Efficacy And Mechanisms Of Phosphodiesterase Type 5 Inhibitors For Treating Overactive Bladder

Background:Overactive bladder(OAB)was defined by the International Continence Society as a syndrome characterized by urgency,often accompanied by symptoms of micturition and nocturia,with or without urge incontinence.As a part of lower urinary tract symptoms(LUTS),OAB presents with symptoms of urinary storage period.It has no definite cause,no urinary tract infections,and other specific pathological changes.With the improvement of people's living level,age structure of aging,the prevalence of bladder excessive activity increased year by year.Therefore,it is considered a social disease with an incidence close to hypertension,bronchial asthma,and heart diseases.Although OAB is not a fatal disease,it can seriously affect the patient's quality of life and bring huge economic burden.At present,the treatment of OAB including behavior therapy,oral medication,botulinum toxin,capsaicin,or RTX intramuscular injection treatment,neuromodulation,and even surgical treatment are other options.However,in China,due to the poor behavioral therapy efficacy,patients prefer oral medication.At present,commonly used oral medications are anticholinergic drugs,such as toherodine,solifenacin,and oxybutynin.Recent studies have found that Phosphodiesterase type 5 inhibitors(PDE5I)exerts therapeutic effects on various LUTS,such as LUTS with or without erectile dysfunction(ED).Also,the study found that PDE5I could effective treatment of OAB which as part of LUTS.It is a pity that relevant report was less,especially lack of randomized,double-blind,placebo-controlled study.So,further study is necessary.In addition,the mechanism about PDE5I treatment of LUTS was not very clear.Up to now,there is no perfect theory to explain PDE5I treatment of LUTS.Seldom research of mechanism could be found in the domestic.NO/cGMP pathway was widely used to explain the mechanism by foreign researchers.But it is hard to explain OAB and other related LUTS.So,further study is necessary.In the following,a multicenter,randomized,double-blind,placebo-controlled clinical study and two animal experiments were designed,to confirm the effectiveness of PDE5I therapy for OAB,and to preliminary discussion on its mechanism may be related to cGMP-PKG-RhoA/Rho kinase pathway,and improvement of local microcirculation on the bladder wall.Part 1 Function of RhoA/Rho kinase in Phosphodiesterase Type 5 Inhibitors Treating Overactive BladderObjectives:To observe the change of urodynamics in spontaneously hypertensive rats(SHRs),the contraction effects and cGMP in SHRs isolated bladder detrusor muscle after PDE5 inhibitors daily and discontinuously given,in order to investigate its possible mechanism on the overactive bladder.Methods:1.24 adult male SHRs with weight from 230 to 250g were randomly divided into 3 groups.Each group respectively received 2-weeks drug intervention by the way of intragastric administration as follows:? vardenafil daily given;? vardenafil discontinuously given;? normal saline daily given.8 adult male SD as another group also received 2-weeks intragastric administration with normal saline.Urodynamic examinations were conducted in each group after two-weeks interventions,and bladder contraction statuses were recorded and compared between each group.2.After urodynamic examinations,bladder detrusor muscle strips were isolated from all 4 groups rats.Each group was then divided into two subgroups.Samples were used in electrophysiologic studies.All samples was first precontracted with carbachol,then different concentration of sodium nitroprusside was added into one subgroup samples and another subgroup samples were added with different concentration of Y-27632.Changes of electrophysiologic curves in two subgroups were recorded and compared.3.The cGMP concentration in bladder detrusor muscle was measured by ELISA,and then was compared between each group.Results:1.Compared with SD controls,the bladder intercontraction interval(ICI)and bladder capacity(BC)in the group of SHRs daily given saline were shorter and smaller(P<0.001).And compared with the group of SHRs daily given saline,the ICI and BC in the group of discontinuously given vardenafil were longer and bigger(P<0.05);while the ICI and BC in the group of SHRs daily given vardenafil were more longer and bigger than in the group of discontinuously given vardenafil(P<0.01),and similar with SD controls.Compared with SD controls,the bladder pressure threshold for voiding(PT)in the group of SHRs daily given saline was higher(P<0.001).And compared with the group of SHRs daily given saline,the PT in the discontinuously given vardenafil group was lower but having no significances;while in the group of daily given vardenafil was much lower(P<0.001).The bladder nonvoiding contractions(NVC)in the group of daily given vardenafil were more less than the other groups.The bladder maximum voiding pressure(MP)between each group had no significant differences.2.The relaxant effect of sodium nitroprusside was relatively weak on the bladder