Akiyoshi Ohtake

Effects of Tamsulosin on Bladder Blood Flow and Bladder Function in Rats With Bladder Outlet Obstruction

OBJECTIVES To investigate the mechanism underlying the ameliorating effect of tamsulosin, an alpha(1)-adrenoceptor antagonist, on storage symptoms associated with benign prostatic hyperplasia, the effects of tamsulosin on bladder blood flow (BBF) and bladder function was evaluated in rats with bladder outlet obstruction (BOO). METHODS BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. Tamsulosin was subcutaneously administered via an osmotic pump for 2 weeks immediately after the BOO surgery. The BBF in the sham-operated rats, the control BOO rats, and the tamsulosin-treated BOO rats was measured using the fluoromicrosphere method. Each rat was kept in a metabolic cage for observation of micturition behavior. Expression of the alpha(1)-adrenoceptor subtype mRNA in the vesical artery was measured by reverse transcriptase-polymerase chain reaction. RESULTS BBF was significantly reduced in BOO rats compared with sham-operated rats, and tamsulosin significantly increased the BBF in BOO rats. Tamsulosin ameliorated the decrease in mean voided volume in BOO rats with bladder masses < 500 mg. Expression of the alpha(1)-adrenoceptor subtype in the vesical artery was alpha(1a)- > alpha(1d)-adrenoceptors; almost no expression was observed of alpha(1b)-adrenoceptors in either sham-operated or BOO rats. CONCLUSIONS Tamsulosin increased BBF in BOO rats via an antagonistic effect, presumably on the alpha(1A)- and/or alpha(1D)-adrenoceptor in the vesical artery mainly, and improved the decrease in mean voided volume. Therefore, the results of this study suggest that tamsulosin improves bladder overactivity via improvement of BBF.

Effect of mirabegron, a novel β3-adrenoceptor agonist, on bladder function during storage phase in rats

Mirabegron, a selective β3-adrenoceptor agonist, facilitates urine storage function by exerting a relaxing effect on bladder smooth muscle. Here, we investigated the effect of mirabegron on bladder function during the storage phase. We assessed the effect of mirabegron on the resting intravesical pressure in anesthetized rats and also tested antimuscarinics (oxybutynin and tolterodine) under the same experimental conditions. Mirabegron dose-dependently decreased the resting intravesical pressure, while oxybutynin and tolterodine showed no statistically significant effects on resting intravesical pressure. We also investigated the effect of mirabegron on bladder function using cystometry technique in conscious rats with bladder outlet obstruction. While mirabegron dose-dependently decreased the frequency of nonvoiding contractions, considered an index of abnormal response in bladder storage, no significant effects were noted on the amplitude of nonvoiding contractions, micturition pressure, threshold pressure, voided volume, residual volume, or bladder capacity. Neither oxybutynin nor tolterodine affected the frequency of nonvoiding contractions; however, oxybutynin increased residual volume and tended to decrease voided volume in a dose-dependent manner, and tolterodine dose-dependently decreased voided volume. Taken together, these results shed light on the suggestion of mirabegron as a therapeutic agent, compared with antimuscarinics, with its most prominent effect being the facilitation of bladder storage.

Effect of Tamsulosin on Bladder Blood Flow and Bladder Function in a Rat Model of Bladder Over Distention/Emptying Induced Bladder Overactivity

PURPOSE Decreased bladder blood flow was the subject of a recent study as a pathophysiological cause of bladder overactivity. We developed a rat model of bladder over distention/emptying induced bladder overactivity and investigated the effect of the α(1)-adrenoceptor antagonist tamsulosin on bladder blood flow and bladder function in this model. MATERIALS AND METHODS The bladder was distended with 2 ml saline using anesthesia for 2 hours (over distention) and then emptied. Bladder blood flow was measured using a perfusion imager. Micturition behavior and parameters were observed using a metabolic cage and a cystometry method, respectively, from 2 hours after bladder emptying. After model establishment was confirmed we examined the participation of afferent C-fibers and the effects of tamsulosin in rats pretreated with capsaicin (Sigma-Aldrich®) (125 mg/kg) and tamsulosin (1 μg/kg per hour), respectively, using a metabolic cage. RESULTS Decreased bladder blood flow was observed upon over distention with partial recovery at emptying. Bladder over distention/emptying increased micturition frequency and decreased mean voided volume in the micturition recording study, and decreased the intercontraction interval and voided volume without affecting micturition pressure, threshold pressure or post-void residual volume in the cystometry study. Capsaicin pretreatment did not affect bladder overactivity. However, 1-week continuous treatment with tamsulosin increased bladder blood flow after bladder emptying, resulting in decreased micturition frequency and increased voided volume. CONCLUSIONS Bladder over distention/emptying induced bladder blood flow decrease/partial recovery and caused bladder overactivity via a mechanism other than capsaicin sensitive C-fiber activation. Findings in tamsulosin treated rats confirmed the potency of tamsulosin to increase bladder blood flow and ameliorate bladder overactivity.

