Search

Objectives: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex. Methods: In urethane‐anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM‐3 (CO donor) or ZnPP (non‐selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABAA receptor antagonist) or SCH50911 (GABAB receptor antagonist) on the CORM‐3‐induced response. Results: CORM‐3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single‐voided volume and bladder capacity without affecting MVP, post‐voided residual volume, or voiding efficiency. The ZnPP‐induced ICI shortening was reversed by CORM‐3. The CORM‐3‐induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively. Conclusions: Brain CO can suppress the rat micturition reflex through brain γ‐aminobutyric acid (GABA) receptors. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo Zuzhi Gongcheng Yanjiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel β3‐adrenoceptor agonist approved for the treatment of overactive bladder. However, how β3‐adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease. Methods: In a rat model of Parkinson's disease induced by unilateral 6‐hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity. Results: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter‐contraction interval (p <.05) and reduced voiding pressure (p <.01). However, no significant effects on urethral function were observed. Conclusions: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of β3‐adrenoceptor agonists. [ABSTRACT FROM AUTHOR]

Objective: The present study investigated the inhibitory effects of a novel minimally invasive implanted tibial nerve stimulation device on non-nociceptive bladder reflexes in cats. Materials and methods: A wireless minimally invasive implanted nerve stimulator was implanted adjacent to the left tibial nerve in seven cats. Multiple cystometrograms (CMGs) were obtained to determine the inhibitory effects of tibial nerve stimulation (TNS) at different frequencies and intensities on the micturition reflex by infusing normal saline (NS). Results: TNS at 6 Hz did not significantly change the bladder capacity (BC) compared to the control level at the intensity threshold (T), while TNS significantly (P < 0.05) increased the BC to 158.89 ± 20.57% of the control level at 2 T. When stimulated at 15 Hz, TNS did not significantly (P > 0.05) change the BCs at 1 T and 2 T. Conclusions: The minimally invasive implanted TNS device was shown to be effective in inhibiting the micturition reflex under physiologic conditions. Further studies are warranted to determine the inhibitory effects of TNS on nociceptive bladder reflexes. [ABSTRACT FROM AUTHOR]

Aim: Brain nitric oxide (NO) have been reported in regulation of the sympatho‐adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3‐(4‐morpholinyl)sydnonimine, hydrochloride (SIN‐1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho‐adrenomedullary system and on brain N‐methyl‐D‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptors in urethane‐anesthetized (0.8 g/kg, ip) male Wistar rats. Methods: Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN‐1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN‐1 administration or intracerebroventricular pretreatment with other drugs. Results: SIN‐1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN‐1, 0 µg] and 54.9% [SIN‐1, 250 µg] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.59]) without affecting plasma noradrenaline or maximal voiding pressure. SIN‐1 (250 µg/animal) reduced single‐voided volume and bladder capacity without affecting post‐voiding residual volume. The SIN‐1 (250 µg/animal)‐induced adrenaline elevation and ICI reduction were attenuated by 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide, sodium salt (carboxy‐PTIO) (NO scavenger, icv) (ICI values; 44.7% [vehicle + SIN‐1] and 77.5% [carboxy‐PTIO + SIN‐1] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.51]). Acute bilateral adrenalectomy abolished SIN‐1‐induced adrenaline elevation, while showed no effect on the SIN‐1‐induced ICI reduction. The ICI reduction was attenuated by MK‐801 (NMDA receptor antagonist, icv) (ICI values; 47.0% [vehicle + SIN‐1] and 87.6% [MK‐801 + SIN‐1] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.61]), but not by DNQX (AMPA receptor antagonist, icv). Conclusion: Brain NO is involved in facilitation of the rat micturition reflex through brain NMDA receptors, independently of the sympatho‐adrenomedullary outflow modulation. [ABSTRACT FROM AUTHOR]

