Premicturition Contractions Research Articles

Influence of urothelial or suburothelial cholinergic receptors on bladder reflexes in chronic spinal cord injured cats

The effects of intravesical administration of a muscarinic receptor agonist (oxotremorine-M, OXO-M) and antagonist (atropine methyl nitrate, AMN) and of a nicotinic receptor agonist (nicotine) and antagonist (hexamethonium, C6) on reflex bladder activity were investigated in conscious female chronic spinal cord injured (SCI) cats using cystometry. OXO-M (50μM) decreased bladder capacity (BC) for triggering micturition contractions, increased maximal micturition pressure (MMP), increased frequency and area under the curve of pre-micturition contractions (PMC-AUC). Nicotine (250μM) decreased BC, increased MMP, but did not alter PMC-AUC. The effects of OXO-M on BC and PMC-AUC were suppressed by intravesical administration of AMN (50–100μM), and the effects of nicotine were blocked by hexamethonium (1mM). Antagonists infused intravesically alone did not alter reflex bladder activity. However, AMN (0.2mg/kg, subcutaneously) decreased PMC-AUC. 8-OH-DPAT (0.5mg/kg, s.c.), a 5-HT1A receptor agonist, suppressed the OXO-M-induced decrease in BC but not the enhancement of PMC-AUC. These results indicate that activation of cholinergic receptors located near the lumenal surface of the bladder modulates two types of reflex bladder activity (i.e., micturition and pre-micturition contractions). The effects may be mediated by activation of receptors on suburothelial afferent nerves or receptors on urothelial cells which release transmitters that can in turn alter afferent excitability. The selective action of nicotine on BC, while OXO-M affects both BC and PMC-AUC, suggests that micturition reflexes and PMCs are activated by different populations of afferent nerves. The selective suppression of the OXO-M effect on BC by 8-OH-DPAT without altering the effect on PMCs supports this hypothesis. The failure of intravesical administration of either AMN or hexamethonium alone to alter bladder activity indicates that cholinergic receptors located near the lumenal surface do not tonically regulate bladder reflex mechanisms in the SCI cat.

MP19-13 INHIBITION OF 5-ALPHA REDUCTASE AND INDUCTION OF APOPTOSIS OF SEORITAE EXTRACT REDUCED THE PROSTATE WEIGHT AND SUPPRESSED THE PROLIFERATION OF THE PROSTATE IN THE RAT MODEL OF BENIGN PROSTATE HYPERPLASIA.

INTRODUCTION AND OBJECTIVES: In the rat partial urethral obstruction produces bladder hypertrophy and hyperactive voiding. We previously reported that Alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA) glutamatergic receptors are thought to participate in the control of micturition in bladder outlet obstruction (BOO) rats (AUA 2007). To determine the role of AMPA receptors in the development of functional bladder changes after partial urethral obstruction we investigated the effects of chronic administration of CFM-2, a specific AMPA receptor antagonist, on the micturition reflex in conscious BOO rats. METHODS: In female Wistar rats osmotic pump ware implanted just prior to the creation of partial urethral obstruction until 4 weeks after obstruction (0.07mg/kg, or 0.70mg/kg per day). Seven days after the pump was stopped conscious filling cystometry was performed and compared with that in obstructed rats treated with vehicle. Conscious filling cystometry was also compared in sham operated rats treated CFM-2 and vehicle, respectively. RESULTS: Partial urethral obstruction caused a significant increase in bladder weight. However, chronic CFM-2 treatment did not affect bladder weight in obstructed or sham operated rats. In the obstructed/ CFM-2 vs the obstructed/vehicle group chronic treatment with CFM-2 significantly increased bladder capacity and voided volume without changes in voiding efficiency or micturition pressure (Table). However, neither the frequency nor amplitude of premicturition contractions (PMCs: associated with increased activation of sensory nerve endings, resulting in urgency) was not significantly changed chronic treatment with CFM-2. In sham operated rats chronic CFM-2 treatment did not change any parameters (Table). CONCLUSIONS: The results in the current study suggest that BOO causes AMPA receptor mediated alterations in bladder afferent pathways in the rat. However, generations of PMCs have linked to other mechanisms.

