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Unlabelled: It has previously been shown that elocalcitol might protect bladder contractile function in experimental models and that elocalcitol has beneficial effects in patients with LUTS. In humans, elocalcitol was demonstrated with a very good safety profile but only exhibited limited efficacy on LUTS in patients with BPH and overactive bladder (OAB). Recent reports show that therapies with antimuscarinics, when combined with other drugs in clinical use, might perform better than a monotherapy in managing LUTS. It is not known how a combination of elocalcitol and an antimuscarinic performs on bladder dysfunction. The present study suggests that concomitant use of secosteroids and antimuscarinics has additive beneficial effects on obstruction-related functional changes in an experimental model. If confirmed also in a clinical setting, this could allow for individual dose adjustments to improve efficacy in obstruction-related LUTS, and possibly reduce unwanted adverse activities by antimuscarinic therapy., Objective: To evaluate the effects of tolterodine on urodynamics in elocalcitol- or vehicle-treated rats with partial urethral obstruction (PUO)., Materials and Methods: After ethical approval, 20 female Sprague-Dawley rats were subjected to PUO and treated (gavage) for 14 days (once daily) with elocalcitol (75 µg/kg) or vehicle. Cystometries were performed on day 15 in awake rats before and after i.v. administration of tolterodine (1, 10 and 100 µg/kg)., Results: No differences in bladder weights or body/bladder weight ratios were noted between groups. Tolterodine dose-dependently increased micturition intervals and volumes and bladder capacity in both elocalcitol- (n = 11) and vehicle-treated rats (n = 9). In elocalcitol-treated rats, flow pressure (FP) was dose-dependently reduced (12-20%) by tolterodine, whereas no effect on FP was noted in vehicle-treated animals (P < 0.05). Flow compliance (FC) was increased by tolterodine by 21-54% in vehicle-treated rats, and by 47-131% (P < 0.05 vs vehicle) in elocalcitol-treated animals. Maximal tension vs bladder weight was improved in elocalcitol-treated rats in comparison to vehicle (P < 0.05). The area under the curve (AUC) was reduced by tolterodine with 11-16% in vehicle-treated rats and 26-30% in elocalcitol -treated rats (P < 0.05)., Conclusions: Elocalcitol-treatment improved the effects of tolterodine on bladder compliance at the start of flow. The effects of tolterodine on AUC suggest that elocalcitol exerts additional beneficial actions on PUO-induced functional changes during the filling phase of micturition. The reduction of FP and increase in FC by elocalcitol and tolterodine could have translational value and, if valid in humans, support combined therapy in benign prostatic obstruction (BPO)-related lower urinary tract symptoms (LUTS)., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Objective: To study the role of α(2)-adrenoceptors (α(2)-AR) in micturition of anaesthetized male rats, with specific focus on the effects on the electrical activity (by electromyography, EMG) of the rhabdosphincter, and actual urinary flow rate, as the effects mediated by α(2)-ARs on sphincter activity and urethral pressures have not been established., Materials and Methods: Adult anaesthetized male Noble rats were used; intravesical pressure, rhabdosphincter EMG and urinary flow rate from the distal urethra were recorded. After baseline recordings, an α(2)-AR agonist (dexmedetomidine, DEX) or α(2)-AR antagonist (atipamezole), were injected intravenously., Results: DEX treatment significantly decreased the maximum bladder pressure and urinary flow rate, and the amplitude of rhabdosphincter EMG was significantly reduced. Intraluminal pressure high-frequency oscillations, usually observed during rat voiding were abolished. The effects of DEX were fully reversed within 31 min. Atipamezole treatment significantly increased actual urinary flow rates and rhabdosphincter EMG amplitude, but the number of times flow was interrupted was increased during the voiding cycle, leading to increased overall micturition time., Conclusion: Stimulation and blockade of α(2)-ARs have a significant effect on lower urinary tract function. If the data from this rat model are also valid in humans, a study of the effects of atipamezole on urethral sphincter activity and urethral pressures in humans would be of interest, and might show therapeutic potential of the drug., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Objective: To characterize the contractile activity that occurs in the bladder during the filling phase of the micturition cycle (non-micturition contractions, NMCs), which generate transient rises in intravesical pressure not associated with urine flow., Materials and Methods: The experiments were conducted using anaesthetized (chloral hydrate) and un-anaesthetized rats. In un-anaesthetized rats bladder contractile activity was measured using an intravesical cannula implanted under full surgical anaesthesia 3 days previously. In the anaesthetized rats the bladder was exteriorized and a cannula inserted through the dome. In these experiments electrical activity within the detrusor was also measured with a suction electrode on the bladder surface. For each rat, the experimental protocol involved filling the bladder at a constant rate (10 mL/h) to evoke micturition cycles, or infusion of a fixed volume and recording made under effective isovolumetric conditions., Results: In both anaesthetized and un-anaesthetized rats there were transient rises in bladder pressure (0.5-3 cmH2O). In the anaesthetized rats the amplitude of the transients increased throughout the filling phase, with little change in frequency. The phasic NMCs generating these pressure transients were accompanied by electrical changes in the detrusor. In the middle phase of bladder filling the slow pressure changes were accompanied by slow waves of electrical activity which changed in the pressure cycles immediately before micturition to high-frequency low-amplitude signals. In the un-anaesthetized rats there was a period immediately after voiding where there was no activity. As filling proceeded, low-amplitude low-frequency NMCs appeared that gradually increased in frequency and amplitude during the filling phase. However, the frequency of the transients decreased immediately before micturition despite an increase in amplitude. Similar responses were seen during isovolumetric recording., Conclusion: The present results show the presence of NMCs in the rat bladder, identify volume-dependent changes in the pattern of this activity during the micturition cycle, and show that NMCs are accompanied by electrical changes in the detrusor. The physiological significance of NMCs is not known but it might be linked to the generation of afferent discharge from mechanoreceptors in the wall, so contributing to sensations related to bladder volume.