Objectives: To identify the types of serotonin (5‐hydroxytryptamine) receptors of the prefrontal cortex related to the micturition reflex. Methods: Female Sprague–Dawley rats and a microinjection method were used for this study. Stainless steel guide cannulas were implanted bilaterally into the prefrontal cortex, and a polyethylene catheter was inserted into the bladder. Cystometric parameters (intercontraction interval and maximum voiding pressure) were measured before and after injection of any one of six specific antagonists of 5‐hydroxytriptamine receptors (5‐hydroxytryptamine 1A, 5‐hydroxytryptamine 2A, 5‐hydroxytryptamine 2C, 5‐hydroxytryptamine 3, 5‐hydroxytryptamine 4 and 5‐hydroxytryptamine 7) into the prefrontal cortex. The prefrontal cortex was divided into two regions, namely the prelimbic cortex and the infralimbic cortex. The experiments were carried out in conscious and free‐moving rats. Results: The intercontraction interval value increased significantly after injection of the 5‐hydroxytriptamine 2A receptor antagonist, MDL11939, into the prelimbic cortex of the rat prefrontal cortex (7.68 ± 1.28 vs 9.02 ± 1.41 min, P < 0.05), whereas the intercontraction interval value decreased significantly after injection of the 5‐hydroxytriptamine 7 antagonist SB269970 into the prelimbic cortex (9.42 ± 0.39 vs 8.14 ± 0.71 min, P < 0.05). The intercontraction interval was unaffected by injection of either of these two antagonists into the infralimbic cortex. The other four antagonists (5‐hydroxytryptamine 1A, 5‐hydroxytryptamine 2C, 5‐hydroxytryptamine 3 and 5‐hydroxytryptamine 4) had no effect on the intercontraction interval after injection into the prelimbic cortex and the infralimbic cortex. The maximum voiding pressure was unaffected by injection of any one of the six 5‐hydroxytriptamine antagonists into the prelimbic cortex and infralimbic cortex. Conclusions: In the rat prefrontal cortex5‐hydroxytryptamine 2A receptors excite the micturition reflex, whereas 5‐hydroxytryptamine 7 receptors inhibit this reflex. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine if the duration of the micturition reflex modulation could be prolonged by repeated periods of afferent stimulation in the decorticated rat. Methods: Eighteen female Sprague‐Dawley rats were used for the study, 10 for intravesical electrical stimulation (IVES), and 8 for Ano‐genital pudendal afferents stimulation. Repeated constant flow cystometries were performed with body‐warm saline (0.06‐0.1 mL/min) at about 10 min interval. The selected afferents were stimulated continuously for 5 min at maximal intensity. The same stimulation was repeated six times with a pause of 5 min between the stimulations. The mean threshold volume of cystometries performed during one hour before and each hour after the stimulation were compared. Results: After six periods of IVES, the micturition threshold volume decreased to its lowest value (62% of control) during the first hour and remained at 80% 4 h later (n = 10, P < 0.01). Ano‐genital afferent stimulation produced a corresponding increase in the micturition threshold volume. The long‐lasting poststimulation effect was again observed for more than 5 h. During the first hour the mean threshold volume increased to 211% of controls and it remained at about this level for the entire observation period (n = 8, P < 0.01). Conclusions: Repeated short periods of stimulation prolonged the modulatory effect well beyond the stimulation period. The findings provide experimental evidence supporting the clinical application of IVES and ano‐genital stimulation for treatment of neurogenic urinary bladder dysfunction. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Kunming Medical University / Kunming Yike Daxue Xuebao is the property of Kunming Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims To investigate the role of the PFC in the micturition reflex using an in vivo microdialysis study in rats. Methods Adult female Sprague-Dawley rats were used and microdyalysis in the PFC and cystometrography (CMG) were performed under consciousness and free movement in the present study. Experiment 1: Samples including extracellular neurotransmitters were collected by microdyalysis and analyzed by high performance liquid chromatography. At the same time, CMG were performed to measure intercontraction interval (ICI) and maximum voiding pressure (MVP). Experiment 2: SSRI (citalopram, 1 µM) was administered into the PFC, and microdyalysis and cystometrography (CMG) were performed simultaneously. Experiment 3: Following SSRI administration, 5-HT1A agonist (8-OH-DPAT, 300 µM), which has the effect of decreasing the level of serotonin (5-HT) in the PFC, was administered into the PFC, and microdyalysis and CMG were performed simultaneously. Results Experiment 1: Extracellular level of 5-HT in the PFC significantly increased during micturition reflex ( P < 0.05), whereas levels of glutamate or dopamine were not significantly changed. Experiment 2: Local administration of SSRI in the PFC increased the 5-HT level up to approximate 600% of the basal level. It also significantly increased ICI ( P < 0.05), whereas no significant change was found in MVP. Experiment 3: The extracellular level of 5-HT gradually decreased after local administration of 5-HT1A agonist, thereby ICI significantly decreased ( P < 0.05). Conclusions The results of the present study suggest that the PFC has a suppressive effect on neural control of the micturition reflex via serotonin. Neurourol. Urodynam. 35:902-907, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives To elucidate the possible involvement of glutamate and serotonin (5-hydroxytryptamine) neurons in the ventrolateral midbrain periaqueductal gray during noxious stimulation. Methods The study was carried out by evoking a noxious stimulation by acetic acid in an animal model of cystitis. Changes in glutamate and 5-hydroxytryptamine in the periaqueductal gray during the micturition reflex and acetic acid-induced cystitis were determined using in vivo microdialysis combined with cystometry in rats. Results Extracellular glutamate levels slightly, but significantly, increased during the micturition reflex induced by saline infusion into the bladder. Intravesical infusion of acetic acid facilitated the micturition reflex characterized by increases in voiding pressure and decreases in the intercontraction interval. Glutamate levels were markedly increased by acetic acid, and this enhancement was sustained for at least 3 h. 5-Hydroxytryptamine levels, which were not altered during the micturition reflex, were increased after intravesical infusion of acetic acid. Conclusion The results suggest that periaqueductal gray glutamate and 5-hydroxytryptamine neurons differentially participate in the modulation of both nociception and the micturition reflex. Furthermore, periaqueductal gray 5-hydroxytryptamine levels appear to reflect the nociceptive stimuli. [ABSTRACT FROM AUTHOR]

