partial obstruction in rats

Objectives To determine the functional changes in the bladder and the expression of adhesion molecules in bladder tissue during chronic partial urethral obstruction and after release of partial obstruction in rats. Methods Twenty-one male Sprague-Dawley rats were separated into three groups, each containing 7 rats. A sham operation was performed in group 1 and cystometry was done 6 weeks later. In groups 2 and 3, hypertrophied unstable bladders were developed by partial infravesical outflow obstruction during a 6-week period. After this period, cystometry was performed in all group 2 rats. In group 3, the ligature was removed, the rats were followed up for 6 weeks, and then cystometry was performed. After cystometric evaluation, the bladders in all the rats were removed, weighed, and studied immunohistopathologically. Results After release of infravesical outflow obstruction, the bladder weight, residual volume, bladder capacity, maximal voiding pressure, voiding amplitude, and bladder contraction time decreased and bladder compliance increased in group 3 compared with group 2. CD44 and E-cadherin expression in the interstitial space and uroepithelial bladder tissue in group 2 rats stained intensely compared with those of groups 1 and 3. Conclusions After release of 6 weeks of infravesical outflow obstruction, the cystometric parameters were significantly improved. Expression of CD44 and E-cadherin in the obstructed bladder tissue may be a pathologic sign of inflammation.

EFFECTS OF CHRONIC PARTIAL OUTLET OBSTRUCTION ON BLOOD FLOW AND OXYGENATION OF THE RAT BLADDER

Experimental partial bladder outlet obstruction in rats and rabbits drives the bladder through 3 sequential responses, referred to as hypertrophy, compensation and decompensation. The hypertrophy phase, which is a period of rapid bladder growth, has previously been shown to be accompanied by a significant increase in bladder blood flow in rats and rabbits in a manner that likely supports the bladder cell growth process. However, chronic periods of obstruction in the rabbit have been shown to reduce significantly bladder blood flow, especially to the detrusor smooth muscle, corresponding with a loss of bladder contractile function or decompensation in these animals. We determined the effects of chronic 1 to 4-week partial outlet obstruction on rat bladder blood flow and directly correlated them with hypoxia in the rat bladder. Rats underwent surgical partial bladder outlet obstruction under anesthesia. At weekly intervals after surgery relative blood flow to the bladder and spleen was measured by a fluorescent microsphere infusion technique. Sham operated rats were also studied 2 and 4 weeks following surgery. In a second experiment groups of similarly obstructed rats were treated with Hypoxyprobe-1 (Natural Pharmacia International, Inc., Research Triangle Park, North Carolina), a chemical probe for hypoxia, 3 days, 1 and 2 weeks after partial bladder outlet obstruction. The bladders were subsequently fixed and immunostained using a monoclonal antibody that detects Hypoxyprobe-1 adducts that are selectively formed in hypoxic cells. Neither bladder weight nor bladder relative blood flow was affected by sham surgery. Likewise, control and sham obstructed rat bladders were found to be free of Hypoxyprobe-1 reactive areas. In contrast, obstructed rats had significantly increased bladder weight at all time points. Relative weight of the obstructed rat bladders indicates the response to mild-moderate obstruction. Bladder relative blood flow in obstructed rats was significantly elevated 1 and 2 weeks after partial bladder outlet obstruction but it returned to almost control levels by 3 and 4 weeks. Hypoxyprobe-1 staining demonstrated a sequential transition of hypoxia from bladder mucosa and submucosal regions at 3 days to muscularis and serosal fibroblasts 1 week and finally to smooth muscle cells by 2 weeks after obstruction. In contrast to the rabbit model, global blood flow in the mild-moderate chronically obstructed rat bladder was found to be higher or nearly equivalent to blood flow in unobstructed control rat bladders. However, even in the presence of normal or above normal blood flow focal regions of hypoxia were still observed in obstructed rat bladders and these regions changed with time. These results provide a reason to understand better why rats are more resistant to the onset of bladder decompensation than rabbits and support the concept that hypoxia is involved in bladder remodeling as well as in progressive functional impairment of the bladder after partial bladder outlet obstruction.