Effect of tamsulosin on bladder microcirculation in a rat ischemia-reperfusion model, evaluated by pencil lens charge-coupled device microscopy system.

OBJECTIVES To investigate the effect of tamsulosin hydrochloride on bladder microcirculation in a rat ischemia-reperfusion model using a pencil lens charge-coupled device microscopy system (PLCMS). METHODS Changes in blood flow through a submucosal capillary of the rat bladder were measured during bladder filling using the PLCMS. One week after starting infusion of either physiological saline or tamsulosin, blood flow in the bladder was halted by bladder overdistention via an infusion of physiological saline. The bladder was then emptied to be reperfused with blood. Changes in blood flow through a submucosal capillary of the bladder during ischemia and reperfusion were measured using a PLCMS, and the data obtained for the control group and tamsulosin group were compared. RESULTS As the bladder was distended, the velocity of red blood cell flow in a submucosal capillary of the bladder slowed and stopped altogether when the bladder became overdistended. In the control group, capillary blood flow improved over time after release from overdistention but failed to return to the baseline level, demonstrating that reperfusion injury to bladder microcirculation was caused by bladder overdistention and emptying. In the tamsulosin group, capillary blood flow rapidly returned to baseline after release from overdistention. CONCLUSIONS Using a PLCMS, bladder microcirculation was able to be visualized and quantitatively assessed by measuring the velocity of blood flow in a submucosal capillary of the bladder. Findings from the present study suggest that tamsulosin hydrochloride exerts a protective effect on blood flow in ischemia-reperfusion injury of the bladder.

Comparison of muscarinic receptor selectivity of solifenacin and oxybutynin in the bladder and submandibular gland of muscarinic receptor knockout mice

Solifenacin is a novel selective antagonist of M(3) muscarinic receptor developed for the treatment of overactive bladder. The current study was undertaken to characterize in vivo muscarinic receptor subtype selectivity of solifenacin in the bladder and submandibular gland by using muscarinic receptor subtype knockout (KO) mice. Muscarinic receptors in the bladder and submandibular gland of wild type, M(2)R KO and M(3)R KO mice under in vitro and after oral administration of solifenacin and oxybutynin were measured by radioligand binding assay using [N-methyl-(3)H]scopolamine ([(3)H]NMS). There was little difference between the bladder and submandibular gland of M(2)R KO mice in the receptor binding activities of oxybutynin and solifenacin in vitro, suggesting equal affinity for residual (predominantly M(3) subtype) muscarinic receptors in both tissues. In contrast, compared with oral oxybutynin, oral administration of solifenacin exerted a significantly greater activity to bind muscarinic receptors in the bladder of M(2)R KO mice, while exhibiting a significantly less activity to bind those in the submandibular gland. In the bladder and submandibular gland of M(3)R KO mice, the binding activity of solifenacin and oxybutynin showed no significant difference. Plasma concentrations of solifenacin and oxybutynin after oral administration differed little among wild type, M(2)R KO and M(3)R KO mice. The results indicate that oral solifenacin, unlike oral oxybutynin, may selectively bind to the muscarinic M(3) subtype in the bladder compared with such receptors in the submandibular gland in vivo. Oral solifenacin may be advantageous for the treatment of overactive bladder, in terms of high affinity for M(3) receptors in the bladder.

Urodynamics and bladder muscarinic receptors in rats with cerebral infarction and bladder outlet obstruction.

