Voiding Pressure Research Articles

Antenatal urodynamic studies in the fetal lamb: experimental protocol and preliminary results.

To set up a fetal lamb model for intrauterine fetal urodynamic studies. Fourteen fetal lambs underwent placement of a bladder catheter at a mean gestational age of 87 days. Three fetuses also had a partial urethral obstruction by the simultaneous placement of a peri-urethral constricting ring. Urodynamic and ultrasound studies were performed weekly by the filling cystometry method. Hundred and six voiding cycles were recorded during 25 urodynamic studies between 84- and 133-days gestation. All voiding profiles were biphasic with a mean duration of 4.2 min (range 1-10), a mean voiding pressure of 23 cm of water (range 7-33) and a mean periodicity of 19.2 min (range 11-50). The obstructed animals had bladder overactivity. This correlated with ultrasound and post-mortem findings of megacystis and bilateral hydroureteronephrosis. The fetal mortality rate was 85.7% and the mean duration of survival post surgery was 45 +/- 5.7 days. Serial urodynamic studies could be performed in a fetal lamb model. Following partial urethral obstruction, bladder overactivity was observed.

Murine in vitro whole bladder physiology.

The function of the bladder is twofold: 1) to store urine at low pressure, and 2) under control of the nervous system, to generate a contractile force coordinated with a lowered urethral resistance that allows for emptying.20 Clinically, this system is most commonly affected by bladder outlet obstruction, and the response of the detrusor is remarkable in its variability. Experimentally, most investigators agree that after outlet obstruction, there is an increase in bladder mass seen irrespective of the model used. Within most experimental models of partial obstruction (as with humans), there exists a degree of variability in terms of detrusor response. Some bladders enter a state of compensation and are able to sustain elevated voiding pressures and empty satisfactorily. Others enter a state of decompensation and lose their ability to empty effectively.15 The molecular mechanisms for such decompensations are under current investigation, and may involve alterations in cytosolic calcium handling,19,21 disruptions in mitochondrial function,4 and changes in the expression of contractile filaments.1 In the late stages, as the bladder slides into the decompensated state, major depositions of extracellular matrix are seen in a variety of species.3,9,11

Botulinum toxin treatment of urethral and bladder dysfunction.

Botulinum toxin (BTX) is the most lethal naturally occurring toxin known to mankind. Injection of BTX into the urethral sphincter or bladder is an effective treatment for lower urinary tract dysfunction. We reviewed the literature on the mechanisms of action and clinical efficacy of BTX treatment in urologic diseases, with a focus on lower urinary tract dysfunction. Injection of BTX is safe and effective in the treatment of detrusor-sphincter dyssynergia, non-neurogenic pelvic floor spasticity, and refractory overactive bladder. Urodynamic assessment after sphincter injection with BTX reveals a decrease of bladder voiding pressure, urethral pressure profile, and post-void residual urine. An increase of the functional bladder capacity and a decrease of the bladder voiding pressure can be seen after bladder injection with BTX. Clinical improvement was found in a moderate percentage of treated patients in most reported series and lasted for 3 to 14 months without significant adverse effects. In addition, BTX-A treatment inhibits afferent-nerve-mediated bladder contraction. This analgesic effect may expand the application of BTX in the localized genitourinary tract pain syndrome, such as interstitial cystitis and prostatodynia. In conclusion, application of BTX is a promising treatment for lower urinary tract dysfunction with profound basic and clinical implications.

Role of protein kinase C in central muscarinic inhibitory mechanisms regulating voiding in rats

To evaluate the role of protein kinase C in central muscarinic mechanisms regulating voiding, cystometry was performed in conscious rats. Oxotremorine methiodide, a muscarinic agonist was injected i.c.v. in a dose (0.1 μg/rat) shown previously to alter voiding function. Oxotremorine methiodide was also tested after i.c.v. injection of chelerythrine chloride (a protein kinase C inhibitor, 2 μg/rat) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, a protein kinase inhibitor, 5 nmol/rat). In untreated rats, oxotremorine methiodide elicited a bimodal response consisting of an initial increase in bladder capacity, maximal voiding pressure, pressure threshold and post voiding intravesical pressure, but reduced voiding efficiency and bladder compliance. The second response consisted of a decrease in bladder capacity and bladder compliance, increases in maximal voiding pressure and post voiding intravesical pressure, but no change in pressure threshold or voiding efficiency. However, approximately 20 min after pre-treatment with chelerythrine chloride or H-7 in doses that did not alter voiding function, oxotremorine methiodide decreased bladder capacity, increased maximal voiding pressure, but did not change pressure threshold or voiding efficiency. These results indicate that inhibitory and facilitatory muscarinic mechanisms in the brain that control voiding function involve different second messenger systems. Inhibitory mechanisms which are blocked by chelerythrine chloride or H-7 must involve protein kinase C and normally be inactive because the protein kinase inhibitors alone did not alter voiding. On the other hand, facilitatory muscarinic mechanisms which previous studies showed were tonically active are not mediated by chelerythrine chloride or H-7 sensitive signaling pathways.