Unlabelled: A growing body of evidence suggests that 5-hydroxytryptamine (5-HT; serotonin) has both physiological and pathological functions in the lower urinary tract. A wide variety of 5-HT receptor subtypes are variably expressed in different organs, both peripheral and central. On urinary bladder smooth muscle, 5-HT1A, 5-HT2, 5-HT3, and 5-HT7 subtypes could function as postjunctional receptors. Postjunctional 5-HT2 receptors induce detrusor contraction of the bladder body. 5-HT1A is suggested to have a similar effect to 5-HT2, while 5-HT3 might suppress detrusor contraction evoked by direct muscle stimulation. Postjunctional 5-HT7 is reported to induce relaxation of the bladder neck, which might be required for efficient voiding. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes also could act as prejunctional receptors in autonomic excitatory nerve terminals. 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes facilitate the neurogenic contraction of the detrusor by enhancing cholinergic or purinergic transmission, whereas 5-HT1A receptors might inhibit the release of acetylcholine in the detrusor. Furthermore, 5-HT1D could be involved in the suppression of ATP release from the urothelium, aiding visceral sensation of the urinary bladder. In the central pathways controlling the micturition reflex, 5-HT1A, 5-HT2A, and 5-HT7 are involved in regulation of bladder and urethral sphincter activities. Their functions, especially that of 5-HT1A, vary in a species- and site (spinal or supraspinal)- dependent manner. In addition to urinary bladder, 5-HT could be involved in prostate contraction and cell proliferation. Evidence indicates that 5-HT receptor subtypes may be novel therapeutic targets for lower urinary tract symptoms.Funding: Grants-in-Aid for Scientific Research (C) (KAKENHI 23590707, 24590722, and 26460694) from the Japan Society for the Promotion of Science. [ABSTRACT FROM AUTHOR]

Background and Objectives: Micturition reflex is long been taught as an interplay of autonomic and somatic nervous system. This reflex is expected to vary with bladder-habits, gender and BMI differences but no study supports this theory sufficiently. The objective of this study is to provide evidence for variation in bladder capacity to hold urine by bladder-habits, gender and BMI. Methods: A total of 69 1st year dentistry students (20 males & 49 females) who consented were asked to empty their bladder naturally followed by drinking measured amounts of mineral water in glass-beaker to the level that they would not be able to hold urine any further. They were advised to note down all their feelings during that process as mentioned in the response form. They also accounted their usual bladder-habit of postponing the visit and lastly expressed that they passed urine in presence of favorable or unfavorable condition. Results: Male students due to comparatively greater mean height and weight had significantly higher maximum capacity of bladder to hold urine independent of BMI. Likewise there was gender-wise significant difference in appearance of 1st desire to micturate, discomfort and pain in terms of filling capacity of bladder. Micturition-postponing-behavior did not affect significantly the maximum capacity to hold urine but played significant role on voluntary control of micturition under unfavorable circumstances. Conclusions: Bladder capacity and voluntary control varies with gender and accommodating behavior respectively. This study may help in establishing a data base in our study population and may add to scientific knowledge. [ABSTRACT FROM AUTHOR]

Background and Purpose: Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood.Experimental Approach: We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [(3) H]-ACh overflow experiments.Key Results: Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [(3) H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid.Conclusions and Implications: Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors. [ABSTRACT FROM AUTHOR]

Background and purpose Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood. Experimental approach We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [ 3H]-ACh overflow experiments. Key results Instillation of UDP or PSB0474 into the bladder increased the voiding frequency ( VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [ 3H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid. Conclusions and Implications Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors. [ABSTRACT FROM AUTHOR]

Barrington's nucleus ( BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre-sympathetic output ( PSO) and pre-parasympathetic output ( PPO) neurons in the BN using patch-clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13-L1 and S1-S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A-type K+ currents were significantly larger in PPO than in PSO neurons. Blocking A-type K+ channels increased the excitability more in PPO than in PSO neurons. Stimulting μ-opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABAA receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs. [ABSTRACT FROM AUTHOR]

