A double-blind,cross-over study of the effects of terodiline in women with unstable bladder

Abstract In a double-blind, cross-over study, the effects of terodiline were evaluated in 12 women with motor urge incontinence. The patients were investigated by simultaneous urethro-cystometry before and after treatment for 2-week periods with placebo and terodiline 12.5 mg twice daily. The effects on subjective symptoms were also assessed. In all patients but one, terodiline increased the bladder capacity and also the bladder volume at which urgency was experienced. No effects on the urethral pressure profile or residual urine were found. Subjective improvement was reported by all but one of the patients. Placebo treatment had no effect on the measured parameters or on the subjective symptoms. No side effects were reported during any of the treatment periods. — It is concluded that terodiline can be used for treatment of female motor urge incontinence, and that it is a promising alternative to drugs presently used for this disorder.     

Effects of the anticholinergic drug prifinium bromide on urinary bladder contractions in rat in vivo and in guinea-pig in vitro.

The parenteral and enteral effects of prifinium bromide (CAS 4630-95-9; in the following referred to as prifinium), a quaternary ammonium anticholinergic drug, were investigated on contractions of the rat urinary bladder by cystometry and compared with those of atropine, oxybutynin and terodiline. Additionally, in vitro experiments were carried out with the isolated guinea-pig detrusor muscle to clarify the mechanisms of action of these effects. In intravenous doses, all the drugs reduced the amplitude of the contractions in the cystometric studies. The inhibition was dose-dependent, but was not entirely even at the respective largest doses. According to the 40% inhibitory doses, prifinium was as active as atropine, and 10 and 100 times more active than oxybutynin and terodiline, respectively. The potency ratios of the drugs in their in vivo effects were in good agreement with those of their in vitro anticholinergic effects, which were determined with carbachol-induced contractions in the isolated guinea-pig detrusor muscle. On the other hand, in the in vitro studies, prifinium and atropine had little or no effect on contractions induced by electrical stimulation, KCl and BaCl2, whereas oxybutynin and terodiline antagonized all of the stimuli to a similar extent. These findings indicate that the anticholinergic activity of prifinium may be only one factor in the mechanisms of its in vivo inhibition of the rat bladder contractions. Finally, intraduodenal doses of prifinium also inhibited the contractions of the rat bladder, and the effects of the drug by this route were almost the same as those of oxybutynin and terodiline.     

Effects of tiropramide hydrochloride on the isolated detrusor and intravesical pressure of the bladder in situ in rats]

The effects of tiropramide on the isolated detrusor and intravesical pressure of the bladder in situ in rats were compared with those of flavoxate, oxybutynin and terodiline. The IC50 values (x 10(-5) M) of tiropramide for carbachol (CCh)-, K+ (60 mM)-, Ba2+ (10 mM)-, and electrical stimulation-induced contractions were 3.6, 4.2, 5.8, and 2.9, respectively. The four antispasmodics used (2 and 4 mg/kg, i.v., each) abolished the rhythmic bladder contractions in situ in anesthesized rats. Of the four compounds, oxybutynin was most potent and no significant differences were observed between the inhibitory effects of tiropramide, flavoxate and terodiline. The administration of flavoxate (30 and 60 mg/kg) into the duodenum little influenced the rhythmic bladder contractions. Tiropramide, flavoxate, oxybutynin and terodiline (8 and 12 mg/kg, i.v., each) dose-dependently prolonged the time to the volume-evoked micturition reflex, and the activity of tiropramide was not statistically different from those of the other three antispasmodics. Under unilateral pelvic and bilateral hypogastric nerve transection, both of the contractions induced by electrical stimulation of the peripheral and central cut ends of the pelvic nerve were dose-dependently inhibited to the same extent by tiropramide and terodiline. These results suggest that the effects of tiropramide on the function of urinary bladder in rats may be mainly due to direct actions on the smooth muscle, and that tiropramide is more potent than flavoxate and less potent than oxybutynin and terodiline.     