MP19-11 EFFECTS OF CHRONIC BLOCKADE OF ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONATE (AMPA) GLUTAMATERGIC RECEPTORS ON NEUROPLASTICITY OF THE MICTURITION REFLEX PATHWAY AFTER PARTIAL URETHRAL OBSTRUCTION IN THE RAT

INTRODUCTION AND OBJECTIVES: In the rat partial urethral obstruction produces bladder hypertrophy and hyperactive voiding. We previously reported that Alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA) glutamatergic receptors are thought to participate in the control of micturition in bladder outlet obstruction (BOO) rats (AUA 2007). To determine the role of AMPA receptors in the development of functional bladder changes after partial urethral obstruction we investigated the effects of chronic administration of CFM-2, a specific AMPA receptor antagonist, on the micturition reflex in conscious BOO rats. METHODS: In female Wistar rats osmotic pump ware implanted just prior to the creation of partial urethral obstruction until 4 weeks after obstruction (0.07mg/kg, or 0.70mg/kg per day). Seven days after the pump was stopped conscious filling cystometry was performed and compared with that in obstructed rats treated with vehicle. Conscious filling cystometry was also compared in sham operated rats treated CFM-2 and vehicle, respectively. RESULTS: Partial urethral obstruction caused a significant increase in bladder weight. However, chronic CFM-2 treatment did not affect bladder weight in obstructed or sham operated rats. In the obstructed/ CFM-2 vs the obstructed/vehicle group chronic treatment with CFM-2 significantly increased bladder capacity and voided volume without changes in voiding efficiency or micturition pressure (Table). However, neither the frequency nor amplitude of premicturition contractions (PMCs: associated with increased activation of sensory nerve endings, resulting in urgency) was not significantly changed chronic treatment with CFM-2. In sham operated rats chronic CFM-2 treatment did not change any parameters (Table). CONCLUSIONS: The results in the current study suggest that BOO causes AMPA receptor mediated alterations in bladder afferent pathways in the rat. However, generations of PMCs have linked to other mechanisms.

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.

An α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate glutamate‐receptor antagonist can inhibit premicturition contractions in rats with bladder outlet obstruction

To explore the possible involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamate-receptors in bladder dysfunction associated with bladder outlet obstruction (BOO), as detrusor overactivity (DO) is common in men with benign prostatic hyperplasia. Proposed mechanisms of DO include the myogenic or neurogenic theory, and the autonomous bladder hypothesis. In rats, BOO produces premicturition contractions (PMCs) that are assumed to be a consequence of inappropriate non-micturition activity during the filling phase. Using pharmacology, we explored the cause of PMCs to provide new insights into DO in humans. BOO was created in female Wistar rats; 6 weeks after obstruction we evaluated them using conscious-filling cystometry. A specific AMPA receptor antagonist, 1-(4'-aminophenyl)- 3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2) was administered intravenously (i.v.) (0.003-3 mg/kg) or intrathecally (i.t.) (0.01-10 microg). The i.v. administration of CFM-2 in rats with BOO significantly decreased the threshold pressure and micturition pressure. The most remarkable findings were that i.v. administration of CFM-2 in rats with BOO significantly and dose-dependently decreased the amplitude and number of PMCs. The highest dose of CFM-2 almost completely eliminated PMCs. The i.t. administration of CFM-2 had no significant effect on PMCs. AMPA receptors have never been suggested as a neural mechanism of bladder dysfunction associated with BOO. Although PMCs in rats with BOO have been assumed to be mainly of myogenic origin, PMCs were suppressed by the i.v. administration of CFM-2. Thus, we think that PMCs have neurogenic components that are linked with AMPA receptors. In the present study, i.v. but not i.t. administration of CFM-2 suppressed PMCs, suggesting peripheral and/or supraspinal sites of inhibitory action of CFM-2 on PMCs.

1353: Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Glutamate Receptor Antagonist can Inhibit Premicturition Contractions in Rats with Bladder Outlet Obstruction

You have accessJournal of UrologyPodium 39, Tuesday, May 22, 2007, 10:00 am - 12:00 pm1 Apr 20071353: Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Glutamate Receptor Antagonist can Inhibit Premicturition Contractions in Rats with Bladder Outlet Obstruction Takeya Kitta, Hidehiro Kakizaki, Hiroshi Tanaka, Hiroshi Sano, Tsuyoshi Furuno, Takahiko Mitsui, Kimihiko Moriya, and Katsuya Nonomura Takeya KittaTakeya Kitta More articles by this author , Hidehiro KakizakiHidehiro Kakizaki More articles by this author , Hiroshi TanakaHiroshi Tanaka More articles by this author , Hiroshi SanoHiroshi Sano More articles by this author , Tsuyoshi FurunoTsuyoshi Furuno More articles by this author , Takahiko MitsuiTakahiko Mitsui More articles by this author , Kimihiko MoriyaKimihiko Moriya More articles by this author , and Katsuya NonomuraKatsuya Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)31567-2AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1353: Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Glutamate Receptor Antagonist can Inhibit Premicturition Contractions in Rats with Bladder Outlet Obstruction." The Journal of Urology, 177(4S), p. 446 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 446 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Takeya Kitta More articles by this author Hidehiro Kakizaki More articles by this author Hiroshi Tanaka More articles by this author Hiroshi Sano More articles by this author Tsuyoshi Furuno More articles by this author Takahiko Mitsui More articles by this author Kimihiko Moriya More articles by this author Katsuya Nonomura More articles by this author Expand All Advertisement Loading ...

