The Translational Role of Animal Models for Estrogen-Related Functional Bladder Outlet Obstruction and Prostatic Inflammation

The prevalence of LUTS and prostatic diseases increases with age both in humans and companion animals, suggesting that a common underlying cause of these conditions may be age-associated alterations in the balance of sex hormones. The symptoms are present with different and variable micturition dysfunctions and can be assigned to different clinical conditions including bladder outlet obstruction (BOO). LUTS may also be linked to chronic non-bacterial prostatitis/chronic pelvic pain syndrome (CP/CPPS), but the relationship between these conditions is unknown. This review summarizes the preclinical data that supports a role for excessive estrogen action in the development of obstructive voiding and nonbacterial prostatic inflammation. Preclinical studies that are emphasized in this review have unequivocally indicated that estrogens can induce functional and structural changes resembling those seen in human diseases. Recognizing excessive estrogen action as a possible hormonal basis for the effects observed at multiple sites in the LUT may inspire the development of innovative treatment options for human and animal patients with LUTS associated with functional BOO and CP/CPPS

Short-term exercise affects cardiac function ex vivo partially via changes in calcium channel levels, without influencing hypoxia sensitivity

Exercise is known to improve cardiac recovery following coronary occlusion. However, whether short-term exercise can improve cardiac function and hypoxia tolerance ex vivo independent of reperfusion injury and the possible role of calcium channels in improved hypoxia tolerance remains unknown. Therefore, in the current study, heart function was measured ex vivo using the Langendorff method at different oxygen levels after a 4-week voluntary wheel-running regimen in trained and untrained male mice (C57Bl/6NCrl). The levels of cardiac Ca2+-channels: L-type Ca2+-channel (CACNA1C), ryanodine receptor (RyR-2), sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), and sodium-calcium exchanger were measured using western blot. Trained mice displayed lower cardiac afterload pressure generation capacity (rate and amplitude), but unaltered hypoxia tolerance when compared to untrained mice with similar heart rates. The level of CACNA1C positively correlated with the pressure generation rate and amplitude. Furthermore, the CACNA1C-RYR-2 ratio also positively correlated with the pressure generation rate. While the 4-week training period was not enough to alter the intrinsic cardiac hypoxia tolerance, interestingly it decreased pressure generation capacity and slowed pressure decreasing capacity in the mouse hearts ex vivo. This reduction in pressure generation rate could be linked to the level of channel proteins in sarcolemmal Ca2+-cycling in trained mice. However, the Ca(2+-)channel levels did not differ significantly between the groups, and thus, the level of calcium channels cannot fully explain all the functional alterations, despite the detected correlations. Therefore, additional studies are warranted to reveal further mechanisms that contribute to the reduced intrinsic capacity for pressure production in trained mouse hearts

Urodynamic effects of the K+ channel (KCNQ) opener retigabine in freely moving, conscious rats.

Purpose: Retigabine is a novel anticonvulsant drug that not only augments gamma-aminobutyric acid mechanisms, but also opens voltage gated K+ channels (KCNQ). In this study we investigated the effects of retigabine on detrusor activity in rats. Materials and Methods: To conscious, female Sprague-Dawley rats undergoing continuous cystometry retigabine was given intravenously (0.5, 1 and 5 mg/kg(-1)). The KCNQ channel blocker linopirdine was given intravenously (2 mg/kg(-1)) 5 minutes prior to retigabine (1 mg/kg(-1)). In addition, retigabine was given intracerebroventricularly (1, 5 and 10 mug) and intravesically (100, 500 and 1,000 ng ml(-1)). The effects of the drug (intravesical administration) on capsaicin induced bladder overactivity were also tested. Results: Retigabine given intravenously (1 mg/kg(-1)) decreased baseline and maximal bladder pressures, increased voided and infused volumes, and increased voiding intervals. Retigabine (10 mug) given intracerebroventricularly decreased baseline pressure and increased voided and infused volumes as well as voiding intervals. However, bladder pressures were not significantly affected. Intravesical retigabine (1,000 ng.ml(-1)) decreased maximal bladder pressure, increased voided and infused volumes, and increased voiding intervals. Given intravesically for 30 minutes prior to intravesical capsaicin (30 muM) instillation retigabine (1,000 ng.ml(-1)) decreased the detrusor overactivity induced by capsaicin. The KNCQ channel blocker linopirdine (2 mg/kg(-1)) completely blocked the effects of intravenous retigabine (1 mg/kg(-1)). Conclusions: Retigabine given intravenously, intracerebroventricularly and intravesically increased micturition volume and voiding intervals and, when given intravesically, it decreased capsaicin induced detrusor overactivity, suggesting that KCNQ channels can be interesting targets for drugs aiming at micturition control. Retigabine may be a candidate to test as a treatment for detrusor overactivity in humans

Antihypertensive properties of rapeseed-derived bioactive peptides

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A dose-dependent dual effect of oestrogen on voiding in the male mouse?