Anticholinergic and calcium antagonistic effects of terodiline in rabbit urinary bladder

Abstract The effects of terodiline on contractions induced in isolated rabbit detrusor by carbachol and potassium, and by electrical field stimulation were investigated. Terodiline relaxed preparations contracted by carbachol and potassium and, when added 15 min before stimulation, decreased the contractile responses to these agents in a concentration-dependent way. Terodiline more effectively inhibited carbachol than potassium induced contractions. The “pure” calcium antagonist nifedipine had the opposite effect. Both atropine and terodiline caused a parallell shift to the right of the concentration-response curve to carbachol. The maximum contractile tension and slope were not affected, suggesting a competitive antimuscarinic effect within the concentration range used. Atropine was approximately 750 times more potent than terodiline. The maximum inhibitory effect of atropine and the calcium antagonist nimodipine on the electrically induced response were 40 % and 69 %, respectively. Terodiline caused complete inhibition of the response, as also did a combination of nimodipine and atropine. — The results suggest that terodiline in low concentrations has mainly an antimuscarinic action. To this, a calcium antagonistic effect is added at higher concentrations. The two-fold action of the drug makes it an effective inhibitor of bladder contraction, and an interesting tool for investigations of bladder contractility.     

Effect of terodiline hydrochloride on the function of urinary bladder in rats

The effect of terodiline on the function of urinary bladder was investigated in anesthetized rats. When saline was infused continuously into the urinary bladder of rats, terodiline (1-10 mg/kg, i.v.) prolonged the time to micturition in a dose-dependent manner. When enough saline was infused into the urinary bladder to induce the voiding contraction in urethra-ligated rats, terodiline (1-10 mg/kg, i.v.) and verapamil (1 mg/kg, i.v.) abolished the contraction, of which amplitude and frequency were partially inhibited by atropine (1 mg/kg, i.v.). Efferent discharge from the pelvic nerve on the micturition reflex was inhibited by terodiline (3 mg/kg, iv.v.). Both of the bladder contractions evoked by the electrical stimulation of the peripheral or central cut end of the pelvic nerve were dose-dependently inhibited by terodiline (1-10 mg/kg, i.v.). At 3 mg/kg or more, terodiline significantly inhibited the contraction, and the effects were long lasting. The effect of atropine (1 mg/kg, i.v.) was similar to that of terodiline (3 mg/kg, i.v.). Increase in frequency of urination and decrease in total urinary volume per micturition after the bilateral transection of the hypogastric nerve were improved after on oral administration of terodiline (1-10 mg/kg).     

In vivo effects of different antispasmodic drugs on the rat bladder contractions induced by topically applied KCl.

The model originally proposed by Postius and Szelenyi for in vivo screening of spasmolytic compounds on the rat urinary bladder, has been modified and tested to verify its predictivity. The topically applied KCl induced reproducible contractions of the bladder that were dose dependently inhibited by i.v. administration of calcium antagonists like nifedipine, nicardipine, and verapamil. The other spasmolytics tested (oxybutynin, terodiline, flavoxate, and papaverine), showed a non-dose-related inhibition of the contractions. The in vivo potency of the calcium antagonists was related to their in vitro activity on the agonist-induced contractions of rat bladder strips, whereas the activity of the other spasmolytics appeared higher than that predicted on the basis of their in vitro efficacy. Nicardipine showed a dose-dependent inhibition of KCl-induced contractions also after oral administration, whereas oxybutynin and papaverine behaved as after i.v. administration. The described model represents, therefore, a good, quantitative, and reproducible tool of screening at the bladder level only for antispasmodic drugs endowed with strong calcium antagonistic activity.     

Effects of (+/-)-4'-ethyl-2-methyl-3-(l-pyrrolidinyl) propiophenone hydrochloride (HY-770) on the bladder function