Functional Role of Central Muscarinic Receptors for Micturition in Normal Conscious Rats

Antimuscarinic agents, which are used in to treat urgency and urge incontinence, have well-known effects on peripheral muscarinic receptors. However, some currently used drugs may have effects on muscarinic receptors in the brain and/or spinal cord involved in voiding control. We tested if muscarinic receptors within the central nervous system mediate a tonic excitatory influence on voiding in rats and if these receptors can be differently influenced by antimuscarinic drugs. The effects on cystometrography of intracerebroventricular atropine, oxybutynin, tolterodine and darifenacin were investigated in normal conscious rats. Atropine (0.2 to 2 nmol.) dose dependently affected urodynamic parameters. At 2 nmol. in 6 rats the drug decreased voiding pressure (p <0.01), and increased bladder capacity (p <0.001), voided volume (p <0.05) and post-void residual volume (p <0.05). In 6 rats oxybutynin (6 to 40 nmol.) given at a dose of 6 nmol. caused no change in cystometric parameters, while at 20 nmol. the drug decreased voiding pressure (p <0.01). Tolterodine (2 to 20 nmol.) dose dependently changed urodynamic parameters, while at 20 nmol. in 6 rats the drug decreased voiding pressure (p <0.01) and increased bladder capacity (p <0.05) and voided volume (p <0.05). Darifenacin given at a dose of 20 nmol. in 6 rats caused no change in cystometric parameters. Muscarinic receptor mechanisms in the central nervous system mediate a tonic excitatory influence on voiding in rats, while nonsubtype selective antimuscarinic drugs may have an inhibitory effect on these mechanisms.

Immunoneutralization of Nerve Growth Factor in Lumbosacral Spinal Cord Reduces Bladder Hyperreflexia in Spinal Cord Injured Rats.

We investigated the effects of intrathecal application of nerve growth factor (NGF) antibodies (Ab) on bladder hyperreflexia in chronic spinalized rats. In adult female rats an intrathecal catheter was implanted at the level of the L6 to S1 spinal cord, followed by complete transection of the Th8 to 9 spinal cord. At 10 days after spinalization the intrathecal catheter was connected to an osmotic pump for continuous delivery of vehicle or NGF Ab (10 microg daily) for 2 weeks. Awake cystometry was then performed. NGF levels in the L5 to S1 dorsal root ganglia, L6 spinal cord and bladder were also measured using enzyme-linked immunosorbent assay. The number of uninhibited bladder contractions per voiding cycle, maximal pressure of uninhibited bladder contraction and maximal voiding pressure were significantly decreased in NGF Ab treated versus vehicle treated spinalized rats. Intercontraction interval, baseline intravesical pressure, pressure threshold for voiding and voiding efficiency were not significantly changed by NGF Ab treatment. NGF levels in the bladder, L6 spinal cord and L5 to S1 dorsal root ganglia of vehicle treated spinalized rats was 1.6 to 4.8 times higher than in spinal cord intact rats. After intrathecal NGF Ab treatment NGF levels were significantly lower in the L6 to S1 dorsal root ganglia (30% to 35%) and L6 spinal cord (53%) but not in the bladder or L5 dorsal root ganglia compared with levels in vehicle treated spinalized rats. Increased levels of NGF in the bladder, spinal cord and dorsal root ganglia were associated with bladder hyperreflexia after spinal cord injury. Immuno-neutralization of NGF in the spinal cord suppressed NGF levels in the L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, and also suppressed bladder hyperreflexia. Thus, suppression of NGF levels in afferent pathways could be useful for treating bladder hyperreflexia associated with spinal cord injury.