ALTERATION OF THE INSULIN-LIKE GROWTH FACTOR SYSTEM OF MITOGENS IN HYPERPLASTIC BLADDERS OF PARAPLEGIC RATS

Smooth muscle cells of the bladder retain the ability to proliferate in response to injury or mechanical stimulation. Insulin-like growth factor (IGF) I is a mitogenic and hypertrophic agent for smooth muscle cells. The purpose of this study is to examine if spinal cord injury could lead to bladder hypertrophy via the IGF system. The study involved spinal cord transection of female Sprague Dawley rats (approximately 250 to 300 gm.). Six weeks following surgery the urinary bladder was collected. Northern and Western blotting, and IGF-I receptor (IGF-IR) affinity labeling were used to determine the expression of the IGF system, IGFBP levels, and IGF-IR levels respectively. Chronic spinal cord injury leads to an increase in the wet weight of the bladder and in the level of proliferation cell nuclear antigen expression. IGF-I mRNA levels increase, while IGFBP 3 and 5 mRNA and protein levels dramatically decrease. The gene expression of IGFBP 2 and 4 varies from rat to rat, and IGF-IR expression slightly increases. Our results suggest that following spinal cord injury, overexpression of IGF-I and underexpression of IGFBP 3 and 5 may lead to hyperplasia of the smooth muscle layer of the bladder.

EXPERIMENTAL BLADDER INSTABILITY FOLLOWING BLADDER OUTLET OBSTRUCTION IN THE FEMALE RAT

Purpose In rats, urethral obstruction was previously shown to lead to detrusor instability, but bladder instability in conscious animals has not been well characterized. The present study was designed to describe the consequences of bladder outlet obstruction on urodynamic parameters in the conscious rat. A categorization of different types of bladder instability in conscious rats is described. Materials and Methods Cystometry was performed on conscious animals with chronically implanted lines. Recordings of the micturition pattern and the bladder pressure during the micturition cycle were made from normal female rats and those with instability caused by infravesical outflow obstruction. Results In control rats, the peak micturition pressure was low (45.6 +/− 2.5 cm. H 2 O) and only small pressure fluctuations occurred before or after micturition. Rats with outlet obstruction exhibited bladder hypertrophy, high micturition pressure (95.5 +/− 6.8 cm. H 2 O) as well as marked spontaneous activity throughout the micturition cycle. According to the spontaneous activity profile we identified four main patterns of abnormal micturition cycles. Conclusion Urethral obstruction in rats leads to a significant increase in bladder weight and to altered micturition patterns which reveal clear similarities with features of the cystometric profiles performed in men with infravesical outflow obstruction. These modifications are not consistently correlated with an increase in bladder weight.

Experimental bladder instability following bladder outlet obstruction in the female rat.

In rats, urethral obstruction was previously shown to lead to detrusor instability, but bladder instability in conscious animals has not been well characterized. The present study was designed to describe the consequences of bladder outlet obstruction on urodynamic parameters in the conscious rat. A categorization of different types of bladder instability in conscious rats is described. Cystometry was performed on conscious animals with chronically implanted lines. Recordings of the micturition pattern and the bladder pressure during the micturition cycle were made from normal female rats and those with instability caused by infravesical outflow obstruction. In control rats, the peak micturition pressure was low (45.6+/-2.5 cm. H2O) and only small pressure fluctuations occurred before or after micturition. Rats with outlet obstruction exhibited bladder hypertrophy, high micturition pressure (95.5+/-6.8 cm. H2O) as well as marked spontaneous activity throughout the micturition cycle. According to the spontaneous activity profile we identified four main patterns of abnormal micturition cycles. Urethral obstruction in rats leads to a significant increase in bladder weight and to altered micturition patterns which reveal clear similarities with features of the cystometric profiles performed in men with infravesical outflow obstruction. These modifications are not consistently correlated with an increase in bladder weight.

Evaluation of the role of neurokinins and urecholine hypersensitivity in an animal model of infravesical outflow obstruction

Objectives. To determine whether detrusor muscle strips from a male rat with infravesical outflow obstruction model demonstrate supersensitivity to parasympathomimetic and neurokinin NK-1 and NK-2 selective agonists. Methods. Bladder instability developed after 6 weeks of partial urethral obstruction. The micturition frequency and voided volume were determined in unanesthetized animals. Detrusor hypertrophy was confirmed by evaluation of bladder weight. In vitro organ bath was used to compare the affinity and maximal activity of bethanechol and neurokinin NK-1 and NK-2 selective agonists on strips from the detrusor muscle of sham and obstructed rats. Bethanechol, N-Ac[Arg 6, Sar 9, Met(O 2)]-SP(6-11), and [β-Ala 8]-NKA(4-10) were used to characterize cholinergic muscarinic, neurokinin NK-1 and NK-2 receptors. Results. No significant differences in affinities and maximal responses were found using 10-mg detrusor muscle strips with each of the three agonists. Conclusions. Bladder instability produced by outlet obstruction does not involve changes in the affinity or maximal activity of cholinergic muscarinic, neurokinin NK-1 and NK-2 receptors. Furthermore, detrusor supersensitivity to neurokinins or bethanechol was not seen. This suggests that bladder instability is not due to an increased affinity or maximal response to neurokinins or parasympathomimetics.

