Effects of propiverine hydrochloride and its metabolites on isolated guinea pig urinary bladder

The effects of P-4 and its active metabolites in human blood and urine and the effects of 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide [P-4(N----O)], 1-methyl-4-piperidyl benzilate N-oxide [DPr-P-4(N----O)] and 1-methyl-4-piperidyl benzilate (DPr-P-4) on isolated guinea pig urinary bladder were investigated. At doses of 10(-6) or 10(-5) M, P-4 shifted the dose-response curve for acetylcholine (ACh) to the right, and at a dose of 10(-5) M, it also inhibited the maximum response of ACh. At doses of 10(-5) M or more, P-4(N----O) inhibited the maximum response of ACh. DPr-P-4(N----O) or DPr-P-4 shifted the dose-response curve for ACh to the right at doses of 10(-6)-10(-4) M or at doses of 10(-7)-10(-5) M. P-4 at doses of 10(-6) M or more inhibited the KCl (100 mM)-induced contraction in a dose-dependent manner, and its potency was quite equal to that of terodiline. The inhibitory effect of P-4(N----O), DPr-P-4(N----O) and DPr-P-4 in the KCl (100 mM)-induced contraction were weaker than that of P-4. P-4 and P-4(N----O) had a dose-dependent inhibitory effect on K+-induced 45Ca influx in isolated guinea-pig urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

盐酸丙哌维林对豚鼠离体膀胱平滑肌条的钙拮抗作用

目的　研究盐酸丙哌维林 (P 4)对豚鼠离体膀胱平滑肌条的钙拮抗作用及作用机制。方法　采用离体平滑肌条浴槽实验方法 ,以维拉帕米为对照 ,测定P 4对CaCl2 和组胺 (His)所致离体膀胱平滑肌条的收缩及对乙酰胆碱 (ACh)所致膀胱平滑肌依赖细胞内钙、外钙收缩的影响。结果　P 41～ 1 0 0 μmol·L- 1 使CaCl2 累积量效曲线非平行右移 ,最大反应降低 ,pD2 ′为 4 73± 0 1 4。P 41 μmol·L- 1 使His量效曲线平行右移 ,最大效应不变 ,pA2 为 5 44± 0 1 4 ;1 0～ 1 0 0μmol·L- 1 使His量效曲线非平行右移 ,最大效应降低 ,pD2 ′为 4 71± 0 1 0。P 41、1 0和 1 0 0 μmol·L- 1 对ACh所致依赖细胞内钙收缩的抑制率分别为 45 77%± 6 54 %、86 2 6 %± 5 59%和 90 55 %± 3 1 1 % ,对依赖细胞外钙收缩的抑制率分别为 7 30 %± 2 89%、49 1 6 %± 6 0 9%和 88 2 5 %±3 70 %。结论　P 4低浓度时竞争性拮抗His所致膀胱平滑肌条的收缩反应 ,明显抑制膀胱平滑肌条依赖细胞内钙释放的收缩反应 ;高浓度时非竞争性拮抗His和CaCl2 所致膀胱平滑肌条的收缩反应 ,明显抑制膀胱平滑肌条依赖细胞内钙释放和外钙经钙通道内流所致收缩反应     

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?     

Effects of propiverine hydrochloride (P-4) and its metabolites on urinary bladder function in anesthetized rats