Increased abdominal muscle wall activity may be part of a visceromotor reflex (VMR) response to noxious stimulation of the bladder. However, information is sparse regarding the effects of cauda equina injuries on the VMR in experimental models. We studied the effects of a unilateral L6-S1 ventral root avulsion (VRA) injury and acute ventral root reimplantation (VRI) into the spinal cord on micturition reflexes and electromyographic activity of the abdominal wall in rats. Cystometrogram (CMG) and electromyography (EMG) of the abdominal external oblique muscle (EOM) were performed. All rats demonstrated EMG activity of the EOM associated with reflex bladder contractions. At 1 wk after VRA and VRI, the duration of the EOM EMG activity associated with reflex voiding was significantly prolonged compared with age-matched sham rats. However, at 3 wk postoperatively, the duration of the EOM responses remained increased in the VRA series but had normalized in the VRI group. The EOM EMG duration was normalized for both VRA and VRI groups at 8-12 wk postoperatively. CMG recordings show increased contraction duration at 1 and 3 wk postoperatively for the VRA series, whereas the contraction duration was only increased at 1 wk postoperatively for the VRI series. Our studies suggest that a unilateral lumbosacral VRA injury results in a prolonged VMR to bladder filling using a physiological saline solution. An acute root replantation decreased the VMR induced by VRA injury and provides earlier sensory recovery. [ABSTRACT FROM AUTHOR]

Urge urinary incontinence (UUI) is a chronic disorder affecting 12 million men and women in the United States alone, and is characterized by involuntary loss of urine associated with urgency. UUI may be associated with detrusor overactivity (DO), which is the occurrence of involuntary detrusor contractions during a urodynamics evaluation. When DO occurs in the setting of known neurologic disease, it is referred to as neurogenic DO. The presence of DO by urodynamics warrants neurological evaluation in patients without known neurologic disease when there is subjective or objective evidence of neurologic disease, or if there is a high index of suspicion for an occult neurologic disorder. [ABSTRACT FROM AUTHOR]

Sex-specific differences in activity of the lower urinary tract (LUT) responding to acid irritation in mice have been revealed. This study, using continuous infusion cystometry with acetic acid (AA; pH 3.0), was conducted to examine whether the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in the mouse LUT are involved in the sex difference in functional responses of the bladder and urethra to irritation. No differences were found between effects of capsazepine (a TRPV1 blocker: 100 µM) and those of its vehicle on any of the cystometric changes by intravesical AA in either female or male mice. However, capsazepine eliminated the acid-induced sex differences in parameters associated with bladder contraction phase (i.e., maximal voiding pressure, closing peak pressure, 2nd-phase contraction, bladder contraction duration), whereas capsazepine did not affect those in parameters associated with bladder-filling period (i.e., intercontraction interval, actual collecting time). In males, capsazepine reduced the number of bladder contractions accompanying fluid dribbling at 2nd-phase contraction, which is indicative of the urethral response to irritation, whereas in females it increased the number. Together, these results suggest the possibilities that TRPV1 channels in the bladder and urethra are involved in the sex difference in the LUT response to acid irritation and that these participate, e.g., via "cross talk" between the bladder and urethra, in the fine-tuning of intravesical pressure (or bladder emptying) at the bladder contraction phase under irritated LUT conditions but not in sensing for bladder filling during the storage period, although the contribution of the mechanism may be small. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate whether activation of brain and spinal cholinergic pathways affects the micturition reflex in rats. MATERIALS AND METHODS The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the micturition reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin. RESULTS Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M1 mAChR antagonist) = atropine > 4-DAMP (an M3 mAChR antagonist) >> methoctramine (an M2 mAChR antagonist) and tropicamide (an M4 mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively. CONCLUSIONS These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the micturition reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M1/M3 receptor subtypes in the brain, while in the spinal cord, the M1/M2 receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways. [ABSTRACT FROM AUTHOR]

