Inhibitory effects of propiverine, atropine and oxybutynin on bladder instability in rats with infravesical outlet obstruction

British Journal of Urology (1998), 82, 272–277 Inhibitory eVects of propiverine, atropine and oxybutynin on
bladder instability in rats with infravesical outlet obstruction
T. I . K WA K and J . G . L E EDepartment of Urology, Korea University College of Medicine, Seoul, Korea Objective To compare the inhibitory eCects of propiver- atropine increased the RV only in normal rats ine HCl (BUP-4) with those of atropine and oxybutynin (P<0.01) and oxybutynin had no significant eCect on on the detrusor instability induced by partial obstruc- RV. Increases in compliance after the administration tion of the bladder neck of female rats.
of each drug were significant only in obstructed rats Materials and methods Partial obstruction was created (P<0.01) and were markedly higher after oxybutynin using partial ligation of the proximal urethra in 20 (780%) than after the other drugs (180–250%). The female Sprague-Dawley rats. Both the obstructed rats frequencies and amplitude of SA after injection with and a control group of 15 rats were evaluated cysto- each drug were significantly lower only in obstructed metrically about 6 weeks later and the values com- rats, but in these rats, there were no significant pared both at baseline and after injection with BUP-4, diCerences in this reduction after injecting oxybutynin atropine or oxybutynin. During cystometry, the blad- or BUP-4, whereas they were significantly greater der capacity (BC), residual volume (RV), compliance after injecting oxybutynin than after atropine.
and frequency of spontaneous activity (SA) were Conclusion Partial bladder outlet obstruction success- fully created a hyperactive (unstable) bladder, typified Results The BC, RV and frequency of SA were signifi- by increased BC, RV, frequency of SA and a marked cantly increased, and compliance markedly decreased, decrease in compliance. The greater BC, lower MP in obstructed compared with normal rats. The mictur- and frequency and amplitude of SA were prominent ition pressure was significantly decreased only after after the administration of BUP-4. Thus it is suggested injection with BUP-4 in both normal and obstructed that BUP-4 eCectively inhibited bladder instability in rats. For both, the BC was increased significantly after rats induced by infravesical outlet obstruction and injection with atropine or BUP-4 (P<0.05), with the was more eCective than oxybutynin in increasing BC.
increase greater after BUP-4 than after atropine in Keywords Rats, bladder instability, atropine, oxybu- both groups (P<0.01). After injecting BUP-4, the RV was significantly increased in both groups (P<0.05); and responses to drugs. Previous investigations of bladder function during infravesical outlet obstruction in rats Infravesical outlet obstruction in man is often associated have shown that a condition similar to that seen in with detrusor instability and residual urine. Even after patients with BPH develops in these animals [2,3].
the relief of the outlet obstruction, detrusor instability The purpose of the present investigation was to observe persists in about a quarter of patients [1]. The unstable bladder function in rats with infravesical outlet obstruc- detrusor is characterized by involuntary contractions of tion before and after the administration of propiverine large amplitude, which may lead to more or less complete HCl (BUP-4). This spasmolytic agent, a derivative of emptying of the bladder. The pathophysiological back- benzilic acid, is eCective mainly in urinary bladder ground of detrusor instability is unknown and also diseases with detrusor dysfunction [6–8]. Its eBcacy diBcult to investigate in man. Animal models of infraves- seems to result from the favourable combination of direct ical obstruction have therefore been developed in several myotropic papaverine-like eCects and the neurotropic species, including the mouse, rat, rabbit, dog and pig.
anticholinergic mechanism on vesical muscles [9–11].
To some extent, the models in the rat [2,3] and rabbit Before using BUP-4 clinically, we compared its inhibitory [4,5] have been characterized for bladder morphology eCects with other drugs such as oxybutynin, using invivo cystometry in the rat model of detrusor instability induced by partial ligation of the bladder neck.
E F F E C T O F PR O PI V E R I N E , AT R O P I N E AN D O X Y B U T Y N I N O N BL A D D E R I NS TA B I L I TY After the control cystometry, 10 micturition cycles were repeated 5 min after the administration of atropine The study comprised female Sprague-Dawley rats with a (1 mg/kg), BUP-4 (5 mg/kg) and oxybutynin (1 mg/kg) mean (SD, range) body weight of 256 (13, 245–263) g.
in five rats each and compared with baseline values.