The effects of P-4 and its active metabolites, 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide[P-4(N----O)], 1-methyl-4-piperidyl benzilate N-oxide [DPr-P-4 (N----O)] and 1-methyl-4-piperidyl benzilate hydrochloride (DPr-P-4), on urinary bladder function were investigated in urethane anesthetized rats. By cystometrography, P-4 (2, 4 mg/kg, i.v.) and P-4 (N----O) (4 mg/kg, i.v.), which have direct action on smooth muscles, significantly increased the maximum vesical volume. As for rhythmic bladder contractions, P-4 (1,2,4 mg/kg, i.v.) and P-4 (N----O) (2, 4 mg/kg, i.v.) significantly decreased the frequency with a slight decrease in the amplitude. On the other hand, DPr-P-4 (N----O) (0.1, 0.5 mg/kg, i.v.) and DPr-P-4 (0.01, 0.05 mg/kg, i.v.), which have anticholinergic effects, significantly inhibited the maximum vesical pressure on the cystometrograms, and DPr-P-4 (N----O) (0.1, 0.5 mg/kg, i.v.) and DPr-P-4 (0.005, 0.05 mg/kg, i.v.) significantly inhibited the amplitude of the rhythmic bladder contractions. The effects of flavoxate and papaverine were similar to those of P-4 and P-4 (N----O), but the effects of propantheline and atropine were similar to those of DPr-P-4 (N----O) and DPr-P-4 in these two experimental methods. These results suggest that the clinical effects of P-4 are based not only on the actions of P-4 itself but also on those of its active metabolites.     

Inhibitory effects of propiverine on rat and guinea-pig urinary bladder muscle

Summary In muscle strips isolated from guinea-pig and rat urinary bladder, propiverine (3–10 M) inhibited carbachol-induced contractions in the presence of verapamil and Ca²⁺-induced contractions in excess K⁺ medium containing atropine, suggesting it has both anticholinergic and Ca²⁺ channel blocking actions.The Ca²⁺ channel blocking action was also demonstrated by recording inward Ca ²⁺ currents in single cells dispersed from both species. The inhibition of inward currents by propiverine was three times stronger in the rat than the guinea-pig, ID₅₀ being 7 M for rat and 21 M for guinea-pig. The recovery of the current after washout was faster than that of mechanical inhibition. It is concluded that propiverine blocks not only muscarinic receptors, but also Ca²⁺ channels at similar concentrations.Correspondence to: T. Tomita at the above address     

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.     

Effect of oxybutynin hydrochloride on isolated smooth muscles (ileum, urinary bladder and urethra)

Effects of oxybutynin hydrochloride on isolated smooth muscle were investigated in preparations of isolated rabbit bladder body, bladder base, collum vesicae and urethra. ACh produced a marked contraction of the preparation from the bladder body and produced no response in the collum vesicae and the urethra; however, NE caused a marked contraction of the preparations from the collum vesicae and the urethra and relaxation in the bladder body. Oxybutynin and papaverine hardly had any effect on these preparations. Effects of oxybutynin on the contractile response of the isolated ileum or urinary bladder of rabbit, guinea pig and rat in comparison with atropine, papaverine, flavoxate and other drugs were investigated. The responsibility of these preparations to ACh were approximately 100 times higher in the ileum than in the urinary bladder. Oxybutynin showed a competitive inhibition to contractile response induced by ACh in the ileum and urinary bladder, whose potency was about 1/7-1/10 that of atropine. In the ileum of rats which were treated with oxybutynin orally at a dose of 1, 10 or 100 mg/kg for 60 days, the response to ACh in the preparations of the animals treated by 100 mg/kg were decreased, but the anticholinergic action in the groups treated with oxybutynin were not significantly different compared with the nontreated or saline treated group. On the other hand, oxybutynin showed a non-competitive inhibition to contractile response induced by Ba2+, Ca2+ and histamine in the guinea pig ileum and Ba2+, high-K+, Ca2+ and ATP in the rabbit urinary bladder. These potencies of oxybutynin were equal or slightly stronger than that of papaverine or flavoxate. However, oxybutynin had no effect on the contraction induced by NE in the rabbit urethra. The above results suggest that oxybutynin has atropine-like anticholinergic action and direct muscle relaxant action evidenced by non-competitive inhibition to contractile response induced by several agonists.     