Effects of Selective β2 and β3-Adrenoceptor Agonists on Detrusor Hyperreflexia in Conscious Cerebral Infarcted Rats

We evaluated the effects of beta-adrenoceptor agonists on detrusor hyperreflexia in cerebral infarcted rats. To produce cerebral infarction in Sprague-Dawley rats the left middle cerebral artery was occluded by introducing a monofilament nylon thread into the artery. In sham operated rats the same artery was exposed but not occluded. After these operations cystometric and cardiovascular experiments were performed with no anesthesia or restraint. After the operation bladder capacity was significantly decreased and voiding pressure was significantly increased in cerebral infarcted but not in sham operated animals. The difference in cerebral infarcted and sham operated rats was significant for each parameter (p <0.01). Post-void residual urine volume was not affected in either group. In the cerebral infarction group intravenous administration of CL316243 ([R,R]-5-2-[[2-(3-chlorophenyl-2-hydroxyethyl]-amino]propyl] -1,3-benzodioxole-2,2-dicarboxylate) (Kissei Central Laboratories, Hotaka, Japan) a selective beta3-adrenoceptor agonist, significantly increased bladder capacity at 10 and 100 microgram./kg. without affecting voiding pressure or post-void residual urine volume. Procaterol, a selective beta2-adrenoceptor agonist, significantly increased bladder capacity and post-void residual urine volume at 10 microgram/kg. intravenously without affecting voiding pressure. In separate experiments procaterol (1 to 100 microgram./kg. intravenously) decreased mean blood pressure and increased heart rate in a dose dependent manner. In contrast, the effects of CL316243 (0.1 to 100 microgram./kg. intravenously) on mean blood pressure and heart rate were minimal. These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects. If the current results hold true in humans, selective beta3-adrenoceptor agonists may prove useful for treating detrusor hyperreflexia associated with cerebral infarction.

Modulation of Insulin-Like Growth Factor-I System of The Bladder Using a Somatostatin Analogue in Chronic Spinalized Rats

We have previously reported the possible role of the insulin-like growth factor-I (IGF-I) system of mitogens in the development of detrusor smooth muscle hyperplasia and hypertrophy after spinal cord injury. We evaluated the in vivo effects of the anti-growth factor somatostatin analogue octreotide on the IGF-I system as well as subsequent changes in bladder smooth muscle hypertrophy and function after spinal cord injury in rats. Included in this study were 90 adult female Sprague-Dawley rats weighing 200 to 250 gm. Of the rats 18 served as sham operated controls, while the remaining 72 underwent were spinal cord transection at the level of the T10 vertebra. The spinalized animals were randomly divided into 4 equal groups of 18, of which 1 group served as paraplegic controls. The other 3 groups received octreotide (60 microgram. daily for 4 weeks) delivered via a subcutaneously implanted osmotic pump immediately, 2 and 4 weeks after spinal cord injury. At the end of the experiment (6 to 8 weeks) each group of animals was subdivided into 2 subgroups of 9. In the first group filling cystometrography was done, while in the second subgroup wet bladder weight was estimated and Northern blot analysis was performed. Mean wet bladder weight plus or minus standard deviation in sham operated and paraplegic controls was 0.11 +/- 0.01 and 0.64 +/- 0.33 gm., respectively (p <0.05). The increase in bladder weight in paraplegic controls was associated with over expression of the IGF-I gene and with marked suppression of IGF binding proteins-3 and 5 compared with sham operated controls. On the other hand, mean wet bladder weight in the animals that received octreotide immediately after spinal cord injury was 0.17 +/- 0.02 gm., which was associated with a dramatic decrease in IGF-I gene expression and increased expression of IGF binding proteins-3 and 5. Mean cystometric bladder capacity in paraplegic controls was 0.48 +/- 0.18 ml. with an associated voiding pressure of 71 +/- 13 cm. water. All paraplegic controls showed detrusor hyperreflexia. In animals that received octreotide immediately after spinal cord injury mean cystometric bladder capacity was 2.49 +/- 1.75 ml. with an associated voiding pressure of 32 +/- 7 cm. water. Detrusor hyperreflexia disappeared in 88.89% of the rats in this group. There were less marked changes in bladder weight (mean 0.24 and 0.29 +/- 0.3 gm.), IGF-I gene expression and its binding proteins and urodynamic parameters when the drug was given 2 and 4 weeks, respectively, after spinal cord injury. Modulating the IGF-I system of mitogens in detrusor smooth muscle with consequently decreased bladder hypertrophy and improved urodynamic behavior in spinal cord injured animals using somatostatin analogue could be a possible therapeutic modality in patients with spinal cord injury.