Objectives: To record afferent nerve activity and bladder pressure in anesthetized male rats and to investigate whether increased afferent nerve activity induced by nicotine is able to evoke reflex bladder contractions. Methods: Using continuous infusion cystometrography, bladder pressure was measured via a bladder cannula. Afferent activity was recorded in the uncut L6 dorsal root. Nicotine was injected intra-arterially through a cannula placed near the bifurcation of the internal iliac artery a few minutes after micturition. Results: Nicotine (0.15–1.5 µmol) evoked a marked elevation of afferent discharge without a simultaneous increase in bladder pressure. Bladder contractions appeared about 43 and 19 s after bolus injection of nicotine at 0.45 and 1.5 µmol, respectively. Firing rates of afferent nerves were reduced when the contraction appeared. Continuous infusion of nicotine at 0.75 µmol/min for 20 min evoked marked elevation of afferent discharge, which was maintained during infusion of nicotine and after it had been withdrawn. Repetitive contractions were observed thereafter and disappeared when the L6 dorsal roots were bilaterally resected. Conclusions: A transient increase in afferent discharges induced by bolus injection of nicotine was unable to evoke reflex bladder contraction. Repetitive bladder contractions after withdrawal of continuous nicotine infusion were induced in a reflex manner by the increased afferent activity. [ABSTRACT FROM AUTHOR]

We have investigated the effect of intravaginal application of capsaicin on micturition reflex in female rats. Urinary bladder contractility was measured by transurethral pressure recording at isovolumetric and subthreshold conditions in anaesthetized rats. The intravaginal application of capsaicin (15 μg/50 μl rat) induced reproducible bladder phasic contractions, without desensitization upon repeated applications, that were blocked by intravenous atropine (1 mg/kg) or hexamethonium (5 mg/kg) and prevented by removal of paracervical ganglia or systemic capsaicin pretreatment (125 mg/kg, s.c.). The inhibition of sympathetic transmission by guanethidine (30 mg/kg, s.c.) produced significant increase of the bladder reflex contractions activated by intravaginal capsaicin. Intravenous administration of the TRPV1 antagonist, capsazepine (3 mg/kg), significantly reduced the excitatory reflex response to capsaicin. Intravaginal administration of capsaicin (15 μg/50 μl), during distension-induced reflex bladder contractions, produced a transient block of reflexes, unaffected by guanethidine pretreatment. In conclusion, the stimulation of capsaicin-sensitive sensory nerve endings in the rat cervix–vagina induced a dual excitatory or inhibitory bladder response in anaesthetized female rats depending on the degree of bladder distension. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the role of Group I metabotropic glutamate (mGlu) receptor subtypes on reflex-induced micturition in anaesthetized and conscious rats using selective mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) allosteric antagonists. MATERIALS AND METHODS The affinity of the compounds at mGlu1 and mGlu5 receptor subtypes was evaluated by displacement of tritiated R214127 and MPEP, respectively, from rat brain tissue. Effects of intravenous (i.v.) administration of the compounds on isovolumic bladder contractions were evaluated in anaesthetized rats. Effects of MPEP and NPS 2407 on bladder filling and voiding were evaluated by cystometry using saline or diluted (0.2%) acetic acid (MPEP only) infusion of bladders in conscious rats. RESULTS Binding studies confirmed the selectivity of the mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) compounds. Isovolumic bladder contractions were blocked after i.v. administration of all compounds. However, the mGlu5 antagonists were generally more potent than mGlu1 antagonists. In conscious rats with bladders infused with saline, MPEP dose-dependently and significantly increased bladder capacity starting from oral administration of 10 mg/kg. Oral administration of NPS 2407 (up to 30 mg/kg) did not induce consistent changes in bladder capacity or micturition pressure. MPEP (10 mg/kg, orally) was also evaluated in conscious rats with bladders infused with diluted acetic acid. In this model, MPEP reduced bladder instability counteracting the decrease of bladder volume capacity induced by acetic acid. There were no consistent effects on bladder contractility. CONCLUSIONS The results indicate that i.v. and oral administration of selective mGlu5 antagonists, but not those selective for the mGlu1 subtype, have a marked inhibitory effect on reflex micturition pathways in the rat. [ABSTRACT FROM AUTHOR]