Effects of testosterone on neuromuscular transmission in rat isolated urinary bladder

Testosterone was examined for its effects on neuromuscular transmission in rat and shrew urinary bladder. In isolated preparations of detrusor muscle from sexually immature male rats (8-10 weeks old) at concentrations of 100-300 microM, it inhibited neuromuscular transmission in a concentration-dependent manner and it also inhibited responses to applied carbachol and diadenosine pentaphosphate (Ap(5)A, a P2X receptor agonist). Ethanol (at or above 38 mM), the solvent for testosterone, also caused significant inhibition of neurogenic contractions as well as carbachol- and Ap(5)A-induced contractions. In older, sexually mature male rats (over 16 weeks old), testosterone and ethanol had similar effects to those observed in the young male rat, although both were slightly less potent. In young virgin female rats (8-12 weeks old), testosterone and ethanol inhibited neuromuscular transmission; testosterone was approximately 1000 times more potent than in male rats, with a threshold concentration of 30 nM. In the insectivore, Suncus murinus, testosterone (0.1 microM-1 x mM) caused inhibition of neurogenic and chemogenic responses, but ethanol had no significant effect. Flutamide (50 microM), a genomic testosterone-receptor antagonist, did not inhibit any of the responses to testosterone. It is concluded that testosterone acts predominantly on a postjunctional nongenomic receptor to inhibit urinary bladder detrusor muscle contraction.     

Analysis and stability of propiverine hydrochloride (Mictonorm)

In acid, neutral and alkaline solution the hydrolytic degradation of the spasmolytic agent Mictonorm (1) was determined. As degradation products ester- and/or ether fragments (2-5), benzophenone (6) and a compound X (7) were identified. In comparison N-Methylpiperidinyl(4)-benzilate (2) and benzilic acid (3) were also investigated in the isothermal quick-assay test. The test showed that the ether bound in 1 was hydrolyzed before the ester group. The compounds 5-7 are formed also direct from 3.     

钩藤碱对大鼠膀胱逼尿肌舒缩作用的影响

目的观察钩藤碱(rhynchophylline,Rhy)对离体大鼠逼尿肌的作用并探讨其作用机制。方法采用逼尿肌体外张力实验法检测Rhy对大鼠逼尿肌L-型钙通道(ICa-L)及大电导钙离子激活钾离子通道(BKCa)作用。以维拉帕米为对照观察膀胱逼尿肌肌条的收缩及对乙酰胆碱(ACh)依赖细胞内、外钙所致肌条收缩程度的拮抗作用。结果 Rhy和BKCa激动剂NS1619作用相似,亲和力指数(pD2)分别为4.78±0.17、4.53±0.22;BKCa拮抗剂iberiotoxin能竞争性拮抗Rhy,使Rhy累积量效曲线平行右移,拮抗参数(pA2)为7.27±0.16;当Rhy浓度为1~20μmo.lL-1时,使CaCl2累积量效曲线非平行右移,最大反应降低,呈非竞争性拮抗。结论 Rhy通过离子通道(阻滞ICa-L、激活BKCa)抑制膀胱逼尿肌收缩。低浓度(10μmol.L-1)Rhy仅对细胞内钙引起的肌条收缩有抑制作用,而对细胞外钙所致的肌条收缩无影响;随着浓度的增高,Rhy对细胞内、外钙引起的肌条收缩均有抑制作用,且抑制作用逐渐增加。     

Effect of propiverine hydrochloride on the function of the bladder in dogs

Propiverine hydrochloride (P-4) is a new derivative of benzilic acid. The effect of P-4 on the function of the bladder in anesthetized dogs was studied in comparison with flavoxate, which is clinically used for the treatment of pollakiuria. P-4 (4 mg/kg, i.v.) caused a significant increase in maximum vesical volume (Vmax), which was estimated by a cystometrogram. A similar effect was also observed following intravenous administration of verapamil (1 mg/kg), while flavoxate (4 mg/kg, i.v.) caused no significant changes in Vmax. P-4 significantly decreased the frequency of rhythmic bladder contractions at doses higher than 1 mg/kg, i.v., whereas flavoxate first revealed a significant decrease at 4 mg/kg, i.v. Thus the inhibitory effect of P-4 on the micturition movements of the bladder is more potent than that of flavoxate. These findings indicate that P-4 is a useful drug for the treatment of pollakiuria.     

