Background: Patients with diabetes experience lower urinary tract symptoms. Cystopathy may evolve into underactive bladder (UAB), depending on the degree and duration of the symptoms. In the present study, we aimed to investigate the effects of silodosin, an alpha 1A -adrenoceptor (AR) antagonist, on UAB in a rat model of diabetes mellitus (DM). Methods: Female Sprague-Dawley rats (6 weeks old) were administered streptozotocin (STZ) (50 mg/kg, i.v.) to establish a DM model. One week after STZ administration, vehicle or silodosin (0.3 or 1 mg/kg/day) was delivered subcutaneously through an osmotic pump. Nine weeks after STZ administration (8 weeks after drug treatment), a catheter was implanted into the bladder under urethane anesthesia. After the measurement of emptied bladder blood flow (BBF), saline was continuously infused into the bladder and intravesical pressure and micturition volume were measured. In another experiment, the bladder was isolated and nerve markers were quantified. Results: A cystometrogram showed that bladder capacity (BC), residual volume (RV), and bladder extension (BC/ bladder weight) increased by 7.43, 10.47, and 3.59 times, respectively, in vehicle rats in comparison with normal rats. These findings suggested the occurrence of UAB-like symptoms in this model. Silodosin (1 mg/kg/day) inhibited the increase in BC and RV by 49.0% and 46.8%, respectively, and caused a decrease in BBF of approximately 25.5% (when the difference between normal and vehicle was set as 100%) in STZ rats. The nerve marker expression levels tended to be decreased in the bladders of STZ rats and these effects were ameliorated by silodosin. Conclusions: The STZ rats showed increased bladder extension and RV, symptoms that were suggestive of UAB, and these symptoms were ameliorated by silodosin. These results suggested that the alpha 1A -AR antagonist would be useful for the prevention or treatment of UAB.
Background/Aims: To evaluate the effects of silodosin (α1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study. Methods: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system. Results: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone. Conclusions: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an α1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an α1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use.
BackgroundApproximately 30% of patients on dialysis received combination therapy for their phosphate binder prescription; however, few studies for combined effects of phosphate binders are reported. For the purpose of evaluating the efficacy of combination therapy, we compared the efficacy of sucroferric oxyhydroxide (PA21) combined with calcium carbonate with that of lanthanum carbonate hydrate, sevelamer hydrochloride, and ferric citrate hydrate combined with calcium carbonate.MethodsFor in vitro studies, calcium carbonate and the other phosphate binders alone or in combination were stirred in phosphate solution at pH 2–8 for 2 h. After centrifuging the suspension, the phosphorus level in the supernatant was determined. For in vivo studies, rats were orally administered calcium carbonate and the other phosphate binders (except for sevelamer hydrochloride) alone or in combination, followed by oral administration of phosphate solution adjusted to pH 2 or 7. Serum samples were collected from the rats at predetermined timepoints and the serum phosphorus levels were determined and analyzed using a two-way analysis of variance.ResultsIn the in vitro study, the measured phosphate-binding capacity of combining sevelamer hydrochloride, PA21, and lanthanum carbonate hydrate with calcium carbonate was approximately equal to or greater than the theoretical values under most conditions. Furthermore, these combined effects were insensitive to pH in that order. The measured phosphate-binding capacity of ferric citrate hydrate combined with calcium carbonate was smaller than the theoretical values, and the combination did not exhibit efficacy under any of the tested conditions. In the in vivo study, the combined effect of PA21 and calcium carbonate at both pH values and that of lanthanum carbonate hydrate and calcium carbonate at pH 2 were additive. In contrast, the combined effect of lanthanum carbonate hydrate and calcium carbonate at pH 7 and that of ferric citrate hydrate and calcium carbonate at pH 2 were antagonistic.ConclusionsThese results suggest that coadministration of PA21 and calcium carbonate showed good and relatively stable efficacy throughout the range of the gastrointestinal pH and that combining lanthanum carbonate hydrate and ferric citrate hydrate with calcium carbonate may not produce the expected efficacy under certain conditions.
These results indicated that PA21 has a phosphate binding capacity over the entire pH range of the GI tract.
The objective of this study was to investigate the effects of the β3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a β3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment.
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