The periaqueductal gray (PAG) is critically involved in the micturition reflex, but little is known about the neuronal mechanisms involved. The present study elucidated dynamic changes in dopamine (DA), glutamate and γ-aminobutyric acid (GABA) in the rat PAG during the micturition reflex, with a focus on dopaminergic modulation using in vivo microdialysis combined with cystometrography. Extracellular levels of DA and glutamate increased, whereas levels of GABA decreased, in parallel with the micturition reflex. Application of a D1 receptor antagonist into the PAG produced increases in maximal voiding pressure (MVP) and decreases in intercontraction interval (ICI), suggesting that the micturition reflex was facilitated by D1 receptor blockade. The D1 receptor antagonist prevented micturition-induced decreases in GABA efflux but had no effect on DA or glutamate. Neither a D2 receptor antagonist nor a D1/D2 receptor agonist affected these neurochemical and physiological parameters. Micturition-induced inhibition of GABA was not observed in 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of Parkinson’s disease. 6-OHDA-lesioned rats exhibited bladder hyperactivity evaluated by increases in MVP and decreases in ICI, mimicking facilitation of the micturition reflex induced by D1 receptor blockade. These findings suggest that the micturition reflex is under tonic dopaminergic regulation through D1 receptors, in which a GABAergic mechanism is involved. Bladder hyperactivity observed in 6-OHDA-lesioned rats may be caused by dysfunction of GABAergic regulation underlying the micturition reflex. The present findings contribute to our understanding not only of the neurophysiology of the micturition reflex but also of the pathophysiology of lower urinary tract dysfunction in patients with Parkinson’s disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the role of cyclooxygenase (COX) isozymes (COX-1 and -2) in the regulation of bladder volume capacity (BVC) in several rat urodynamic models, using a selection of nonsteroidal anti-inflammatory drugs (NSAIDs), some selective for COX-2, correlating the potency of the tested compounds in the urodynamic models and their in vitro potency as inhibitors of COX isozymes, to verify the relative importance of the different isozymes. MATERIALS AND METHODS The effects of an i.v. administration of several nonselective and selective COX-2 inhibitors (indomethacin, meloxicam, naproxen, aspirin, paracetamol, flurbiprofen, nimesulide, NS-398, celecoxib, rofecoxib and L 745337) on bladder filling and voiding were evaluated in conscious and anaesthetized rats by cystometry. The cystometry was done in conscious rats 1 day after catheter implantation, by filling the bladder with dilute acetic acid (0.2%) or saline, and again with saline 5 days after catheterization. Effects on isovolumic bladder contractions in anaesthetized rats were also evaluated. RESULTS All the NSAIDs tested dose-dependently increased BVC; their potency at increasing BVC during infusion of the bladder with acetic acid was similar to that evaluated with saline on cystometry 1 day after catheterization. When a nonselective (naproxen) and a selective (nimesulide) COX-2 inhibitor were tested in rats with bladders infused with saline 5 days after catheterization, their effects on BVC were significantly lower than those evaluated at 1 day. All tested compounds dose-dependently inhibited isovolumic bladder contractions in anaesthetized rats. There was a good correlation between the potency in inhibiting the isovolumic bladder contractions in anaesthetized rats and in increasing BVC during cystometry in conscious rats with the bladder infused with acetic acid. The potency of the compounds in the cystometry model with bladders infused with acetic and in the isovolumic bladder voiding contractions correlated well with COX-2 inhibition, but not COX-1. CONCLUSIONS Both nonselective and COX-2 selective inhibitors are more active in inhibiting the micturition reflex in rats with bladder overactivity caused by bladder irritation than in normal rats. The potency of the anti-inflammatory compounds in inhibiting bladder overactivity induced by chemical or surgical irritation, and their activity in a cystometrographic model practically independent of bladder irritation (isovolumic bladder contractions in anaesthetized rats), was related to the potency as inhibitors of COX-2 isozyme. This suggests that the involvement of prostaglandins in the micturition reflex in rats is mainly mediated by this isozyme. [ABSTRACT FROM AUTHOR]

