Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions
© Angelico et al; licensee BioMed Central Ltd. 2005
Received: 15 December 2004
Accepted: 11 October 2005
Published: 11 October 2005
Antimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity.
Intravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 μM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed.
In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC.
In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant.
In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment.
Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume.
Despite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.
Overactive bladder is a chronic clinical syndrome characterized by urgency and frequency with or without urinary incontinence affecting millions of people worldwide [1, 2]. Overactive bladder arises from uncontrolled contraction of the detrusor muscle during bladder filling . Although what element(s) trigger(s) unstable contraction is not resolved; myogenic  or neural  theories have been suggested in the attempt to clarify the etiology of this bladder dysfunction.
Nevertheless, since contraction of the detrusor muscle and bladder emptying are primarily mediated by stimulation of muscarinic receptors by acetylcholine, anticholinergic agents are currently recommended as a first-line therapy for overactive bladder. Of the available antimuscarinic agents, oxybutynin and tolterodine are the most widely used to treat this condition [6, 7].
As demonstrated by several investigations in patients, oxybutynin decreases urinary frequency, urgency and episodes of urge incontinence, in addition to increasing bladder volume at first desire to void, enhancing maximum bladder capacity and reducing maximum detrusor pressure during filling [6, 8]. Similar results have been reported after administration of tolterodine in patients affected by overactive bladder [, and references therein].
Despite the favourable results observed in the clinical studies reported above with regard to the cystometrographic modifications induced by treatment with oxybutynin and tolterodine, the only effect generally observed in rats is a decrease in the maximum detrusor pressure at micturition [9–18].
Although purinergic mechanisms appear not to be involved to any extent in the normal function of human bladder , they are involved in human pathological conditions , and they are well documented for contraction of rat urinary bladder .
The aim of the present experiments was, therefore, to study the effect of oxybutynin and tolterodine in rats, using different cystometrographic conditions, attempting to find suitable experimental conditions able to reproduce the effects observed in humans, in particular the increase of bladder capacity.
A preliminary account of this work was presented in an abstract .
Tolterodine and oxybutynin were evaluated as the most widely utilized antimuscarinics.
In general, 2–3 scaled doses of each compound were administered. In some pilot experiments each dose of compound was tested with a matched control group treated with vehicle. In other experiments, control rats and animals treated with different doses of test compound were evaluated simultaneously.
Effect of intravenous and oral administration in conscious rats utilized 1 day after catheter implantation
Effect of intravenous and oral administration in conscious rats treated 5 days after catheter implantation
Effect of intravenous administration in anesthetized rats
Cystometrographic and electromyographic recordings performed during micturition in rats under anesthesia show that the striated muscle of external urethral sphincter (EUS) exhibits high-frequency bursting that induces corresponding high-frequency oscillations (HFO) in the pressure recorded intravescically. HFO are correlated with the bursting pattern in the EUS, and represent alternate contractions and relaxations of the urethral outlet, functioning like a pump to enhance urine flow. Consequently, pharmacological manipulations that may result in impaired EUS function might result in micturition disturbances, e.g. bladder-urethra dyssynergia.
In anesthetized rats, the i.v. administration of 0.3 mg/kg of oxybutynin (a dose inducing in conscious rats a significant decrease of MP) induced again a significant, although not so relevant decrease of MP, probably owing to the lower basal value of this parameter due to the anesthesia. Neither BVC nor threshold pressure showed a significant reduction. The number and amplitude of HFO were not modified by oxybutynin.
Effect of intravenous administration in conscious rats with bladder infused with diluted acetic acid
In the groups of animals treated with vehicle, the continuous infusion of the bladder with acetic acid during the second hour of experiment induced a further decrease of bladder capacity (generally 10–30%), although this further reduction was not statistically significant. MP did not change during the period. Oxybutynin (1 mg/kg i.v.) and tolterodine (0.3 mg/kg i.v.) had no effect on BVC, but caused a rapid and marked decrease of MP similar to that observed in rats during saline infusion of the bladder (Fig. 9).