Displacement sequence and elastic properties of anterior prostate/urethral interface during micturition of spinal cord injured men

The management of complex micturition problems frequently encountered in patients with spinal cord injury (SCI) may be facilitated by characterization of the elastic properties of the prostate. To this end, we have developed a method of evaluating changes in prostate biomechanics using ultrasound (US) images obtained during routine diagnostic urodynamic evaluations. Ultrasound video sequences of the prostate and urethra during voiding were digitized simultaneously with bladder pressure measurement on 76 patients with spinal cord injury, having a mean age of 47 ± 16 years. Computer enhancement of the bladder/prostate/urethral interface from sequences of 2-D US images facilitated measurement of midprostatic urethral displacement during micturition. Of 76 patients, 21 were able to initiate voiding. Maximum urethral diameter was 12.0 ± 1.3 mm, with corresponding maximum voiding pressure of 61.6 ± 1.9 cmH 2O. Urethral/prostatic pressure strain elastic modulus (Ep) was 960 ± 624 N/m 2 and stiffness (β) calculated as the inverse of compliance was 2.8 ± 0.1. The diameter of the urethra at P det50+, during the opening phase, was 0.4 ± 0.1 mm and, during the closing phase, was 0.7 ± 0.1 mm. During voiding, the anterior prostate was displaced to a greater extent than the posterior prostate. These observations suggest that distension of the prostate/urethra during micturition is hysteretic and nonuniform and indicates regional differences in compliance within the prostate/urethra interface. These regional differences lend support to the concept that the posterior prostate is implicated in the active process of micturition involving the fibromuscular stroma. Clinical application of this method could include quantification of the biomechanics of micturition consequent to spinal injury, prostatic enlargement, and the impact of targeted evaluation of pharmacological interventions. (E-mail: ceconst@leland.stanford.edu)

Effects of Zd6169 And Zd0947, 2 Potassium Adenosine Triphosphate Channel Openers, on Bladder Function of Spinalized Rats

The use of K+ channel openers is emerging as an attractive possibility for treating bladder overactivity. We tested the efficacy of the 2 adenosine triphosphate dependent K channel openers ZD6169 and ZD0947 on detrusor hyperreflexia after spinal cord injury in rats. Included in this study were 72 adult Sprague-Dawley rats. Six animals served as normal controls, while 66 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm detrusor hyperreflexia, while another 12 served as control paraplegics. For each drug 24 animals were used and divided into 2 equal groups of 12. Group 1 received the drug in a dose of 3 mg./kg. daily, while group 2 received a dose of 0.3 mg./kg. daily. Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury. Three weeks after spinal cord injury detrusor hyperreflexia developed in all control paraplegic animals with a mean bladder capacity plus or minus standard deviation of 0.7 +/- 0.2 ml. and a mean voiding pressure of 59 +/- 14.2 cm. water. Detrusor hyperreflexia resolved in 66% of the animals that received ZD6169 for 1 week at either dose. For example, mean bladder capacity was 2.5 +/- 1.8 versus 1.8 +/- 1.2 ml. and mean voiding pressure was 42.1 +/- 15.9 versus 43.2 +/- 21.4 cm. water in animals that received 3 versus 0.3 mg./kg. daily, respectively. All animals that received a dose of 3 mg./kg. ZD0947 daily for 1 week showed no detrusor hyperreflexia with a mean bladder capacity of 2.7 +/- 1.8 ml. and mean voiding pressure of 34 +/- 8.5 cm. water, while at 0.3 mg./kg. daily 83% showed no detrusor hyperreflexia with a mean bladder capacity of 2.5 +/- 2.0 ml. and a mean voiding pressure of 41.5 +/- 13.8 cm. water. Each drug produced better urodynamic results when given for 2 weeks. ZD6169 and ZD0947 are effective treatment for detrusor hyperreflexia after spinal cord injury and they may provide alternative treatment options for overactive bladder. Each drug has time and dose dependent response effects that reflect their wide range of efficacy. However, ZD0947 shows an efficacy profile that is relatively superior to that of ZD6169.