We characterized muscarinic receptor binding and urodynamic parameters in rats with cerebral infarction and chronic bladder outlet obstruction as models of detrusor overactivity. Bladder weight showed little significant difference between the cerebral-infarcted and sham rats, but the bladder weight was about three times greater in the bladder outlet-obstructed rats. Bladder capacity and voided volume were significantly lower (36.7 and 55.1%, respectively) in the cerebral-infarcted than in the sham rats. Involuntary contractions before micturition were seen in the bladder outlet-obstructed rats but not in sham rats. The bladder outlet-obstructed rats showed significant increases (2.65 and 2.57 times, respectively) in bladder capacity and voided volume, compared with those in sham rats. Bmax values for specific [N-methyl-3H]scopolamine ([3H]NMS) binding in the bladder were significantly (34%) increased in the cerebral-infarcted rats compared with sham rats, whereas Kd was unaffected by infarction. On the other hand, there was little significant change in Kd and Bmax for specific [3H]NMS binding in the bladder-obstructed rats compared with sham rats. In conclusion, the present study shows that cerebral infarction but not bladder outlet obstruction in rats causes up-regulation of bladder muscarinic receptors, and that such regulation of bladder muscarinic receptors may be at least partly associated with the symptoms of detrusor overactivity subsequent to cerebral infarction.

Zolpidem increases bladder capacity and decreases urine excretion in rats

To clarify the effects of zolpidem, a γ‐aminobutyric acid (GABA)A receptor agonist, on bladder function, and urine production, we investigated the effects of zolpidem administration on bladder overactivity induced by cerebral infarction (CI) and on urine excretion increased by water overloading in Wistar rats.

EFFECTS OF MIRABEGRON (YM178) ON NON-MICTURITION CONTRACTIONS IN THE BLADDER OF CONSCIOUS RATS WITH BLADDER OUTLET OBSTRUCTION (BOO)

patients within the development cohort was 26 vs. 71 months in the external validation cohort (P<0.001). In overall survival analyses, the median values were 21 vs. 32 months for respectively the development and the external validation cohort (P<0.001). Three variables (age, stage and surgical status) were included in the nomograms predicting cancer-specific and overall mortality. In the external validation cohort, the nomograms achieved between 72 and 80% accuracy for prediction of ACC-specific or overall mortality at 1 to 5 years after either surgery or diagnosis of ACC for non-surgical patients. CONCLUSIONS: Our models are the first standardized and individualized prognostic tools for patients with ACC. Their accuracy was confirmed within a large external population-based cohort of ACC patients.

Effects of tamsulosin on resting urethral pressure and arterial blood pressure in anaesthetized female dogs

The purposes of the present study were to investigate the effects of the α1‐adrenoceptor antagonists tamsulosin, prazosin and urapidil on resting urethral pressure in anaesthetized female dogs, and to compare the results with their effects on arterial blood pressure. Tamsulosin decreased resting maximal urethral pressure in the urethral pressure profile in a dose‐dependent fashion, whereas it had almost no effect on mean arterial blood pressure. Prazosin and urapidil also dose‐dependently decreased resting maximal urethral pressure, but these effects were accompanied by decreases in mean arterial blood pressure. Thus, of these three compounds, tamsulosin dose‐dependently decreased resting maximal urethral pressure with negligible effect on mean arterial blood pressure in female dogs. These results suggest that tamsulosin will be useful in the treatment of voiding dysfunction associated with bladder outlet obstruction in women, with little hypotensive effect.

Effects of α1-adrenoceptor antagonists on phenylephrine-induced salivary secretion and intraurethral pressure elevation in anesthetized rats

α(1)-Adrenoceptor antagonists are widely used for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Activation of α(1)-adrenoceptors is reported to induce salivary secretion in rats and humans. However, the effects of α(1)-adrenoceptor antagonists on salivary secretion remain unknown. Here, we investigated the effects of the α(1)-adrenoceptor antagonists prazosin, silodosin, tamsulosin and urapidil on phenylephrine-induced salivary secretion and compared the results with the effects on phenylephrine-induced intraurethral pressure (IUP) elevation in anesthetized rats. All antagonists inhibited phenylephrine-induced salivary secretion and IUP elevation in a dose-dependent fashion. Comparison of DR(10) values (the dose required to shift the dose-response curve 10-fold to the right) in both tissues showed that the inhibitory effect of silodosin was significantly more potent in the salivary gland than in the urethra (18-fold), but tamsulosin (2.3-fold), prazosin (1.7-fold) and urapidil (1.1-fold) did not show comparable tissue selectivity. These results suggest that α(1)-adrenoceptor antagonists inhibit not only urethral contraction but also salivary secretion, and that high tissue selectivity for the salivary gland over the urethra as shown by silodosin may contribute to the incidence of dry mouth.