The effects of HY-770 on micturition reflexes in rats, dogs and cats and urethral pressure in dogs were compared with those of flavoxate.HC1 (flavoxate), terodiline.HCl (terodiline) and oxybutynin.HCl (oxybutynin). 1) HY-770, in intravenous (2 and 4 mg/kg) and intraduodenal (12.5 and 25 mg/kg) administrations, dose-dependently abolished the rhythmic bladder contractions in anesthetized rats. The activity of HY-770, in intravenous administration (i.v.), was almost equal to those of flavoxate, terodiline and oxybutynin; and the activity of HY-770, like terodiline, was more potent than that of flavoxate in intraduodenal administration (i.d.). 2) In the cystometrograms, HY-770 (3, 4 or 8 mg/kg, i.v.) dose-dependently increased the time to micturition (capacity of bladder) without decreasing the amplitude of micturition contraction in anesthetized rats, dogs and cats, and HY-770 (25 mg/kg, i.d.) also increased the capacity in anesthetized cats. 3) HY-770 (4 and 8 mg/kg, i.v.) dose-dependently increased the capacity of the bladder in the cystometrograms of pollakiuria induced by either transection of both the hypogastric nerves or chronic cannulation to the bladder in anesthetized or conscious rats, respectively. 4) HY-770 (25 mg/kg, i.d.) slightly decreased the urethral pressure in anesthetized dogs. These results suggest that HY-770 is a promising drug for the treatment of pollakiuria induced by a neurogenic bladder or unstable bladder, etc.     

Effects of propiverine hydrochloride (propiverine) on isolated rat and dog urinary bladder]

Propiverine is a drug for the treatment of incontinence and pollakiuria. The effects of propiverine on isolated rat and dog urinary bladder were investigated. At doses of 10(-6)-3 x 10(-5) M, propiverine caused both a rightward shift and inhibition of the maximum response in the acetylcholine (ACh) dose-response curve. The pA2 values for rat and dog urinary bladder were 5.97 and 6.62, respectively. At doses of 10(-5)-10(-5) M, propiverine also dose-dependently inhibited KCl (100 mM)-induced contractions. The IC50 values for rat and dog urinary bladder were 3.9 x 10(-6) M and 3.8 x 10(-6) M, respectively. The pA2 value and the IC50 value of terodiline for rat urinary bladder were 6.08 and 6.6 x 10(-6) M, respectively. In contrast, the pA2 value and the IC50 value of oxybutynin for rat urinary bladder were 7.69 and 4.5 x 10(-6) M, respectively, suggesting that oxybutynin exerts an anti-muscarinic effect at doses at which no discernible anti-KCl effect was observed, whereas propiverine and terodiline exerted both effects at the same doses. The inhibitory effect of drugs on the contraction induced by electrical field stimulation was tested. At a dose of 10(-7) g/ml, tetrodotoxin inhibited the contraction of rat and dog urinary bladder by 76.6% and 92.6%, respectively. Propiverine and verapamil dose-dependently inhibited the contractile response induced by electrical field stimulation at doses of 10(-5) M or more and 3 x 10(-6) M or more, respectively. At these concentrations, a marked anti-KCl effect of the drugs on smooth muscle was observed. On the other hand, atropine caused no inhibition of the contractile response in rat urinary bladder at a dose of 3 x 10(-5) M, and it inhibited the contraction in dog urinary bladder by 14.9% at a dose of 10(-5) M. These findings suggest that although propiverine exhibits both anti-muscarinic and anti-KCl effects in isolated rat and dog urinary bladder, the inhibitory effects of propiverine on the atropine-resistant part of contraction may be mainly due to its anti-KCl effect.     

Terodiline. A review of its pharmacological properties, and therapeutic use in the treatment of urinary incontinence

Terodiline has both anticholinergic and calcium antagonist properties and, as a result, effectively reduces abnormal bladder contractions caused by detrusor instability. When administered to adult patients with urge incontinence (generally as a 25mg twice-daily dose) terodiline reduces diurnal and nocturnal micturition frequency and incontinence episodes. In studies also assessing cystometric parameters, bladder volume at first urge and bladder capacity are increased. Children with diurnal enuresis respond similarly to a daily 25mg dose. Several studies have shown that terodiline 50 mg/day is preferred by patients when compared with emepronium 600 mg/day or flavoxate 600 mg/day, and tends to reduce voluntary micturition frequency and episodes of incontinence more effectively than these drugs. Terodiline is well tolerated in short and long term (up to 3.5 years) studies. Anticholinergic effects are most commonly reported; other adverse effects occur equally during terodiline and placebo treatment. Thus, terodiline is effective and well tolerated in patients with urge incontinence or neurogenic bladder dysfunction, and will claim an important place in the treatment of such patients in light of the limitations of alternative therapies.     