Objective: To investigate the effects of a vitamin D3 analogue (BXL628) in a model of chronic cystitis, as calcitriol analogues might be an interesting new therapeutic option for interstitial cystitis, for although the cause of the disease remains unclear, the increase in mast cells in the mucosa and detrusor muscle are significant., Materials and Methods: We devised a mouse model of allergen-induced allergic cystitis that is associated with the up-regulation of genes for interleukin-13, FcepsilonRIalpha and mast cells-derived proteases, a massive inflammatory reaction in the bladder tissue, and augmented levels of mast cell-derived protease 1 (MMCP1) detected in mouse sera., Results: Oral administration of BXL628 significantly reduced the expression of interleukin-13, FcepsilonRIalpha and MMCP1 in the bladder. Furthermore, histological analysis showed a decrease in oedema and leukocyte infiltration in the bladder wall. BXL628 treatment reduced serum MMCP1 levels, indicating an effect on mast cell degranulation in vivo., Conclusions: Vitamin D3 analogues may successfully be used as anti-inflammatory agents in allergen-mediated inflammatory reactions. Moreover, the modulatory effect shown on mast cell activation by the BXL628 analogue strongly supports its potential therapeutic use in a possibly mast cell-dependent disease such as human interstitial cystitis.

Objectives: To assess in detail the contribution of acetylcholine and ATP to the different phases of the voiding contraction, urine flow and rhabdosphincter electromyographic (RB-EMG) activity in rats, using alpha,beta-methylene-ATP (desensitizing purinoceptors) and atropine (blocking muscarinic receptors). These agents and possibly other transmitters contribute to bladder emptying in rats, but how they contribute to the different phases of the micturition cycle, including the intraluminal pressure high-frequency oscillations (IPHFOs) is unclear., Materials and Methods: Adult anaesthetized female Sprague-Dawley rats were used; intravesical pressure, RB-EMG and urine flow from the distal urethra were recorded. After baseline recordings, alpha,beta-methylene-ATP (0.5 mg/kg), atropine (1 mg/kg), or both, were injected intravenously., Results: Alpha,beta-Methylene-ATP significantly decreased the maximum bladder pressure during the first micturition phase, whereas atropine had little effect; the maximum bladder pressure during the second phase was also reduced. IPHFOs were apparent after both treatments. Atropine significantly reduced the maximum bladder pressure during the third phase. The maximum urinary flow rate was reduced by both alpha,beta-methylene-ATP and atropine; after exposure to both agents together, urinary flow was markedly reduced or stopped, and overflow incontinence developed., Conclusions: ATP contributes mainly to the initial and acetylcholine to the later phases of the voiding cycle in the rat. Neither agent abolished the IPHFOs; even after blocking the receptors for one transmitter and in the presence of IPHFOs, the bladder can still empty. However, if both receptors are blocked, overflow incontinence develops, suggesting that even if further transmitters are taking part in the voiding contraction, their physiological significance is questionable.

Objectives: To obtain information on the mechanisms of female rat micturition using a model in which pressure was measured in the bladder and distal part of the urethra corresponding to the location of the rhabdosphincter, providing information on the role of the sphincter in opening and closing the urethral lumen., Materials and Methods: A micturition reflex was induced in adult anaesthetized (chloral hydrate and urethane) female rats by filling the bladder with saline. Bladder pressure (BP), urethral pressure (UP), electromyography (EMG) of the middle part of the rhabdosphincter, and urinary flow rate in the distal urethra were simultaneously recorded., Results: There were four phases of the micturition contraction, the second characterized by intraluminal pressure high-frequency oscillations (IPHFOs) of BP. When a non-oscillatory micturition contraction started, the BP increased and exceeded UP for the rest of the micturition contraction. Even though the BP increased during this first phase, the urethral lumen stayed closed. Its opening was indicated by a simultaneous decrease in BP and increase of UP as the fluid flowed from the bladder to the urethra. When the rhabdosphincter closed, as indicated by an EMG-burst of the muscle, the UP declined, bladder pressure increased and the flow ceased. Because of momentary contractions of the rhabdosphincter, the UP and urine flow rate had the same periodicity as the IPHFOs of BP., Conclusions: The simultaneous recording of the BP, UP, EMG of the rhabdosphincter and urinary flow rate showed the sequence of events during micturition. The rhabdosphincter acts as an 'on-off' switch, causing interruptions in the urinary flow rate.