The anticholinergic drug propiverine inhibits the protein kinase C activity in the rat urinary bladder

There is ample evidence that non-cholinergic protein kinase C (PKC) mediated signal transduction pathways are involved into regulation of bladder smooth muscle contractions. To evaluate whether the anticholinergic and calcium modulating drug propiverine exerts intracellular effects by inhibition of the PKC, male inbred LEW 1A rats were pretreated with 0.6, 2, 6 and 60 mg/kg body weight for 5 days. Furthermore, competition assays with partially purified PKC were performed with propiverine in vitro. The activities of the membrane-bound and soluble PKC were assessed by 32P enrichment of lysine-rich histone. Results: The active, membrane-bound PKC decreased by about 60% accompanied by increase of the soluble form after propiverine in doses above 0.6 mg/kg. 100 nM of the drug inhibited the PKC also in vitro whereas the propiverine metabolites M5 and M6 and atropine were without any effect. CONCLUSIONS: Propiverine was identified to be an inhibitor of the protein kinase C. Its contribution to the noncholinergic control of hyperactive detrusor smooth muscle cells needs further investigation.     

Effect of propiverine hydrochloride on the function of the bladder in decerebrated dogs

The effect of propiverine hydrochloride (P-4) on the function of the bladder in decerebrated dogs was compared with that of propantheline, an anticholinergic drug which is used for the treatment of micturitional disorders. P-4 (5 and 10 mg/kg, i.v.) significantly increased maximum vesical volume (Vmax); and at the dose of 10 mg/kg, i.v., it also significantly increased effective vesical volume (EV) when determined by cystometry. However, at the dose level of 2, 5 and 10 mg/kg, i.v., P-4 had no effect on residual volume (RV) after micturition contraction. Propantheline (0.25 and 0.5 mg/kg, i.v.) also significantly increased Vmax, but showed no effect on EV. At doses higher than 0.016 mg/kg, i.v., propantheline significantly increased RV. These findings indicate that P-4 is a useful drug for the treatment of pollakiuria.     

The contractile effect of bombesin on the rat isolated urinary bladder

We have investigated and compared the myotropic effects of bombesin (BB) and carbachol (C) in the rat isolated urinary bladder. BB (0.5 x 10(-9) to 0.5 x 10(-5) M) and C (2.7 x 10(-8) to 5.4 x 10(-5) M) were found to produce dose-dependent increases of the basal tone of the rat detrusor muscle. The maximal contraction produced by C was about 4 times greater than that elicited by BB or substance P (SP). However, the threshold concentrations of BB and SP required to stimulate the detrusor muscle were much lower than those of C. The pD2 (-log ED50) values of BB, SP and C were respectively 7.63, 7.05 and 5.8. The tissues exposed to BB relaxed more slowly after washout than those challenged with C or SP. The contractile effects of medium range concentrations of BB were not affected by pretreating the tissues with tetrodotoxin, atropine, antihistaminics, indomethacin, alpha- and beta-adrenergic blockers, methysergide or 8-leucine-angiotensin II. Tissues desensitized with high concentrations of bradykinin maintained their sensitivity to BB. The result suggest that the contractile effect of BB on the rat isolated urinary bladder is likely to be the result of a direct effect on the smooth muscle cells.     