Pharmacological effects of darifenacin on human isolated urinary bladder

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl(2)- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA(2 )values) at the muscarinic M(3) receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10(-6) mol/l, did not inhibit the KCl- and CaCl(2)-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10(-5) mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10(-9)-10(-6) mol/l), propiverine (10(-8)- 10(-5) mol/l), oxybutynin (10(-8)-10(-5) mol/l) and atropine (10(-9)-10(-6) mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca(2+) channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M(3) receptor and support its use as a treatment for overactive bladder.     

盐酸丙哌维林对膀胱平滑肌收缩的影响(英文)

观察了盐酸丙哌维林 ( Pro)对离体豚鼠膀胱平滑肌自动节律性收缩和 KCl诱导离体豚鼠膀胱平滑肌收缩的影响 ;同时观察了 Pro对家犬在体膀胱自动节律性收缩的影响 .Pro在 1 ,1 0 μmol· L-1浓度时 ,对离体豚鼠膀胱平滑肌自动节律性活动具有兴奋作用 ,可使自动节律性收缩频率增加 ,幅度加大 ;在 1 0 0μmol· L-1浓度时则表现为抑制作用 ,可完全抑制豚鼠膀胱平滑肌的自动节律性收缩 ,同时可使平滑肌松弛 ,基础张力降低 .Pro对 KCl引起的豚鼠离体膀胱平滑肌的收缩具有明显的抑制作用 ,在 1 ,1 0 ,1 0 0 μmol· L-1浓度时对 KCl诱导豚鼠离体膀胱平滑肌收缩的抑制率分别为 ( 7.4±6.5) % ,( 31 .3± 1 2 .8) % ,( 68.4± 7.1 ) % ,其 IC50 为( 2 5.2± 4.7) μmol·L-1.十二指肠给 Pro对在体家犬膀胱自动节律性收缩具有明显的抑制作用 ,60 ,30mg· kg-1可明显降低膀胱自动节律性收缩频率和幅度且具有剂量依赖性 ,与药前比有显著性差异 ,60 mg· kg-1药后 1 0 min即可起效 ,药效可持续 90min,Pro在上述剂量下对血压 ,心率无明显影响 .本实验结果提示 Pro在低剂量时对离体膀胱自动节律性收缩具有一定的兴奋作用 ,在高剂量时则表现为明显的抑制作用 ;Pro对 KCl诱导的豚鼠离体膀胱平滑肌收缩和膀胱扩张诱导的家?     

Participation of endogenous endothelin and ETA receptor in premicturition contractions in rats with bladder outlet obstruction

A relationship between endogenous endothelins and bladder overactivity has recently been suggested, but the related endothelin receptor subtype has not been identified. Here, to evaluate the involvement of endothelin-1 and its receptors in bladder overactivity, we investigated endothelin-1 levels and the expression of its receptors in the bladder of rats with bladder outlet obstruction (BOO), a model for bladder overactivity. We also investigated the effects of a selective endothelin ET_A receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on bladder functions in conscious BOO rats. Partial obstruction of the urethra led to a progressive increase in bladder weight from weeks 1 to 6. Binding assays performed using plasma membranes prepared from these bladders to estimate endothelin receptor density from the maximum [¹²⁵I]endothelin-1 binding showed increased endothelin receptor density (about double) at 1, 2, and 6 weeks after the operation in the BOO bladder. The densities of endothelin ET_A receptors in the bladder of sham-operated and BOO rats at 2 weeks after operation were about 3.5 and 5 times those of endothelin ET_B receptors respectively. Furthermore, the endothelin-1 level was also increased in the BOO bladder. Two weeks after operation, BOO rats showed an increase in maximum bladder capacity and micturition volume and the generation of premicturition contractions. The frequency of premicturition contractions was dose-dependently reduced by YM598 (0.1–3 mg/kg, i.v.) without any effect on other voiding parameters in BOO rats. These data suggest that endothelin-1 and endothelin ET_A receptors might be involved in the generation of premicturition contractions in BOO rats, and that endothelin ET_A receptor antagonists such as YM598 may have ameliorating effects in patients with bladder overactivity associated with BOO.     