To partially obstruct the urethra in 35 rats, they were The amplitude and frequency of involuntary contrac- anaesthetized with methohexital sodium (Brevital, Lilly, tion were estimated when the intravesical pressure had USA) 70 mg/kg intraperitoneally, and the bladder and increased by 2.0 cmH O; this point was selected as it proximal urethra exposed through a low midline was the mean intravesical pressure increase at which incision. Double silk ligatures were placed around the the control rats voided. Bladder compliance was calcu- urethra, in the lumen of which was a plastic rod lated as the BC divided by the pressure increase from (diameter 1 mm), and tied. The abdominal wall was the start of infusion to the involuntary contraction or closed and the animals were assessed about 6 weeks micturition. The results were assessed using Student’s after establishing the obstruction. Bladder outlet obstruc- t-test, with P<0.05 considered to indicate significant tion was successful in 24 of the animals; such partial obstruction induces significant bladder hypertrophy andacute retention was probably the main cause of death Partial obstruction of the urethra led to a significantincrease in bladder weight (P<0.01). The mean (SEM, range) bladder weight in the 15 normal rats was 98 Under general anaesthesia with pentobarbital sodium (21, 70–120) mg, whereas the corresponding values for (50 mg/kg) a tracheostomy was placed to aid respiration the 20 obstructed rats was 250 (45, 170–290) mg.
and a cannula placed in the femoral artery to administer During cystometry in normal rats, the bladder pressure drugs. A lower midline incision was made and the was low and almost devoid of spontaneous fluctuations bladder exposed. A double-lumen polyethylene catheter (Fig. 1). A small increase in bladder pressure preceded (PE-50) was inserted into the bladder dome to infuse the micturitional contractions, which occurred regularly.
saline and to monitor bladder pressure. The catheter The most prominent finding in obstructed rats was was connected via a T-tube to a pressure transducer spontaneous bladder contraction during bladder filling; (Statham P23 DC, Statham Instrument Division, Gould during the continuous infusion of saline, bladder pressure Inc, USA) and an infusion pump (Microinject, Bioinvent, fluctuations appeared with increasing amplitude (Fig. 1).
USA). In the anaesthetized rat, the bladder was emptied The cystometric values of normal and obstructed rats and covered with saline-soaked cotton-wool swabs before are shown in Table 1; the BC at the initiation of mictur- starting cystometry. After an equilibration period, the ition was significantly increased in obstructed compared bladder was emptied with a syringe connected to the with normal rats (Table 1), the BP, VV and MP were catheter and warm saline (25–30°C) was continuously similar in both groups, but the RV was also significantly infused at 0.1 or 0.2 mL/min in 15 normal and 20 greater in obstructed than in normal rats. The frequency obstructed animals, respectively. Three reproducible mic- Table 1 Cystometric values in normal and obstructed rats turition cycles, corresponding to a 10–20-min period,were recorded before drug administration and used to obtain the baseline values. The following urodynamicvariables were determined: basal pressure (BP), mictur- ition pressure (MP, the maximum bladder pressure during micturition), bladder capacity (BC, the residual volume at the last micturition plus the volume of infused saline voided), voided volume (VV, volume of expelled urine), residual volume (RV, bladder capacity minus micturition volume), compliance (BC/BP), and spon- taneous contractile activity (SA, the mean amplitudeand frequency of bladder pressure fluctuation before †BP, basal pressure (cmH O); MP, micturition pressure (cmH O); micturition). Initial studies were undertaken to deter- BC, bladder capacity (mL); VV, volume voided (mL); RV, residual mine whether the partial obstruction produced changes volume (mL); Comp, compliance (mL/cmH O); FSA, frequency of in these cystometric values consistent with detrusor spontaneous activity (one cycle of voiding); ASA, amplitude of instability. In repeated cystometry, using 15 normal spontaneous activity (cmH O). *P<0.05, ‡P<0.01, normal vs animals, control values were obtained in the same way.