Effect of Oral Kohki Tea on Bladder Dysfunction Induced by Severe Partial Outlet Obstruction

Extracts of the leaves of Engelhardtia chrysolepis, a subtropical plant that grows wild in southern China, have been used medicinally in east Asia for hundreds of years. A standard extract named Kohki tea (Maruzen Pharmaceuticals, Onomichi City, Japan) is sold over the counter in Japan as a sweet tea shown to confer many beneficial effects on general health and well-being. The tea contains strong antioxidants, including several dihydroflavonol glycosides. The results of previous studies show that natural products with antioxidant activities provide protective effects on the bladder of rabbits with partial outlet obstruction. We determined in vivo and in vitro whether oral pretreatment of rabbits with Kohki tea protects the bladder from dysfunction induced by partial outlet obstruction. A total of 28 New Zealand White rabbits were separated into 4 groups of 7 each. Rabbits in groups 1 and 2 were treated by gavage with 100 mg./kg. Kohki tea daily in distilled water, while those in groups 3 and 4 were given distilled water. After 4 weeks of daily oral administration each rabbit was sedated, the bladder was catheterized and cystometry was performed at a filling rate of 1 ml. per minute. At the completion of cystometry the rabbits were immediately anesthetized. Moderate outlet obstruction was created in groups 1 and 3, and sham surgery was performed in groups 2 and 4. Treatment was continued for an additional 4 weeks, when each rabbit was sedated and cystometry was repeated. After cystometry the bladder was exposed through a midline incision, excised, weighed and 4 strips of bladder body were cut for contractility studies. The balance of the bladder was separated between smooth muscle and mucosa by blunt dissection, frozen in liquid nitrogen and stored at -70C for biochemical analyses. Partial outlet obstruction stimulated similar increases in the bladder weight of all obstructed rabbits. Partial outlet obstruction resulted in a significant decrease in bladder compliance in all obstructed animals. However, the bladder of obstructed rabbits given Kohki tea were significantly more compliant than those given water. Voiding pressures in the control group and the obstructed group given distilled water were approximately equal, while obstructed rabbits given Kohki tea showed significantly higher maximal voiding pressure. The contractile responses to all forms of stimulation were reduced by obstruction to a significantly greater degree in the rabbits not given tea than in those given tea. Sarcoplasmic reticulum Ca2+-adenosine triphosphatase enzyme activity of the bladder was significantly reduced in obstructed rabbits given vehicle but activity was not reduced in obstructed rabbits given Kohki tea. Kohki tea had a significant protective effect on bladder function, contractile responses and bladder biochemistry in rabbits with moderate to severe partial outlet obstruction.

Effect of Bilateral Hypogastric Nerve Transection on Voiding Dysfunction in Rats with Spinal Cord Injury

We determined if bilateral section of the hypogastric nerves (HGN), which provide the major sympathetic input to the urinary bladder neck/proximal urethra, could improve voiding by reducing urethral resistance in conscious, female spinal-cord-injured (SCI) rats 2–3 weeks after T7–9 transection of the spinal cord. Cystometry was performed in animals with HGN intact and with HGN sectioned bilaterally 1–2 h before the experiment. Residual volume (RV), volume threshold for inducing micturition (VT), maximal voiding pressure, and bladder compliance were significantly lower (71, 35, 33, and 31%, respectively) in SCI rats with sectioned HGN than in rats with intact HGN, whereas voided volume (VV), pressure threshold for micturition, and bladder contraction duration (BCD) in the two groups were similar. Voiding efficiency (VE) in the HGN-sectioned group was 36% greater than that in the HGN-intact group. Antagonists for AMPA and NMDA glutamatergic receptors (LY215490 and MK-801, respectively) were administered to rats with sectioned HGN, to determine if activity in the HGN contributes to the previously reported inhibitory effects of these drugs, on voiding function after SCI. MK-801 (3 mg/kg iv) significantly reduced VV (75%) and VE (85%) and increased RV (8-fold), VT (87%), and bladder compliance (60%), whereas LY215490 (10 mg/kg iv) significantly increased VT and BCD by 15 and 19%, respectively. It is concluded that bilateral section of HGN reduces voiding dysfunction in the SCI rat but does not alter the effects of AMPA and/or NMDA glutamatergic receptor antagonists on the micturition reflex in the SCI rat. Thus the effects of these drugs are not dependent on changes in activity of sympathetic axons in the HGN.