Current concepts in the treatment of disorders of micturition

Disorders of micturition may be divided into disturbances of the storage function of the bladder, and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency and incontinence. Hyperactivity of the bladder may lead to urge incontinence, and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating bladder hyperactivity, but their efficacy as judged from controlled clinical trials (when available) is often limited. Bladder contraction in man is mediated by stimulation of muscarinic receptors, and when given parenterally anticholinergic drugs have been shown to depress bladder hyperactivity irrespective of the underlying cause. Clinically, however, treatment of urge incontinence with anticholinergic drugs is often unsatisfactory. Lack of effect of oral treatment and systemic side effects limit the use of available agents. Drugs with "mixed" actions (anticholinergic and 'direct' muscle effects), for example oxybutynin and terodiline, have well-documented efficacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems to be well tolerated. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of orally active alpha-adrenoceptor agonists (e.g. phenylpropanolamine) and/or oestrogens. The main symptom of disturbed bladder emptying is urinary retention. Drug therapy is aimed at improving the contractile activity of the detrusor or reducing urethral outflow resistance. Drugs used for improving bladder contractility include parasympathomimetic agents, e.g. bethanechol or carbachol, and intravesical instillation of prostaglandins. Although the efficacy of both types of treatment is open to question, bethanechol seems to be widely used. Increased outflow resistance may be seen in patients with parasympathetic decentralization of the lower urinary tract or in patients with benign prostatic hypertrophy. These patients may respond favourably to alpha-adrenoceptor blockers such as phenoxybenzamine or prazosin.     

膀胱局限性浸润癌保留膀胱综合性治疗

目的探讨膀胱局限性浸润癌保留膀胱综合性治疗的疗效。方法对9例膀胱局限性浸润癌患者以保留膀胱的综合性治疗,9例术前2～3周行以顺铂为基础的多种药物选择性髂内动脉灌注化疗。化疗后肿瘤分期为T2～T3a患者行经尿道肿瘤电切术,化疗后肿瘤分期为T3b～T4患者行膀胱部分切除术。术后经过病理活检了解肿瘤切除情况,如有肿瘤残留则于术后2～4周行放射治疗。门诊定期随访2～3年,定期膀胱灌注化疗,定期复查膀胱镜。结果所有患者保留膀胱,8例复查6～18月未发现肿瘤复发,1例出现肿瘤复发,总有效率为88．8％（8／9）。结论膀胱局限性浸润癌保留膀胱综合性治疗是不能耐受根治性全膀胱切除术及拒绝切除膀胱患者的最佳选择。     

Effects of propiverine hydrochloride on the spontaneous contractions of isolated guinea-pig urinary bladder strip and rhythmic urinary bladder contractions of anesthetized dog.

The effects of propiverine hydrochloride (P-4, CAS 60569-19-9), a new drug to treat pollakiuria, was investigated on the spontaneous contractions of isolated guinea-pig urinary bladder strip and rhythmic urinary bladder contractions of anesthetized dog. At 10(-6)-10(-5) mol/l P-4 raised the base line of an isolated guinea-pig urinary bladder strip and accelerated its spontaneous contraction. At 10(-4) mol/l P-4 raised, and then lowered the baseline, and accelerated then suppressed its spontaneous contractions. Papaverine at 10(-6)-10(-4) mol/l also showed a similar action as P-4 in the isolated guinea-pig urinary bladder strip. Flavoxate at 10(-6)-10(-4) mol/l raised its base line and accelerated its spontaneous contractions. Those of P-4 at 10(-5) mol/l were not inhibited by tetrodotoxin 10(-6) mol/l). At doses of 50 mg/kg or more, intraduodenal administration of P-4 suppressed the frequency of rhythmic urinary bladder contractions of anesthetized dog in a dose-dependent manner. These results indicate that P-4 shows mainly an accelerating action on the endogenous spontaneous contractions of urinary bladder, but on exogenous contractions induced by the Balloon's method it shows an suppressing action and regulates the functions of the urinary bladder, so P-4 might become a useful drug for the clinical treatment of micturitional dysfunction, for example, pollakiuria.     