Background: We examined the influence of rectal distention on the spinal micturition reflex and the mechanism underlying its inhibition of bladder contraction. Methods: Fourteen conscious female Sprague-Dawley rats were used in this study after transection of the lower thoracic cord. Isovolumetric cystometry was performed before and after distention of the rectum by inflation of a rectal balloon, followed by intrathecal injection of strychnine (a selective glycine receptor antagonist) or bicuculline (a GABAA receptor antagonist) into the lumbosacral cord. Results: Rectal distention (1.0–3.0 cm3) prolonged the interval, decreased the amplitude, and shortened the duration of bladder contraction, and eventually almost abolished bladder activity. After intrathecal injection of strychnine (0.001–10 μg) or bicuculline (0.001–1 μg) in animals with inhibition of bladder activity by rectal distention, the interval, amplitude, and duration of bladder contraction returned to baseline. Conclusion: These results suggest that there is an inhibitory rectovesical reflex in the lumbosacral cord of rats with spinal cord injury, which modulates the spinal micturition reflex via glycinergic or GABAergic mechanisms. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims To examine the effects of 1-(2-pyrimidinyl)-piperazine (1-PP), a buspirone metabolite, on bladder function in vivo. Methods Micturition reflexes in the rat were evaluated in two models of bladder function; a constant infusion model employing 0.5% acetic acid and an isovolumic model. Results In the constant infusion model, 1-PP (0.14-1.32 mg/kg) dose-dependently and significantly decreased the number of bladder contractions measured during a 30 min recording period, with little effect on the pressure developed during each contraction. 1-PP is an α2-adrenergic receptor antagonist. The α2 antagonists BRL44408 (α2A vs. α2B selective; 0.3 and 1 mg/kg), imiloxan (α2B vs. α2A selective; 1 mg/kg), and yohimbine (non-subtype selective; 1 mg/kg; but not 0.3 mg/kg) also significantly reduced the number of contractions. Vehicle was without effect. In the isovolumic model, 1-PP (0.03-1.0 mg/kg) produced a dose-dependent and significant reduction in the number of bladder contractions recorded during a 15 min assessment period, with the maximum effect observed at 0.3 mg/kg. 1-PP had little effect on blood pressure; the only effect was observed at the highest dose (1 mg/kg) where it produced a transient 17% decrease in pressure. Cromakalim and tolterodine served as comparitors in all studies. Conclusions 1-PP decreased the number of bladder contractions evoked by the micturition reflex at doses that had little effect on either the pressure developed during each bladd er contraction or on blood pressure. The effects of 1-PP are likely mediated primarily by α2 receptor antagonism. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The normal bladder functions, storage and elimination of urine, are dependent on neural circuits in the brain and spinal cord that coordinate the activity of the detrusor and that of the smooth and striated muscles of the outflow region. Disturbances at different levels may cause the overactive bladder (OAB) syndrome, characterized by urge, frequency and urge incontinence. Knowledge about the mechanisms controlling both normal and abnormal micturition is mandatory for the detection of targets for pharmacological intervention. Such targets may be found in the central nervous system (CNS) or peripherally. Several CNS transmitters can modulate voiding, but few drugs with a defined CNS site of action have been demonstrated to be clinically useful. Traditionally, drugs for treatment of OAB have had a peripheral site of action. Antimuscarinics are still the gold standard, but their wellknown side effects have focused interest on other modalities of treatment. Promising preclinical results have been obtained for some principles, but so far there are few positive clinical proof of concept studies available. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether micturition reflexes are altered in aged rats. Voiding frequencies and awake cystometrograms (CMGs) were measured in young (3–5 months old) and aged (24 months) F344 male rats. Bladder contractions induced by subcutaneous apomorphine and intravesical capsaicin stimulation were measured using awake CMGs. Urodynamic parameters were compared. Aged rats voided less frequently (4.1 vs 6.9 times/18 h, P=0.006), with a higher volume per void (1.1 vs 0.7 ml, P=0.02) and had a higher micturitional threshold pressure (8.7 vs 4.6 mmHg, P=0.0001) than the young rats. Apomorphine induced a higher frequency of bladder contractions in aged animals compared to young animals (5.5 vs 3.1 contractions/min, P=0.03). Intravesical capsaicin caused a lower pressure bladder response in the aged rats (38.5 vs 70.6 mmHg, P=0.01) compared to the young rats. Bladder afferents and central micturition pathways may be altered in aged rats. Impaired bladder contractility in the elderly may be exacerbated by reduced sensory input, whereas the propensity for detrusor instability could result from altered central processing. This study demonstrated the utility of the F344 animal model to study micturitional changes resulting from aging. [ABSTRACT FROM AUTHOR]

In order to clarify the role of supraspinal tachykinins in volume-induced micturition and in bladder hyperactivity secondary to bladder outlet obstruction, conscious, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular administration of RP 67,580, a selective antagonist of neurokinin (NK)-1 receptors and/or SR 48,968, a selective antagonist of NK-2 receptors. In normal rats, RP 67,580 or SR 48,968, at a dose of 2 nmol, caused no marked changes in cystometric parameters. Higher doses (up to 20 nmol) caused dose-dependent decreases in micturition pressure and increased bladder capacity, micturition volume and residual urine. A combination of the two drugs, each at a dose of 2 nmol, significantly decreased micturition pressure and increased bladder capacity. In rats with bladder outlet obstruction, the antagonists suppressed micturition dose-dependently, producing urinary retention in two out of eight rats already at a dose of 2 nmol. At a dose of 20 nmol, dribbling incontinence, due to urinary retention, was seen in five out of ten rats. A combination of the two drugs (2 nmol of each drug) caused urinary retention in three out of nine animals and significantly increased bladder capacity, micturition volume and residual volume. The results suggest that outflow obstruction in rats increases the effects of tachykinins in supraspinal structures involved in micturition, and that antagonism of supraspinal NK-receptors may depress the micturition reflex. Whether or not this implies that supraspinal NK-receptors can be targets for drugs aimed for inhibiting bladder hyperactivity in humans should be explored. [ABSTRACT FROM AUTHOR]