Role Of Supraspinal α1-Adrenoceptors For Voiding In Conscious Rats With And Without Bladder Outlet Obstruction

Previous studies have shown that spinal alpha1-adrenoceptors can influence voiding in normal rats and in rats with outlet obstruction. Also, at the supraspinal level such receptors may be involved in voiding control. Therefore, we studied in rats the effects on cystometrography of intracerebroventricular administered alpha1-adrenoceptor antagonists. Continuous cystometry was performed in conscious, freely moving rats with and without bladder outlet obstruction. Cystometric parameters were evaluated before and after intracerebroventricular drug administration. In normal rats intracerebroventricular administration of 8 nmol. kg.-1 prazosin (Pfizer Central Research, Sandwich, United Kingdom) or terazosin (Abbott Laboratories, Abbott Park, Illinois) (nonsubtype selective) caused no change in cystometric parameters. At 24 or 80 nmol. kg.-1 the 2 drugs significantly decreased voiding pressure and increased bladder capacity, voided volume and post-void residual urine volume. Administering vehicle had no effect. In rats with outlet obstruction the drug effects were significantly more pronounced than in normal animals (p <0.05), and urinary retention was produced in 50% of rats receiving prazosin. In normal rats the selective alpha1A-adrenoceptor antagonists KMD 3213 (0.8, 8 and 24 nmol. kg.-1) dose dependently depressed voiding pressure, and increased bladder capacity and voided volume, whereas BMY 7378 (selective for alpha1D-adrenoceptors) and A322312 (selective for alpha1B-adrenoceptors) at doses up to 80 nmol. kg.-1 had no effect. The results suggest that in normal rats and in rats with outflow obstruction volume induced bladder activity involves supraspinal alpha1-adrenoceptors. Bladder outlet obstruction seems to enhance the importance of these receptors. At least in normal rats the alpha1A-adrenoceptor subtype seems to mediate the effect.

Connexins 43 and 26 Are Differentially Increased after Rat Bladder Outlet Obstruction

To evaluate the regulation of connexin expression by fluid pressure, we have studied the effects of elevated transmural urine pressure on Connexin43 (Cx43) and Cx26. We chose to focus on these two proteins out of the five connexins (Cx26, 43, 40, 37, and 45) which we found by RT-PCR to be expressed in the rat bladder, since in situ hybridization and immunofluorescence showed that Cx43 is the predominant connexin expressed by smooth muscle cells (SMC), whereas Cx26 is abundantly expressed only in the latter cell type. To evaluate whether these connexins are affected by changes in transmural urine pressure, we used a rat model of bladder outlet obstruction, in which a ligature is placed around the urethra. Under conditions of increased fluid pressure due to urine retention, we observed that the expression of both Cx43 and Cx26 increased at both transcript and protein levels, reaching a maximum 7–9 h after the ligature. Further analysis revealed that these changes were accounted for by a fourfold increase in Cx43 mRNA of SMC but not urothelial cell and by a fivefold increase in Cx26 mRNA of urothelium. Scrape-loading of propidium iodide showed that the latter change was paralleled by a twofold increase in coupling between urothelial cells. The data show that Cx43 and Cx26 are differentially regulated during bladder outlet obstruction and contribute to the response of the bladder wall to increased voiding pressure, possibly to control its elasticity.

BLADDER FUNCTION IN HEALTHY NEONATES AND ITS DEVELOPMENT DURING INFANCY

Bladder function in healthy neonates and its development during infancy are described. Results of free voiding studies of healthy neonates and infants using 4-hour voiding observation and urodynamics studies were reviewed. According to these studies, voiding in the healthy neonate is characterized by small, frequent voids of varying volume in the individual case and interrupted voiding in 30% of the cases. Interrupted voiding is clearly an immature phenomenon since it is seen in 60% of preterm neonates and disappears completely before the age of toilet training. These voidings are considered to be due to a dyscoordination between the sphincter and detrusor, which has also been observed on urodynamic studies and which probably also explains incomplete emptying seen in this age group. Emptying remains incomplete to the age of toilet training when residual urine is median 0 ml. during 4 hours of observation. Voiding rarely occurs during quiet sleep even in the neonatal period, when signs of arousal are often noted before voiding. However, voiding during sleep in 60% occurs of preterm infants, indicating that it may be due to maturation of the central nervous system. Bladder instability is rarely seen in healthy neonates and infants according to urodynamic studies but hyperactivity is suggested in the neonatal bladder with premature voiding contractions after only a few milliliters of filling and with leakage of urine. This latter phenomenon probably explains the low cystometric bladder capacity in this age group. High voiding pressure levels also accompany this low bladder capacity. Thus, it can be suggested that the neonatal bladder is regulated by neuronal pathways with connections to the cerebral cortex in the neonatal period, which is contrary to the earlier concept of voiding as an automatic event in response to a constant volume in the bladder. This theory does not mean that voiding is conscious or voluntary in this age group, but only that the voiding reflex disturbs the neonate. New characteristics include the concept of physiological dyscoordination, such as hyperactivity of the detrusor seen as low bladder capacity, and high voiding pressures in the neonatal period.