To explore the effect of different degrees of oestrogenization on male voiding, by treating adult castrated and 5 alpha-dihydrotestosterone (DHT)-maintained male mice with different doses of oestrogens, as exposure of male mice to excessive amounts of oestrogens can cause bladder outlet obstruction (BOO); in addition, male mice lacking oestrogen receptor (ER)alpha (ERKO) or ER beta (BERKO) were studied to assess the importance of ER subtypes. Castrated, DHT-maintained adult mice were treated with 17 beta-oestradiol (E-2; 50 and 250 mu g/kg) or oestrone (E-1; 5, 50 and 500 mu g/kg) daily for 10 days. Control mice were treated only with the vehicle. BERKO and ERKO mice, and their wild-type littermates used as their controls, remained untreated. Under anaesthesia, the bladder and distal urethra were exposed to record simultaneously the bladder pressure and urinary flow rate from the distal urethra. E-2-treated mice showed obstructive voiding, seen as increased bladder pressure, decreased average flow rate and prolonged micturition time. This was also evident when a high dose (500 mu g/kg) of E-1 was used. After treatment with a dose of 50 mu g/kg, the urodynamic variables were similar to those in the control mice. Surprisingly, after treatment with a low dose (5 mu g/kg) all urodynamic variables improved. There was a minor increase in the bladder pressure in BERKO mice; ERKO mice had a significantly lower urinary flow rate. High doses of oestrogens caused BOO in castrated, DHT-maintained male mice. A small dose of E-1 had a positive effect on voiding, suggesting that oestrogens are needed for normal male voiding. Reduced urinary flow rates in ERKO mice suggest that oestrogen effects on voiding are mediated at least partly via ER alpha

Effects of Tolterodine on Afferent Neurotransmission in Normal and Resiniferatoxin Treated Conscious Rats.

Purpose: The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters. Materials and Methods: The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine. Results: In resiniferatoxin treated animals (0.3 mg kg(-1) subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 kg kg-1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 Ag kg(-1) tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 mu g kg(-1) apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment. Conclusions: Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding

Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats-Effects of bladder outlet obstruction and intravesical PGE(2).

AIMS: A method was developed and evaluated to simultaneously register intraabdominal pressure (IAP) and intravesical pressure (IVP) during cystometry in conscious rats. In addition, IAP and IVP were recorded in rats with experimental detrusor overactivity (DO). METHODS: Sprague Dawley rats (n = 24) were used. Six female rats were subjected to partial bladder outlet obstruction for 2 weeks. A catheter was implanted into the bladder to record the IVP, and a balloon-fitted catheter was positioned in the abdominal cavity to record the IAP. PGE(2) was given intravesically to induce DO. Detrusor pressure (DP) was defined as the IVP corrected for IAP. RESULTS: Recorded as increases in IAP, all rats of both sexes exhibited abdominal straining during every void. In controls, a maximal IAP of 6.0 +/- 1.4 cmH(2)O (range 3-15 cmH(2)O) was registered (n = 12) at the time of the flow pressure (FP). Intravesical administration of PGE(2) or BOO did not affect the IAP at basal pressure, FP or micturition pressure. Changes in IAP due to movement or non-voiding-related straining were subtracted from IVP to generate DP and to visualize DO after BOO or intravesical PGE(2). CONCLUSIONS: The conscious rat uses abdominal straining during voiding, and maximal IAP is recorded at the onset of urinary flow. Simultaneous registration of IAP and IVP during the micturition cycle in conscious rats is a convenient method for accurate quantification of pressures inside the bladder and for studying "true" DO without interference from movement artifacts. Copyright 2007 Wiley-Liss, In

The role of the rhabdosphincter in female rat voiding

Objectves 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