1998 British Journal of Urology 82, 272–277 (BUP-4) injected into the artery of (a,b)normal and (c,d) obstructed rats; notethe regular micturition contraction in the control cystometry (a), the decrease(b) in amplitude of micturition pressure(MP) after administration of propiverine, the spontaneous activity (SA) in (c)during bladder filling and in (d) the and amplitude of SA were markedly increased in tynin caused no significant change in RV. Increases in obstructed compared with normal rats, but only the compliance after administering each drug were signifi- frequency significantly so. The compliance was signifi- cant only in obstructed rats (P<0.01), and were mark- cantly lower in the obstructed rats.
edly higher after oxybutynin (780%) than after the otherdrugs (180–250%).
The frequencies and amplitude of SA after injections ECects of drugs on cystometric values of each drug were significantly decreased only in The MP was significantly decreased only after injection obstructed rats (Table 2); the mean (SEM) frequency was of BUP-4 in both normal and obstructed rats (Table 2).
63 (29)% of the control mean after atropine, 77 (15)% For both normal and obstructed bladders, the BC was after BUP-4 and 86 (22)% after oxybutynin. The ampli- increased significantly after the administration of atro- tude of SA was 70 (15)% of the control mean after the pine and BUP-4 (P<0.05), but not after oxybutynin administration of atropine, 75 (13)% after BUP-4 and (Table 2), with a greater increase after BUP-4 than after 82 (31)% after oxybutynin. There were no significant atropine in normal rats, by a mean (SEM) of 187 (46)% diCerences in the decreases of SA between oxybutynin and 41 (17)%, respectively (P<0.01) in normal rats and BUP-4 but oxybutynin was significantly more eCec- and 108 (38)% and 64 (26)% in obstructed rats, respect- ively (NS). For both normal and obstructed rats, thechanges in BP were not marked after the administration of each drug, nor was the VV significantly diCerent.
After injecting BUP-4, RV was significantly increased in Rats with infravesical outlet obstruction have been both groups (P<0.05; Table 2); atropine increased the shown to develop bladder hypertrophy, instability and a RV only in normal rats (P<0.01; Table 2) and oxybu- clear increase in bladder capacity [12]. Recently, an 1998 British Journal of Urology 82, 272–277 E F F E C T O F PR O PI V E R I N E , AT R O P I N E AN D O X Y B U T Y N I N O N BL A D D E R I NS TA B I L I TY Table 2 ECects of intra-arterial administration of atropine, propiverine and oxybutynin on cystometric variables in normal and obstructedrat bladders; five rats were used for each drug and control treatment †BP, basal pressure (cmH O); MP, micturition pressure (cmH O); BC, bladder capacity (mL); VV, volume voided (mL); RV, residual volume (mL); Comp, compliance (mL/cmH O); FSA, frequency of spontaneous activity (one cycle of voiding); ASA, amplitude of spontaneous activity (cmH O). *P<0.05, ‡ P<0.01.
experimental technique for evaluating bladder function agents (anticholinergic drugs) depress detrusor hyper- urodynamically in obstructed rats was developed [3].
reflexia. However, it has been shown that contraction Using this technique, rats with induced outlet obstruction of detrusor smooth muscle, induced by electrical-field were found to have many characteristics in common stimulation, is partially atropine-resistant in most species with patients with BPH, i.e. there was spontaneous [13]. In the present study, BC was significantly increased bladder contraction during cystometry, the development by atropine and BUP-4, but not by oxybutynin. BUP-4 of residual urine, an altered micturition pattern and has both anticholinergic and calcium-antagonistic activi- bladder wall hypertrophy [3,12]. The model seems to be ties [8]; in contrast, oxybutynin has mainly anticholi- of value for investigating the nature of bladder instability nergic actions. Usually, calcium antagonists have been and further, for assessing drug eCects on this disorder.
shown to increase BC without decreasing MP [14]. This Continuous cystometry rather than a single evaluation diCerence could explain why BUP-4 is more eCective allows several voiding cycles to be investigated, thereby than oxybutynin in increasing BC. In the normal rats, diminishing the intra-individual variation. In the present bladder compliance was not changed significantly after study, partial obstruction successively created detrusor injection of anticholinergic drugs; however, in the instability, evident from the significant increases in BC, obstructed rat bladder, compliance was significantly RV and frequency of SA, and decreased compliance.