Effect of tamsulosin on spontaneous bladder contraction in conscious rats with bladder outlet obstruction: Comparison with effect on intraurethral pressure

We investigated the effect of tamsulosin, an α 1-adrenoceptor antagonist, on bladder function, especially spontaneous bladder contractions before micturition (premicturition contraction), in conscious rats with bladder outlet obstruction induced by partial urethral ligation, and compared the results with the effect on intraurethral pressure response in anesthetized rats. In obstructed rats, the α 1-adrenoceptor antagonists tamsulosin, naftopidil and urapidil and non-selective α-adrenoceptor antagonist phentolamine inhibited premicturition contractions in a dose-dependent fashion. In contrast, yohimbine, an α 2-adrenoceptor antagonist, and atropine, a muscarinic receptor antagonist, hardly inhibited them. Tamsulosin and urapidil showed clearly inhibitory effects on increases in intraurethral pressure induced by phenylephrine, an α 1-adrenoceptor agonist, in the same dose range as that at which they inhibited premicturition contractions, whereas naftopidil required somewhat higher doses to inhibit increases in intraurethral pressure than those at which it inhibited premicturition contractions. In conclusion, premicturition contractions observed in obstructed rats were sensitive to α 1-adrenoceptor antagonists, but not to α 2-adrenoceptor or muscarinic receptor antagonists. Tamsulosin was shown to be effective against both premicturition contraction and intraurethral pressure response in the same dose range in rats. These results partly support the fact that tamsulosin has improved storage symptoms as well as voiding symptoms in patients with lower urinary tract symptoms associated with bladder outlet obstruction by blocking α 1-adrenoceptors.

Participation of endogenous endothelin and ETA receptor in premicturition contractions in rats with bladder outlet obstruction

A relationship between endogenous endothelins and bladder overactivity has recently been suggested, but the related endothelin receptor subtype has not been identified. Here, to evaluate the involvement of endothelin-1 and its receptors in bladder overactivity, we investigated endothelin-1 levels and the expression of its receptors in the bladder of rats with bladder outlet obstruction (BOO), a model for bladder overactivity. We also investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on bladder functions in conscious BOO rats. Partial obstruction of the urethra led to a progressive increase in bladder weight from weeks 1 to 6. Binding assays performed using plasma membranes prepared from these bladders to estimate endothelin receptor density from the maximum [(125)I]endothelin-1 binding showed increased endothelin receptor density (about double) at 1, 2, and 6 weeks after the operation in the BOO bladder. The densities of endothelin ET(A) receptors in the bladder of sham-operated and BOO rats at 2 weeks after operation were about 3.5 and 5 times those of endothelin ET(B) receptors respectively. Furthermore, the endothelin-1 level was also increased in the BOO bladder. Two weeks after operation, BOO rats showed an increase in maximum bladder capacity and micturition volume and the generation of premicturition contractions. The frequency of premicturition contractions was dose-dependently reduced by YM598 (0.1-3 mg/kg, i.v.) without any effect on other voiding parameters in BOO rats. These data suggest that endothelin-1 and endothelin ET(A) receptors might be involved in the generation of premicturition contractions in BOO rats, and that endothelin ET(A) receptor antagonists such as YM598 may have ameliorating effects in patients with bladder overactivity associated with BOO.