Effect of tamsulosin on spontaneous bladder contraction in conscious rats with bladder outlet obstruction: comparison with effect on intraurethral pressure

We investigated the effect of tamsulosin, an alpha(1)-adrenoceptor antagonist, on bladder function, especially spontaneous bladder contractions before micturition (premicturition contraction), in conscious rats with bladder outlet obstruction induced by partial urethral ligation, and compared the results with the effect on intraurethral pressure response in anesthetized rats. In obstructed rats, the alpha(1)-adrenoceptor antagonists tamsulosin, naftopidil and urapidil and non-selective alpha-adrenoceptor antagonist phentolamine inhibited premicturition contractions in a dose-dependent fashion. In contrast, yohimbine, an alpha(2)-adrenoceptor antagonist, and atropine, a muscarinic receptor antagonist, hardly inhibited them. Tamsulosin and urapidil showed clearly inhibitory effects on increases in intraurethral pressure induced by phenylephrine, an alpha(1)-adrenoceptor agonist, in the same dose range as that at which they inhibited premicturition contractions, whereas naftopidil required somewhat higher doses to inhibit increases in intraurethral pressure than those at which it inhibited premicturition contractions. In conclusion, premicturition contractions observed in obstructed rats were sensitive to alpha(1)-adrenoceptor antagonists, but not to alpha(2)-adrenoceptor or muscarinic receptor antagonists. Tamsulosin was shown to be effective against both premicturition contraction and intraurethral pressure response in the same dose range in rats. These results partly support the fact that tamsulosin has improved storage symptoms as well as voiding symptoms in patients with lower urinary tract symptoms associated with bladder outlet obstruction by blocking alpha(1)-adrenoceptors.     

Bladder instillation of Escherichia coli lipopolysaccharide alters the muscle contractions in rat urinary bladder via a protein kinase C-related pathway

Uropathogenic Escherichia coli is a common cause of urinary tract infection. We determined the effects of intravesical instillation of E. coli lipopolysaccharide (LPS, endotoxin) on muscle contractions, protein kinase C (PKC) translocation, and inducible nitric oxide synthase (iNOS) expression in rat urinary bladder. The contractions of the isolated rat detrusor muscle evoked by electrical field stimulations were measured short-term (1 h) or long-term (24 h) after intravesical instillation of LPS. One hour after LPS intravesical instillation, bladder PKC-alpha translocation from cytosolic fraction to membrane fraction and endothelial (e)NOS protein was elevated, and detrusor muscle contractions were significantly increased. PKC inhibitors chelerythrine and Ro32-0432 inhibited this LPS-enhanced contractile response. Application of PKC activator beta-phorbol-12,13-dibutyrate enhanced the muscle contractions. Three hours after intravesical instillation of LPS, iNOS mRNA was detected in the bladder. Immunoblotting study also demonstrated that the induction of iNOS proteins is detected in bladder in which LPS was instilled. 24 h after intravesical instillation of LPS, PKC-alpha translocation was impaired in the bladder; LPS did not affect PKC-delta translocation. Muscle contractions were also decreased 24 h after LPS intravesical instillation. Aminoguanidine, a selective iNOS inhibitor, blocked the decrease in PKC-alpha translocation and detrusor contractions induced by LPS. These results indicate that there are different mechanisms involved in the alteration of urinary bladder contractions after short-term and long-term treatment of LPS; an iNOS-regulated PKC signaling may participate in causing the inhibition of muscle contractions in urinary bladder induced by long-term LPS treatment.     