increased after injection with each agent. This diCerence With this model, changes in cystometric values caused may be due to the relatively higher basal pressure (low by several agents which can suppress bladder contrac- The frequency and amplitude of SA were reduced by It has been reported that atropine and atropine-like 60–67% after the injection of atropine in obstructed 1998 British Journal of Urology 82, 272–277 rats, indicating that there are both cholinergic and latter idea is based on the assumption that KCl-induced noncholinergic (or myogenic) components to instability.
contractions are due to Ca2+ influx through voltage- However, the inhibitory eCects of BUP-4 and oxybutynin gated channels. As KCl-induced contractions are partly against SA were significantly greater than with atropine inhibited by atropine in the guinea-pig urinary bladder, in obstructed rats, suggesting that these agents had it is possible that inhibition of KCl-induced contraction eCects other than anticholinergic activity. Spontaneous by propiverine is not simply due to Ca2+ channel block- activity remaining after administration of muscarinic ade but also to its anticholinergic action [27].
receptor blockade might be of myogenic origin or due to The eCects of BUP-4 in increasing BC and lowering noncholinergic activation. These atropine-resistant spon- MP, with a resultant increase in RV, were marked in taneous contractions seem to be more frequent in patho- both normal and obstructed rats. Also, involuntary logical conditions such as obstruction or neurogenic bladder contraction induced by obstruction were mark- bladder. The factors reported to underlie detrusor insta- edly inhibited by BUP-4. Oxybutynin also almost com- bility induced by outlet obstruction are diverse; postjunc- pletely inhibited the involuntary contraction, but did not tional denervation supersensitivity [15], changes in increase bladder capacity. Considering that the aims of smooth muscle responsiveness (i.e. increased excitability the treatment of detrusor instability are to increase BC and electrical conductivity) [16], a decreased level of to ease irritative bladder symptoms, BUP-4 would be transmitters involved in bladder relaxation (i.e. VIP) better choice for clinically treating detrusor instability.
[17], decreases of b-adrenergic receptors or increaseda-adrenoceptors [18].
Micturition in the rat is mediated mainly by the actions of acetylcholine and ATP; the latter is involved 1 Turner-Warwick R. Bladder outflow obstruction in the in the initiation of emptying, but sustained contraction male. In Urodynamic Principles, Practice and Application.
1984: 183–204 is achieved by the action of acetylcholine [19]. Therefore, 2 Mattiason A, Uvelius B. Changes in contractile properties atropine can only inhibit that part of the micturitional in hypertrophic rat urinary bladder. J Urol 1982; 128: contraction. The present study also confirmed this by the finding that atropine only inhibited part of the MP 3 Malmgren A. Bladder instability and abnormal micturition both in normal (45%) and obstructed (36%) rats. The pattern in rats with infravesical outflow obstruction.
inhibitory action of BUP-4 against the micturitional contraction was greater than that of the other agents, 4 Mayo ME, Hinman F. Structure and function of the rabbit suggesting that BUP-4 can inhibit the action of ATP or bladder altered by chronic obstruction or cystitis. Invest Many authors suggest that a major part of the atro- 5 Levin RM, High J, Wein AJ. The eCect of short-term pine-resistant contractions is mediated by nonchol- obstruction on urinary bladder function in the rabbit.
J Urol 1984; 132: 789–91 inergic, nonadrenergic neurotransmitters, such as ATP, 6 Chowdhury HJU, Tomita T. Inhibitory eCect of propaverine prostaglandin and VIP [13,20]. It has been frequently on rat and guinea-pig urinary bladder muscle. Arch reported that ATP is a possible noncholinergic, nonadre- nergic parasympathetic neurotransmitter. Zar et al. [21] 7 Muller C, Siegmund W, Hupponen R et al. Kinetics of have shown that an atropine-resistant component of the propaverine on assessed by radioreceptor assay in poor and response to nerve stimulation is more sensitive to calcium expensive metabolizer of debrisoquine. Eur J Drug Metab influx than the cholinergic component. Furthermore, Hoyle et al. [22] showed in the rat bladder that decreasing 8 Eiji M, Hiroshi M, Mineo M, Joichi M, Shinichiro M. Clinical the calcium influx with a calcium-channel blocker was eCects of propaverine hydrochloride for uninhibited neuro- more eCective in inhibiting the atropine-resistant compo- genic bladder disorder. Nishinihon J Urol 1990; 52: 233–40 nent of the contraction induced by electrical-field stimu- 9 Katsuyoshi M, Yasuhiro M, Toshihiko M et al. Study on therapeutic and adverse eCect of propaverine hydrochloride lation than was a,b-methylene ATP. Again, the bladder for pateint with urinary frequency and incontinence.
instability seen in obstructed rats seems to be particularly related to the atropine-resistant contraction component 10 Buttarazzi PJ. Oxybutynin chloride (ditropan) in enuresis.