Suppression of bladder reflex activity in chronic spinal cord injured cats by activation of serotonin 5-HT1A receptors

The effects of 8-OH-DPAT (5-HT1A receptor agonist) and WAY100635 (5-HT1A receptor antagonist) on reflex bladder activity were investigated in alpha-chloralose anesthetized or conscious chronic spinal cord injured cats. The results were similar in both anesthetized and conscious animals. Cystometrograms revealed that 8-OH-DPAT (0.5 mg/kg, s.c.) significantly increased the bladder volume threshold for eliciting a large amplitude micturition contraction, but only slightly reduced the amplitude of the contractions and did not alter the small amplitude pre-micturition contractions. 8-OH-DPAT also reduced the amplitude of isovolumetric bladder contractions. The inhibitory effect of 8-OH-DPAT was reversed by WAY100635 (0.5 mg/kg) or blocked by pre-treatment with WAY100635. Reflex bladder contractions evoked by tactile stimulation of the perigenital region were not altered by 8-OH-DPAT. These results suggest that the inhibitory effect of 8-OH-DPAT is mediated by an action on interneuronal pathways in the spinal cord or on the C-fiber afferent limb of the spinal micturition reflex and not on bladder smooth muscle or the efferent limb of the reflex pathway. Drugs that activate 5-HT1A receptors might be useful in treating detrusor overactivity after spinal cord injury.

1446: Participation of Endothelin Eta Receptors in Pre-micturition Contractions in Rats with Bladder Outlet Obstruction

1446: Participation of Endothelin Eta Receptors in Pre-micturition Contractions in Rats with Bladder Outlet Obstruction

Twenty-four-hour ambulatory urodynamics in healthy young men

To describe normal natural fill urodynamics in young men during normal and increased fluid intake. Thirty healthy males aged 21-32 years volunteered for an ambulatory urodynamic 24 h investigation with a suprapubic catheter. The recorded micturition data were: frequency (f), voided volume (VV), voiding time, maximal flow rate (Qmax) and time to Qmax. The number of sensed and not-sensed bladder contractions, duration and time in relation to voiding were also recorded. During the recording day subjects were randomized to normal (30 ml/kg body weight per day) or larger (60 ml/kg body weight per day) fluid intake. As expected there was a larger urine production and an increased voiding frequency in the fluid-loaded group (p<0.0001). The detrusor pressure (Pdet) Qmax was significantly higher in the fluid-loaded group (73 cmH2O, range 57-94) than in the normal fluid intake group (60 cmH2O, range 45-86) (p=0.003). No other urodynamic data differed significantly between the two groups. When comparing the ambulatory urodynamic data with previously obtained home flowmetry recordings from the same volunteers differences were only found in voiding frequency. The majority of participants had detrusor contractions, felt and unfelt, during the filling phase. Three types of detrusor activity during voiding phase could be described: type 1, with one micturition contraction, type 2, with several small contractions before micturition, and type 3, with large prolonged contractions leading to micturition. Ambulatory urodynamics in normal young men showed a large interindividual variation. Bladder contractions during filling were frequently recorded, and premicturition contractions were consistently found. The data found in this study were similar to previous home flow recordings in the same group.

Effects of Chronic Blockade of N-Methyl-D-Aspartate Receptors by MK-801 on Neuroplasticity of the Micturition Reflex Pathway After Partial Urethral Obstruction in the Rat

To determine the role of N-methyl-D-aspartate (NMDA) glutamatergic receptors in the development of functional bladder changes after partial urethral obstruction we investigated the effects of repeat injection of MK-801, a noncompetitive NMDA receptor antagonist, on the micturition reflex in conscious obstructed rats. In 9 female Wistar rats 1.0 mg/kg MK-801 was injected intramuscularly once weekly just prior to the creation of partial urethral obstruction until 5 weeks after obstruction. Five to 7 days after the last injection of MK-801 conscious filling cystometry was performed and compared with that in 9 obstructed rats treated with vehicle (saline). Conscious filling cystometry was also compared in 9 and 7 sham operated rats treated with repeat injection of MK-801 and vehicle, respectively. Partial urethral obstruction caused a significant increase in bladder weight. However, chronic MK-801 treatment did not affect bladder weight in obstructed or sham operated rats. In the obstructed/MK-801 vs the obstructed/vehicle group chronic treatment with MK-801 significantly increased bladder capacity (2.29 +/- 0.12 vs 1.73 +/- 0.16 ml, p <0.01) and voided volume (2.00 +/- 0.10 vs 1.56 +/- 0.17 ml, p <0.05) without changes in voiding efficiency (87.5% +/- 1.6% vs 87.8% +/- 1.7%) or micturition pressure (55.8 +/- 2.3 vs 56.4 +/- 3.0 cm water). Interestingly neither the frequency nor amplitude of premicturition contractions during filling was different in the groups. In sham operated rats chronic MK-801 treatment did not change bladder capacity, voided volume, voiding efficiency or micturition pressure significantly. The results in the current study suggest that bladder outlet obstruction causes NMDA receptor mediated alterations in bladder afferent pathways in the rat.