The treatment of urinary incontinence by means of electrical stimulation is a physiologic way to handle the problem. When selected afferent nerve fibers within the perineal area are stimulated with appropriate pulse parameters, normally silent, powerful reflex mechanisms are evoked, resulting in inhibitory effect on pathologic bladder overactivity. Vaginal stimulation (utilizing afferents within the clitoral nerves) elicits bladder inhibition by a reflex designed for bladder inhibition during intercourse. Anal electrical stimulation evokes a similar bladder inhibitory reflex via pelvic nerve afferents. Electrical stimulation also improves striated muscle function. Based on the available knowledge of lower urinary tract neurophysiology, indications, methods and modalities are reviewed. [ABSTRACT FROM AUTHOR]

1. The effect of capsaicin on bladder motility in vivo (urethane anaesthesia) and in vitro, plasma extravasation (Evans blue leakage technique) and content of substance P-like immunoreactivity (SP-LI) of the urinary bladder was investigated in various mammalian species. 2. Systemic capsaicin desensitization (rat and hamster, 50 mg/kg s.c. 4 days before; guinea-pig 55 mg/kg s. c. 4-7 days before) increased bladder capacity in rats and guinea-pigs and reduced voiding efficiency in guinea-pigs. All other urodynamic parameters were unaffected in both rats, guinea-pigs and hamsters. 3. Reflex bladder voiding was abolished by spinal cord transection in anaesthetized rats and hamsters. On the other hand, hexamethonium-(20 mg/kg i.v.)sensitive voiding contractions were obtained in response to saline filling 45 min from cord transection in guinea-pigs, indicating a profound interspecies variation in the basic organization of micturition. 4. Exposure to capsaicin (1 μM) produced a contraction of the isolated bladder from rats, guinea-pigs (dome) and mice. Capsaicin produced only a slight contractile response in the guinea-pig bladder base. The motor response to capsaicin of the rat, guinea-pig and mouse bladder exhibited marked desensitization, suggesting a specific effect on sensory nerves. On the other hand, capsaicin (1 μM) produced a slight relaxation of the hamster isolated bladder but this effect was reproducible at 1-2 h intervals, suggesting an unspecific effect. Capsaicin (1-10 μM) did not affect motility of strips from the dome or the base of the rabbit bladder. 5. Intravenously administered capsaicin produced a marked plasma extravasation (Evans blue leakage) in the lower urinary tract of rats, mice and guinea pigs. In rats but not guinea-pigs the reaction in the bladder base was greater than in the dome. In hamsters intravenous capsaicin failed to induce any significant Evans blue leakage in the lower urinary tract. 6. SP-LI was detected in the lower urinary tract of rats, guinea-pigs, rabbits and mice but not hamsters. Bladder SP-LI was depleted by systemic capsaicin desensitization in rats, guinea-pigs and mice. Reverse phase HPLC indicated that all the immunoreactive material co-eluted with authentic substance P or its oxidized form. 7. These findings indicate that noticeable species-related differences exist with regard to the functions mediated by the Capsaicin-sensitive neurons in the urinary bladder. [ABSTRACT FROM AUTHOR]

1. The effect of streptozotocin (STZ) induced diabetes on rat urinary bladder function was investigated by means of 'in vivo' cystometry and 'in vitro' recording of bladder strips contractility. A group of sucrose-fed animals was included to determine to what extent the STZ-induced changes were ascribable to the increased diuresis. 2. After 7-9 weeks from STZ injection there was a marked increase in weight of bladder and ureters. Cystometry revealed a marked increase in bladder capacity (volume threshold) although pressure threshold and amplitude of micturition contraction were unaffected. Sucrose-fed animals, having normal blood glucose levels but a similar increase in urine production exhibited cystometric changes identical to those of STZ animals. 3. 'In vitro' experiments indicated that the response to field stimulation (0.1-20 Hz) is reduced in STZ-pretreated but increased in sucrose-fed animals, as compared to controls. 4. The content of urinary bladder and ureters in sensory neuropeptides (substance-P, neurokinin-A and calcitonin-gene related peptide-like immunoreactivity) was increased by STZ diabetes when values were corrected for the increased weight of these organs. 5. The capsaicin-induced contraction of the rat isolated bladder strips, presumably caused by neuropeptides released from intramural sensory nerves, is unaffected by STZ diabetes. 6. These findings indicate that STZ diabetes produces, at an early stage, changes similar to those reported to occur in the human disease, e. g. a greater bladder capacity with unimpaired voiding function. The increased bladder capacity of STZ-rats seems largely, if not solely, ascribable to changes in physical properties of the detrusor muscle, thereby allowing accomodation of greater than normal volumes with similar increase of intraluminal pressure. No sign of diabetic neuropathy of the capsaicin-sensitive sensory nerves can be observed at this stage (7-9 weeks) of STZ diabetes. [ABSTRACT FROM AUTHOR]