detrusor muscle strips precontracted with carbachol from the groups of SHRs and SD both given normal saline.The sensitivity was obviously enhanced with the presence of vardenafil,the maximum relaxant effect on the groups of SHRs daily or discontinuously given vardenafil were increased.And the relaxation on the group of daily given was more significant than the group of discontinuously given(P<0.001).Compared with the group of SD given normal saline,the dose-effect curve of Y-27632 on relaxation in the group of SHRs given normal saline could shift more left:the maximum effect was increased(P<0.001).However,the dose-effect curve of Y-27632 on relaxation with the presence of vardenafil could shift right and the sensitivity to Y-27632 decreased significantly(P<0.001)in the groups of SHRs discontinuously or daily given vardenafil.The sensitivity to Y-27632 was weaker and the maximum effect was lower in the group of SHRs daily given than in the group of SHRs discontinuously given(P<0.001).3.The cGMP in the bladder detrusor muscle was significantly higher in the groups of SHRs daily or discontinuously given vardenafil than in the group of SHRs given normal saline(P<0.001).Furthermore,the cGMP in the bladder detrusor muscle was much higher in the group of daily given than in the group of discontinuously given(P<0.01).Conclusions:Vardenafil was effective in inducing bladder detrusor muscle relaxation in vitro.In addition,the relaxant effect of the Rho kinase inhibitor Y-27632 was higher in bladder detrusor muscle from SHRs than from SD and reduced by vardenafil.These phenomenons all demonstrated that the effect might be related to the NO-cGMP-dependent PKG-RhoA/Rho kinase signaling pathway.Part 2 Influence of Vardenafil on blood oxygen saturation of the instable obstructed bladderObjectives:To determine the effect of Vardenafil on bladder function and Blood oxygen saturation(BOS)in an in vivo animal model of bladder outlet obstruction.Methods:Thirty-two guinea pigs;sham operated(n = 8),sham operated + vardenafil(n = 8),urethrally obstructed(n = 8)and urethrally obstructed + vardenafil(n = 8)were studied during an 8 week period.BOS of the bladder wall was measured by spectroscopy before obstruction,at day 0,and at week 8.The bladder function was evaluated by urodynamic studies every 4 weeks.Results:Before surgery and after sham operation all study parameters were comparable.After sham operation,bladder function and BOS did not change.In the obstructed group the urodynamic parameters were deteriorated and BOS was decreased.In the group obstruction + vardenafil,bladder compliance remained normal and overactivity occurred only sporadic.BOS remained unchanged compared to the sham group and was significantly higher compared to the obstruction group.Conclusions:In an obstructed bladder the loss of bladder function is accompanied by a significant decrease in BOS.Treatment of obstructed bladders with vardenafil yields a situation of high saturation,high bladder compliance and almost no overactivity.Maintaining the microcirculation of the bladder wall might result in better bladder performance without significant loss of bladder function.Part 3 Efficacy of daily low-dose Tadalafil for treating Overactive Bladder:results of a randomized,double-blind,placebo-controlled trial.Objectives:To evaluate the efficacy of daily low-dose tadalafil therapy for overactive bladder(OAB)in women.Methods:A total of 96 women with idiopathic OAB from three medical centers in the south of Zhejiang Province of China were randomly assigned to treatment with daily low-dose tadalafil(5 mg,n=48)or placebo(n=48)for 3 months.The Indevus urgency severity scale(IUSS),overactive bladder symptom score(OABSS),and a 3-day micturition diary with frequency,incontinence,and urgency episodes were recorded and compared before the treatment,every 2 weeks following the treatment,and 3 months after the treatment.Uroflowmetry and transabdominal ultrasound were also conducted following the treatment to determine the maximum flow rate(MFR),voided volume(VV),post-void residual volume(PVR),total bladder capacity(TBC),and voiding efficiency(VE).The patient's overall rating of improvement in symptoms(PORIS)was assessed as worse,none,25%,50%,75%,or 100%.The therapy was regarded as effective when the value of PORIS was above 50%.Results:The OABSS significantly decreased,and the frequency,incontinence,and urgency episodes significantly improved in the tadalafil treatment group as compared with the placebo group and baselines at weeks 4,6,8,10,and 12 as well as 3 months post-treatment(P<0.05).In addition,VV and TBC obviously increased in the treatment group(P<0.05).The IUSS decreased from week 4 to 3 months post-treatment in the treatment group(P<0.05).No changes were found in MFV,PVR,and VE.The efficiency of the treatment reached 52.1%.Flushing,headache,and backache were the most common treatment-related adverse symptoms.All adverse symptoms were mild to moderate,transient,or endurable.Conclusions:Daily low-dose tadalafil is a considerable,well-tolerated,and effective treatment for OAB in women.