Effect of Preemptive Treatment of Capsaicin or Resiniferatoxin on the Development of Pre-micturition Contractions After Partial Urethral Obstruction in the Rat

Neuroplasticity in afferent pathways, including C-fiber bladder afferents, is believed to be one of the major causes of changes in bladder function after partial urethral obstruction. We determined if capsaicin sensitive C-fiber bladder afferents are involved in the development of pre-micturition contractions after partial urethral obstruction in the rat. Female Wistar rats were preemptively treated with capsaicin (100 mg/kg subcutaneously) or resiniferatoxin (0.3 mg/kg subcutaneously) prior to the creation of obstruction. Before and 6 weeks after obstruction micturition profiles were compared among the 3 groups, including obstructed rats preemptively treated with capsaicin (BO/CAP) or resiniferatoxin (BO/RTX) and untreated obstructed rats (BO/-). In addition, conscious filling cystometry was performed after obstruction. Instillation of capsaicin solutions into the eye or bladder induced significant irritative reactions in BO/- but not in BO/CAP or BO/RTX, indicating that the effect of pretreatment with capsaicin or resiniferatoxin lasted 6 weeks. Voided volume per micturition on micturition profiles was decreased after partial urethral obstruction in all 3 groups. On conscious filling cystometry a significant increase in bladder capacity, voided volume and micturition threshold pressure was noted in BO/CAP but not in BO/RTX compared with BO/-. In contrast, there was no significant change in residual volume, voiding efficiency or micturition pressure among the 3 groups. The prevalence of pre-micturition contractions was 100% in BO/CAP and BO/RTX, and 83% in BO/-. Capsaicin sensitive C-fiber afferents are not essential to induce pre-micturition contractions but they are involved in functional alterations in bladder afferent pathways after partial urethral obstruction in rats.

Micturition and Premicturition Contractions in Unanesthetized Rats with Bladder Outlet Obstruction

The cholinergic and purinergic neurotransmission involved in micturition contraction and premicturition contractile activity (bladder hyperactivity) were investigated by continuous cystometry in unanesthetized rats with outlet obstruction. Adenosine triphosphate (ATP), administered intraarterially close to the bladder, produced rapid, phasic dose-dependent increases in bladder pressure and micturition immediately after the injections. The percentage volume expelled was 74 ± 9% after 5 mg./kg. Intra-arterial α,β-methylene ATP also produced a rapid, phasic increase in bladder pressure and micturition immediately after the injection. The percentage volume expelled was 96 ± 3% after 1 mg./kg.; the residual volume of the following voidings increased, and the micturition pressure tended to decrease. However, dribbling incontinence was not produced. The amplitude of the premicturition contractions decreased significantly (p <0.01) after the administration. Intraarterial carbachol produced rapid, longlasting dose-dependent increases in bladder pressure and micturition. The percentage volume expelled was 88 ± 4 after 5 Mg./kg. Bladder capacity and micturition volume decreased significantly (p <0.05) during the following spontaneous voidings. Intra-arterial atropine (1 mg./kg.) increased bladder capacity (p <0.01) and residual volume (p <0.01), and tended to decrease micturition pressure (by 25%) and micturition volume. However, micturition contractions still remained after the injection, even if they changed appearance, and were of shorter duration. Atropine had no effect on the premicturition contractions. In the presence of atropine, α,β-methylene ATP initially produced a rapid, phasic increase in bladder pressure with micturition. Then, dribbling incontinence was observed in 1 of 5 animals.Hexamethonium, administered intra-arterially in doses producing urinary retention and dribbling incontinence (20 or 40 mg./kg.), increased the amplitude of the premicturition contractions, but decreased the frequency of the contractions. Intra-arterial tetrodotoxin (15 μg./kg.) inhibited micturition, and produced dribbling incontinence in all animals tested (n = 6). However, the amplitude of the premicturition contractions was not suppressed. Intra-arterial (±)-pinacidil (0.2 mg./kg.) significantly (p <0.05) decreased both amplitude and frequency of these contractions.It is concluded that both cholinergic and purinergic transmission seem to be of importance for pressure generation and emptying of the bladder in rats with outlet obstruction. The present results also give further support for the view that the premicturition contractions seen in these animals are of myogenic origin.