Inhibitory Effects of BUP-4 on the Bladder Instability in Rats Induced by Infravesical Outflow Obstruction

Inhibitory Effects of BUP-4 on the Bladder Instability in Rats Induced by Infravesical Outflow Obstruction

Angiotensin II and bladder obstruction in the rat: influence on hypertrophic growth and contractility.

The mechanisms and mediators of hypertrophic growth secondary to infravesical urinary outflow obstruction are unknown. The renin-angiotensin system has been implicated in vascular and cardiac hypertrophy, but the involvement of angiotensin II (ANG II) as a trophic factor in the lower urinary tract has not been investigated. In this study, the ANG II subtype AT1 receptor antagonist losartan (DuP 753) was administered perorally (15 mg.kg-1.day-1) for 28 days to rats subjected to partial urethral obstruction or sham surgery. Partial urethral obstruction caused a 3.5-fold increase in bladder weight and a 3-fold increase in bladder protein content compared with sham rats. However, no difference was observed in bladder weight or bladder protein content between losartan-treated rats and rats receiving no drug. Cystometric evaluation of bladder function revealed significant increases in micturition volume, bladder capacity, bladder compliance, and spontaneous contractile activity in rats subjected to partial urethral obstruction compared with sham rats. However, bladder function in rats treated with losartan was not different from bladder function in rats receiving no drug. In vitro studies of isolated bladder tissue showed a weak contractile response to ANG II (1 microM) that amounted to 4.4 +/- 1.0% of the response to K+ (124 mM). The ANG II-induced contraction was abolished by losartan (10 microM) and indomethacin (10 microM). The contractile response to ANG II (1 microM), K+ (124 mM), and transmural nerve stimulation (2 Hz) was reduced in bladder strips from obstructed rats. In conclusion, no evidence was found for involvement of ANG II in development of bladder hypertrophy. The effect of ANG II on bladder smooth muscle tone was minor but was mediated by stimulation of the AT1 subtype receptor.

A rat model for investigation of spinal mechanisms in detrusor instability associated with infravesical outflow obstruction.

A rat model of infravesical outflow obstruction was modified to allow cystometric investigation in conscious, free-moving animals after intrathecal drug administration. The catheter position and extent of drug distribution were controlled by injection of dye and dissection of the spinal canal. Continuous cystometries were performed in awake normal rats as well as rats with bladder hypertrophy and hyperactivity following infravesical outflow obstruction. In some animals of each group, cystometry was performed with simultaneous recording of intra-abdominal pressure. The possible effects of the presence of the intrathecal catheter were studied, as well as the effects of saline, local anesthetics, morphine and naloxone administered through the catheter. Neither the presence of the intrathecal catheter nor injection of saline affected the cystometric pattern. Bupivacaine (50 micrograms) produced paralysis of both lower extremities and a complete, though reversible, suppression of micturition in normal rats. In rats with hypertrophy, intrathecal bupivacaine in doses of 50 micrograms and 100 micrograms produced decreases in micturition pressure, increases in bladder capacity and dribbling incontinence. However, the amplitude of spontaneous contractile activity increased after the administration. The inhibitory effects of morphine (0.5-10 micrograms) on micturition in normal rats, which were rapidly reversed by naloxone, were in accordance with results obtained in previous studies in anesthetized animals. Rats with bladder hypertrophy showed a similar response to morphine and naloxone. However, the bladder hyperactivity was not inhibited by morphine. We conclude that the present model seems reliable for the study of spinal mechanisms in the development of detrusor instability associated with infravesical outflow obstruction.