针灸治疗BPH致膀胱逼尿肌收缩无力TURP术后的临床观察

目的观察针灸治疗良性前列腺增生致膀胱逼尿肌无力患者经尿道前列腺电切术后效果。方法选择因良性前列腺增生、膀胱过度充盈致逼尿肌损伤,引起膀胱逼尿肌收缩无力并行经尿道前列腺电切术38例患者,术后采用电针刺激关元、中极、肾俞、次髎、三阴交、足三里穴,观察疗效。结果治疗4个疗程后,35例TURP术后留置膀胱造瘘管（1～8）周后全部拔除,排尿通畅。3例膀胱逼尿肌收缩功能几乎无任何改善。长期留置膀胱造瘘治疗。结论针灸治疗良性前列腺增生致膀胱逼尿肌无力经尿道前列腺电切术后疗效明确,可以减少膀胱造瘘率,提高患者的生活质量。     

Effects of propiverine hydrochloride (propiverine) on the muscarinic receptor binding affinity in guinea pig tissues and on salivation in conscious dogs]

Propiverine is a drug for the treatment of incontinence and pollakiuria. Such micturitional disorders are principally caused by a hyperactive bladder. The effects of propiverine, its active metabolite, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N-->O)), oxybutynin and terodiline on muscarinic receptors in guinea pig urinary bladder, salivary glands, cerebral cortex, ileal longitudinal muscle and heart were compared. Both propiverine and DPr-P-4 (N-->O) competitively inhibited specific binding of 3H-quinuclidinyl benzilate (3H-QNB) to membrane fractions of these tissues. Oxybutynin, terodiline, pirenzepine and atropine also competitively inhibited the binding of 3H-QNB. The order of these drugs in terms of their affinity for muscarinic receptors was as follows: atropine > oxybutynin > pirenzepine, DPr-P-4 (N-->O), terodiline > propiverine. Propiverine and DPr-P-4 (N-->O) had no selectivity for muscarinic receptors in these tissues, the same as atropine. In contrast, pirenzepine, a M1-selective drug, had 10.1 times greater affinity for muscarinic receptors in the cerebral cortex than in urinary bladder, and the affinity of oxybutynin for muscarinic receptors in salivary glands and in cerebral cortex was 10.9 times and 13.9 times higher, respectively, than in urinary bladder. The affinity of terodiline for muscarinic receptors in the cerebral cortex was 4.4 times higher than in urinary bladder. In this study, the effect of propiverine and oxybutynin on pilocarpine (1 mg/kg, s.c.)-induced salivation in conscious dogs was also compared. Propiverine (5 mg/kg, i.v.) had no effect on pilocarpine-induced salivation, whereas oxybutynin (0.1 mg-0.5 mg/kg, i.v.) inhibited it significantly and dose-dependently. The ID50 values (95% confidence limits) for propiverine and oxybutynin during the 20 min after intravenous administration were 6.88 mg/kg (4.71-15.67) and 0.154 mg/kg (0.115-0.205), respectively. These findings suggest that although propiverine, its active metabolite DPr-P-4 (N-->O), oxybutynin and terodiline competitively inhibit the binding of 3H-QNB to muscarinic receptors, the affinity of these drugs for the muscarinic receptors of these tissues is very different and that propiverine has less effect on salivation than oxybutynin.     

GABAB receptor mediated inhibition of field stimulation-induced contractions of rabbit bladder muscle in-vitro

The effects of GABA and selective GABAA and GABAB receptor agonists and antagonists have been investigated on field stimulation-induced contractions (0.1 Hz) of rabbit urinary bladder strips in-vitro. Atropine inhibits twitches of bladder strips obtained from the bladder dome more effectively than those obtained from the bladder base. Both GABA and the selective GABAB receptor agonist, (+/-)-baclofen inhibited field stimulation-induced contractions to about the same extent, while the selective GABAA receptor agonist, homotaurine had no effect. In the presence of atropine, GABA failed to inhibit further the amplitude of twitches. The effects of either GABA or (+/-)-baclofen were antagonized by the GABAB receptor antagonists homotaurine and 5-aminovaleric acid, while the GABAA receptor antagonist picrotoxin had no effect. Neither GABA nor (+/-)-baclofen had any significant effect on acetylcholine-induced contractions of unstimulated bladder strips, but they were abolished by atropine. These results suggest that GABAB receptors inhibit field stimulation-induced contractions of rabbit bladder muscle by reducing the amount of acetylcholine released per nerve impulse.