[23,24] that is highly sensitive to calcium antagonists 11 David M, Holmes M, Fritz M, Stuart L, Stanton M.
In muscle strips of guinea-pig urinary bladder, propiv- Oxybutynin versus propatheline in the management of erine has been reported to inhibit the contraction induced detrusor instability. A patient-regulated variable dose trial.
by acetylcholine and KCl [26,27]. These results have been interpreted to indicate that propiverine has both 12 Malmgren A, Sjogren C, Uvelius B, Mattiason A, Andersson anticholinergic and Ca2+ channel-blocking actions. The K-E, Andersson PO. Cystometrical evaluation of bladder 1998 British Journal of Urology 82, 272–277 E F F E C T O F PR O PI V E R I N E , AT R O P I N E AN D O X Y B U T Y N I N O N BL A D D E R I NS TA B I L I TY instability in rats with infravesical outflow obstruction.
22 Hoyle CHV, Chapple C, Burnstock G. Isolated human bladder: Evidence for an adenosine dinucleotide acting on 13 Wada M, Yoshida K, Kitani H et al. Comparison of eCects P2a-purinoceptors and for purinergic transmission. Eur of various anticholinergic drugs on human isolated bladder.
23 Sjogren C, Andersson KE, Husted S, Mattiasson A, Moller- 14 Sasaki Y, Hamada K, Yamazaki C. ECects of NS-21, an Madsen B. Atropine resistance of transmurally stimulated anticholinergic drug with calcium antagonistic activity, on isolated human bladder muscle. J Urol 1982; 128: 1368–71 lower urinary tract function in a rat model of urinary 24 Sibley GNA. A comparison of spontaneous and nerve- mediated activity in bladder muscle from man, pig, and 15 Speakman MJ, Brading AF, Gilpin CJ, Dixon JS, Gilpin SA, Gosling JA. Bladder outlet obstruction — a cause of denervation supersensitivity. J Urol 1987; 138: 1461–6 Comparative eCects of five diCerent calcium channel 16 Gabella G, Uvelius B. Urinary bladder of rat: fine structure blockers on the atropine-resistant contraction in electrically of normal and hypertonic musculature. Cell Tissue Res stimulated rabbit urinary bladder. Neurourol Urodyn 1986; 17 Gu J, Restorick JM, Blank MA et al. Vasoactive intestinal 26 Haruno A, Yamasaki Y, Miyoshi K et al. ECects of polypeptide in the normal and unstable bladder. Br J Urol propiverine KCl and its metabolites on isolated guinea pig urinary bladder. Folia Pharmacol Japan 1989; 94: 145–50 18 Perlberg S, Caine M. Adrenergic response of bladder muscle 27 VietinghoC G, Hammer S. Untersuchng der antispasmod- in prostatic obstruction. Urology 1982; 20: 524–7 ischen Wirkung von a,aDiphenyl-a, n-propoxy-essigsaure- 19 Levin RM, Ruggieri MR, Wein AJ. Functional eCects of the 4-(1-methylpiperidyl)-ester (Mictonorm) an der isolierten purinergic innervation of the rabbit urinary bladder.
20 Burnstock G, Dumsday B, Smythe A. Atropine resistant excitation of the urinary bladder. The possibility of transmission via nerves releasing a purine nucleotide. BrJ Pharmacol 1972; 44: 451–61 21 Zar MA, Travani MM, Luheshi GN. ECect of nifedipine on J.G. Lee, MD, PhD, Professor of Urology.
the contractile response of the isolated rat bladder. J Urol Correspondence: Dr T.I. Kwak, Department of Urology, Korea University College of Medicine, Seoul, Korea.
1998 British Journal of Urology 82, 272–277


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