High-pressure bladder: an underlying factor mediating renal damage in the absence of reflux?

To assess urodynamic studies of children with nonrefluxing pyelonephritis, investigate the possible connection between renal damage (as approximately 40% of children with febrile urinary tract infections and no evidence of vesico-ureteric reflux have irreversible renal cortical scarring) and lower urinary tract dysfunction, to test the hypothesis that bladders with high storage and voiding pressures may be the cause of renal damage in these patients. The clinical records and urodynamic studies of 52 children (46 girls and six boys, mean age 6.6 years) with febrile urinary infections, no evidence of reflux and photopenic areas on renal scintigraphy were evaluated retrospectively. Each child was evaluated by urinary ultrasonography, a voiding cystogram, 99mTc-dimercaptosuccinic acid (DMSA) scan and urodynamic studies. The storage phase of the urodynamic study was divided into two equal segments to consider the filling variables of each. During the emptying phase, voiding pressures and voiding pressures with reference to peak detrusor contraction were evaluated. Despite no child having reflux, the DMSA scans showed bilateral renal scarring in 39 (75%) and unilateral scarring in the remaining children. Forty-eight (93%) children had abnormal urodynamic values: high filling pressures (34), high-pressure uninhibited contractions (32), high voiding pressures (31) and discoordinated voiding (28). The cystometric bladder capacity was lower than the expected bladder capacity (- 75 mL) in 82% of the patients; in only four patients were the urodynamics considered normal. Most children with renal scarring and no reflux had lower urinary tract dysfunction. Common findings include high storage and voiding pressures, and discoordinated voiding. These findings suggest that abnormal bladder dynamics play a role in the development of renal scars that occur in the absence of reflux.

TEST-RETEST VARIATION OF PRESSURE FLOW PARAMETERS IN MEN WITH BLADDER OUTLET OBSTRUCTION

We assess short-term (5 to 10 minutes) and long-term (24 weeks) test-retest changes of repeated pressure flow examinations. The pressure flow charts of 84 patients with benign prostatic enlargement and bladder outlet obstruction who had received either androgen suppressive therapy or placebo were reviewed retrospectively. Pressure flow examinations were performed at baseline, and at weeks 24 and 48. Each pressure flow session included 3 sequential voids. Median detrusor opening pressure, maximum detrusor pressure, detrusor pressure at maximum flow rate and minimum voiding pressure decreased statistically significantly from void 1 to 2, ranging from 9.5% to 15.8%. From void 2 to 3 during the same pressure flow session there was a further reduction in obstruction parameters. Median Abrams/Griffiths number was 10.7% lower at void 2 compared to void 1 (p <0.0001) and the urethral resistance algorithm was 3.2% lower (p <0.0001). Long-term test-retest changes from baseline to week 24 and from week 24 to week 48 for the pressure flow parameters studied were negligible. Changes in pressure flow parameters at short-term test-retesting are considerable and probably of clinical significance. The standard pressure flow nomograms, which are based on single void pressure flow studies, might need modification when applied to repeat void studies.

Bladder functional outcome after delayed vesicostomy closure and antireflux surgery in young infants with 'primary' vesico-ureteric reflux.