Facilitatory Effect of Vasoactive Intestinal Polypeptide on Spinal and Peripheral Micturition Reflex Pathways in Conscious Rats with and without Detrusor Instability

In unanesthetized, normal rats, and rats with bladder hypertrophy following infravesical outflow obstruction, cystometry was performed to investigate the effects of spinal and peripheral administration of vasoactive intestinal polypeptide (VIP) on micturition. In addition, the direct effects of the peptide on isolated smooth muscle preparations of detrusor and urethra were studied. In normal animals, 10μg. of VIP administered intrathecally as well as intra-arterially close to the bladder, but not intravenously, decreased micturition volume and bladder capacity, and facilitated spontaneous bladder contractions. In animals with bladder hypertrophy, the same dose of VIP intrathecally had similar effects on these three parameters, but the effects of VIP given intra-arterially were less pronounced. VIP given intravenously was ineffective. Hexamethonium 5mg. × kg.−1 given intraarterially did not block the stimulatory effect of VIP 10μg. given intra-arterially to normal animals. VIP had negligible effects on isolated detrusor muscle contracted by carbachol or electrical stimulation, or on urethral preparations contracted by noradrenaline. These results suggest that VIP has a facilitatory action on the micturition reflex at the spinal cord and ganglionic levels.

Effects of oxybutynin, terodiline, and nifedipine on the cystometrogram in conscious rats with infravesical outflow obstruction

The effects of i.v. administration of different drugs utilized in the therapy of detrusor instability have been studied in conscious catheterized female rats with infravesical outflow obstruction induced by partial urethral ligature, in comparison to normal animals. The effects of oxybutynin (1 mg/kg), terodiline (10mg/kg), and nifedipine (1 mg/kg), were evaluated with regard to bladder capacity (BVC) and micturition pressure (MP) both in normal and obstructed rats. The effects on micturition and residual volume, as well as on spontaneous contractile activity representative of bladder instability, were also observed in obstructed rats. In normal animals, terodiline and oxybutynin induced a significant decrease in micturition pressure without changes in BVC. In obstructed rats, these drugs administered at the same doses did not induce any significant change in all the observed parameters. Nifedipine that in normal rats also reduced the MP, in obstructed animals induced an inhibition of bladder instability (about 50%) with no effects on the other cystometrographic parameters.

On the Reversibility of Functional Bladder Changes Induced by Infra Vesical Outflow Obstruction in the Rat

Rats were subjected to infravesical outflow obstruction for six weeks. The bladder function was followed by cystometrical and in vitro investigations and by recordings of micturition pattern before and after removal of the obstruction.Cystometrical investigations showed that outflow obstruction for six weeks induced a bladder instability. Further, in the presence of obstruction the micturition pressure was large as was the bladder capacity and the rats had residual urine. After removal of the obstruction the bladder function rapidly normalized. The bladder instability disappeared within one week, bladder capacity decreased as did the micturition pressure. Moreover, only a minor amount of residual urine was present post-obstruction.In vitro investigation showed that the response to carbachol and to electrical stimulation was similar in normal and obstructed bladders. However, after removal of the obstruction a supersensitivity to carbachol as well as to electrical stimulation had developed. Obstructed bladders showed a markedly decreased response to substance P. The sensitivity to substance P was rapidly enhanced post-obstruction and after four days the response was restored to the control level.The present study shows that the bladder function in rats with infravesical outflow obstruction rapidly normalized after removal of the obstruction. The disappearance of the bladder instability despite the developed supersensitivity to muscarinic receptor stimulation supports the opinion that the bladder instability is not of muscarinic origin. (J. Urol., 143:1026-1031, 1990)

Infravesical outflow obstruction in rats: A comparison of two models

1. 1. A new model of infravesical outflow obstruction was developed in male rats by the repeated s.c. administration of testosterone for 5–15 days (3 mg/kg die). The effects of this treatment which produced a 65% increase of prostate weight (10 days) on bladder voiding was evaluated in urethane anesthetized rats by the transvesical infusion of saline and compared to the cystometric alterations produced by application of a silk ligature at urethral level in female rats (4–8 weeks before) as described by Malmgren et al. (1987a, b). 2. 2. Testosterone-pretreatment for 10 days produced little changes in bladder weight, bladder capacity or amplitude of micturition contraction but determined a marked increase in residual volume, indicating that infravesical outflow obstruction impaired significantly bladder voiding. Furthermore, detrusor instability was observed in the majority of testosterone-treated rats. 3. 3. The participation of an active component to voiding impairment in testosterone-treated rats was suggested by the effect of intravenous prazosin which improved voiding efficiency. 4. 4. In urethra-ligated female rats there was a marked increase in bladder weight which was paralleled by a dramatic alteration in micturition reflex that is marked increase in bladder capacity and residual volume. 5. 5. It is concluded that these two models of infravesical outflow obstruction produce cystometric patterns simulating the urodynamic alterations observed in patients with benign prostatic hyperplasia and are potentially suitable for development of drugs in this field.