Effects of cannabinoid receptor agonists on neuronally-evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human

This study investigated the cannabinoid receptor, known to inhibit neuronally-evoked contractions of the mouse isolated urinary bladder, in bladder sections isolated from mouse, rat, dog, pig non-human primate or human. The CB(1)-like pharmacology of the cannabinoid receptor in mouse isolated bladder observed previously was confirmed in this study by the rank order of agonist potencies: CP 55940>/=WIN 55212-2>HU 210>JWH 015>anandamide, the high affinity of the CB(1) selective antagonist, SR 141716A (apparent pK(B) 8.7), and the low affinity of the CB(2) antagonist, SR 144528 (apparent pK(B)<6.5). In these studies, SR 141716A (10-100 nM) significantly potentiated electrically-evoked contractions in this tissue by an undetermined mechanism. A similar rank order of agonist potencies was determined in rat isolated bladder sections (CP 55, 940> or =WIN 55212-2>JWH 015). In this tissue, the maximal inhibitory effect of all agonists was lower than in the mouse bladder. Indeed, the effects of both HU 210 and anandamide were too modest to quantify potency accurately. In the rat isolated bladder, SR 141716A (30 nM) or SR 144528 (100 nM), reversed the inhibitory effect of WIN 55212-2 (apparent pK(B) = 8.4 and 8.0, respectively) or JWH 015 (apparent pK(B) = 8.2 and 7.4, respectively). These findings may demonstrate pharmacological differences between the rat and mouse orthologues of the CB(1) receptor. Alternatively, they may be attributed to a mixed population of CB(1) and CB(2) receptors that jointly influence neurogenic contraction of the rat bladder, but cannot be differentiated without more selective ligands. WIN 55212-2 had no effect on electrically-evoked contractions of bladder sections isolated from dog, pig, cynomolgus monkey and human. These findings suggest that the effect of cannabinoid agonists to inhibit neurogenic contraction of the mouse and rat bladder is not conserved across all mammalian species.     

Subtypes of purinoceptors in rat and dog urinary bladder smooth muscles.

1. The role of the adhesion glycoproteins CD18 and intercellular adhesion molecule-1 (ICAM-1) in inflammatory responses produced during a reversed passive Arthus (RPA) reaction and induced by zymosan and zymosan-activated plasma (ZAP) were studied in rabbit skin. 2. Oedema formation and haemorrhage were quantified by measuring accumulation of 125I-albumin and 111In-labelled red blood cells (111In-RBC) respectively. 3. Monoclonal antibody (mAb) R15.7 (anti-CD18), administered intravenously, abolished accumulation of 125I-albumin and 111In-RBC in dermal RPA reactions and in response to locally injected zymosan and ZAP. 4. When administered intravenously, the mAb RR1/1 (anti-ICAM-1) suppressed 125I-albumin and 111In-RBC accumulation in dermal RPA reactions and at sites treated with zymosan and ZAP. 5. Oedema formation in response to platelet-activating factor (PAF) and bradykinin (BK) either in the presence or absence of prostaglandin E2 (PGE2) were not affected by mAb R15.7 or by mAb RR1/1.1.1. 6. We conclude that oedema formation and haemorrhage associated with RPA reactions and in responses to zymosan and ZAP are completely CD18-dependent, and are mediated, at least in part, via ICAM-1. Responses to the neutrophil-independent oedema forming mediators, PAF and BK are not dependent upon CD18 or ICAM-1.     

Effects of adenosine 5'-triphosphate (ATP) and beta-gamma-methylene ATP on the rat urinary bladder.

1 High concentrations of adenosine 5'-triphosphate (ATP, 100 to 1000 micrometer) were required to cause contraction of the rat urinary bladder, while adenosine and adenosine 5'monophosphate (AMP, 1 to 50 micrometer) produced relaxation. 2 One hundred fold lower concentrations of beta-gamma-methylene ATP, which is resistant to degradation to AMP and adenosine, caused dose-dependent, phasic contractions which mimicked atropine-resistant responses to nerve stimulation. 3 Adenosine and AMP caused dose-dependent inhibition of carbachol-induced contractions; theophylline competitively antagonized this inhibition but not the contractile responses to beta-gamma-methylene ATP, ATP or atropine-resistant nerve stimulation. 4 These results suggest that the insensitivity of the rat bladder to ATP is due to its rapid degradation to AMP and adenosine and support the hypothesis that the bladder receives a purinergic excitatory innervation.     

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.