To evaluate bladder function by conventional urodynamic investigations in young infants with primary vesico-ureteric reflux (VUR) who had undergone an initial temporary cutaneous vesicostomy followed by later antireflux surgery and vesicostomy closure. From 1983 to 1990, nine boys (10-360 days old) with primary VUR were treated with an initial vesicostomy, followed by delayed closure of the vesicostomy and the simultaneous surgical correction of reflux. Severe VUR was detected bilaterally in seven and unilaterally in two infants at the time of the initial diagnosis. The mean (SD, range) age at vesicostomy was 12.4 (8, 3-23) months and the duration of bladder defunctionalization 38.7 (25.5, 18-90) months. All patients were assessed urodynamically after closing the vesicostomy, using rapid-fill cystometry with normal saline solution at room temperature. The mean (range) age at the time of urodynamic testing was 7.3 (5-15) years; the mean (SD, range) follow-up was 10.1 (4.1, 5-17) years. Six boys with bilateral VUR underwent successful ureteroneocystostomy; nephroureterectomy was required in one patient. In two patients the VUR resolved with time. After re-functionalization, the mean (SD, range) maximum cystometric capacity, expressed as a percentage of the mean bladder capacity for age, was 1.4 (0.5, 0.6-2.2)%. In three patients the bladder capacity was higher (> or = 40%) than expected for age, while one had diminished (< 70%) bladder capacity. The mean (range) end-filling detrusor pressure was 14.5 (5-42) cmH2O and the mean (SD, range) compliance 24 (13.9, 4-44) mL/cmH2O. Two patients had a compliance of < 10 mL/cmH2O, one of whom had associated unstable detrusor contractions of 90 cmH2O. The mean (SD, range) detrusor voiding pressure at peak flow was 47.3 (16.8, 5-76) cmH2O. One patient had a residual urine volume of 8% of bladder capacity. At the follow-up, only one patient (aged 5 years) with detrusor instability had urinary incontinence. This study shows that the bladder of young infants with primary VUR treated with temporary vesicostomy regained normal function after re-functionalization of the lower urinary tract.

Effect of different 5-hydroxytryptamine receptor subtype antagonists on the micturition reflex in rats.

To evaluate the effects of antagonists of different subfamilies of 5-hydroxytryptamine (5-HT) receptors on bladder function in anaesthetized and conscious rats. MATEERIALS AND METHODS: The urinary bladder of female anaesthetized rats was catheterized urethrally and filled with physiological saline until spontaneous bladder contractions occurred. Infravesical pressure was measured by a pressure transducer and displayed continuously on a chart recorder. The time of bladder quiescence (to the disappearance of rhythmic contractions) after injection with different compounds tested was recorded. Conscious rats underwent cystometry with chronically (infravesical) implanted catheters to continuously record bladder capacity (evaluated as amount of saline infused between voiding cycles) and maximal voiding pressure. The affinity for the human recombinant serotoninergic 5-HT1A subtype (inhibition of specific binding of [3H]8-hydroxy-2-(di-n-propylamino) tetralin) and the effects on the [35S]guanosine 5'-(gamma-thio) triphosphate (GTPgammaS) binding in HeLa cells was also evaluated. Among the compounds tested, only 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethyl-piperazine (p-MPPI) and methiothepin showed nanomolar affinity for the 5-HT1A receptors, the former being a neutral antagonist and the latter an inverse agonist in the [35S]GTPgammaS binding model. Intravenous injection of low doses of p-MPPI and methiothepin induced a dose-dependent disappearance of isovolumic bladder contractions in anaesthetized rats (> 10 min). At the highest doses, the dose-response curves were bell-shaped. The amplitude of bladder contractions was not markedly altered. The tested antagonists of 5-HT2, 5-HT3, 5-HT4, and 5-HT6 serotoninergic subtypes were poorly active or inactive in the model. Similarly, these compounds were inactive on cystometry in conscious rats, whereas p-MPPI and methiothepin induced a consistent increase in bladder capacity. Methiothepin also decreased the voiding pressure, whereas p-MPPI did not affect this variable. These findings confirm that only selective 5-HT1A receptor antagonists have favourable effects on the bladder, inducing an increase in bladder capacity with no derangement of bladder contractility.

AVALIAÇÃO URODINÂMICA DE PACIENTES CHAGÁSICOS

No presente trabalho estudou-se a fisiologia urinária de pacientes com Doença de Chagas nas suas diversas formas. Grupo A (controle) com 21 indivíduos normais; Gupo B: 16 pacientes com sorologia positiva; Grupo C: com 16 pacientes com cardiopatia chagásica e Grupo D: 21 pacientes com esofagopatia e/ou megacolon chagásicos. Os resultados mostraram que não houve diferenças significantes (p &gt; 0,05) entre os 4 grupos estudados para os parâmetros: capacidade cistométrica, pressão de micção e fluxo urinário. Entretanto, houve diferenças significantes (p &lt; 0,05) para os parâmetros: pressão abdominal, pressão do detrusor, pressão uretral e tempo de micção na análise comparativa entre o grupo D e o controle A. Esses achados sugerem que a Doença de Chagas, em sua forma digestiva, também pode comprometer o trato urinário baixo, alterando sua fisiologia.