Effect of intravenous administration in conscious obstructed rats
Effect of intravenous administration of oxybutynin on cystometrographic parameters in anesthetized rats
0.47 ± 0.04
4.74 ± 0.55
25.0 ± 3.6
4.2 ± 0.2
1.82 ± 0.19
0.47 ± 0.04
4.88 ± 0.58
20.9 ± 2.0
4.6 ± 0.2
1.63 ± 0.11
Oxybutynin 0.3 mg/kg
0.44 ± 0.11
3.44 ± 0.84
20.3 ± 2.3
4.6 ± 0.2
1.68 ± 0.27
0.27 ± 0.05
2.34 ± 0.51
15.5 ± 1.7 **
4.2 ± 0.7
1.63 ± 0.24
Effect of intravenous administration of oxybutynin on cystometrographic parameters in conscious obstructed rats
NVC: frequency (N°/2 min)
NVC: amplitude (mmHg)
1.27 ± 0.16
1.36 ± 0.24
5.3 ± 0.9
5.2 ± 0.9
1.14 ± 0.25
1.32 ± 0.30
4.9 ± 0.9
4.9 ± 0.9
Oxybutynin 0.3 mg/kg
1.98 ± 0.12
2.02 ± 0.46
5.9 ± 0.4
11.7 ± 1.8
2.58 ± 0.70
2.77 ± 0.50
5.5 ± 0.6
9.7 ± 2.1
Summary of results obtained after treatment with tolterodine and/or oxybutynin in the different models/conditions utilized.
Effect on BVC
Effect on MP
Conscious rats – 1 day after surgery – i.v. and p.o. administration
Conscious (freely-moving/discontinuos cystometry) rats – 1 day after surgery – p.o. administration
Conscious (cystometry at different rate of filling) rats – 1 day after surgery – p.o. administration
Conscious (bladder infused with suramin) rats – 1 day after surgery – p.o. administration
Conscious (bladder infused with acetic acid) rats – 1 day after surgery – p.o. administration
Conscious (obstructed) rats – 2 days after surgery – i.v. administration
Conscious rats – 5 days after surgery – i.v. and p.o. administration
Anesthetized rats – at the day of surgery – i.v. administration
Cystometrographic evaluation performed in conscious normal rats utilized one day after catheter implantation showed that neither oxybutynin nor tolterodine increased BVC after oral or i.v. administration. In agreement with previously reported data [9, 13, 15, 16], however, both drugs induced a strong dose-dependent decrease of MP. Furthermore, this behaviour was maintained when a discontinuous cystometry was performed or when different filling rates were utilized.
Available evidence indicates that arachidonic acid metabolites produced along the cyclooxygenase pathway are involved in the physiological regulation of micturition during reflex activation of the urinary bladder. Furthermore, endogenous prostaglandins are produced locally following distension of the bladder wall and modulate the afferent branch of reflex micturition by lowering the threshold for eliciting voiding contractions, serving as a link between detrusor muscle stretch produced by bladder filling and activation of capsaicin-sensitive afferents [22–25]. Different authors [26, 27] have shown that cystometrograms in conscious rats with bladders infused with saline and recorded during the first 1–3 days after catheter implantation showed bladder overactivity with relatively low urine volume and a high frequency of micturition. Cystitis is also present at this time and is characterized by edema in the submucosa and an increased tissue content of prostaglandins that stimulate capsaicin-sensitive sensory fibers in the afferent branch of the micturition reflex . In the present study, cystometrographic recordings performed in conscious rats one day after catheter implantation and during saline infusion of bladder, confirmed that bladder capacity is significantly reduced in comparison with BVC values observed 5 days after catheter implantation, as previously reported . It is therefore conceivable that in our experiments, performed under conditions of bladder inflammation, that a strong influence of prostaglandin levels on afferent firing was present. On the other hand, when the activity of oxybutynin or tolterodine was evaluated in rats 5 days after catheter implantation, the same effect as seen after 1 day, still occurred; namely, a decrease in MP with no change in BVC. These results indicate that the involvement of the inflammatory mediators is not the reason for the lack of antimuscarinic activity on BVC.
The involvement of ATP in non adrenergic, non cholinergic (atropine-resistant) contraction of urinary bladder is well documented . Recently, it has also been demonstrated that ATP is released from the urothelium of isolated urinary bladder following increased intraluminal pressure . Furthermore, it has been reported that intravesical ATP stimulates the micturition reflex in awake, freely moving rats  and that during cystometry the number of impulses generated in the afferent neurons was halved by treatment with suramin . Consequently, suramin infusion into rat bladder has been reported to increase BVC . Outflow obstruction may be associated with changes in the cholinergic function of the bladder associated with an increase of atropine-resistance. Again, the bladder instability seen in obstructed rats seems to be particularly related to the atropine-resistant contraction component, where ATP and prostaglandins play an important role . However, we found that oxybutynin did not increase BVC either in rats under infusion of the bladder with suramin, or in obstructed rats. In addition, in this last experimental condition, oxybutynin did not modify the frequency and amplitude of the non-voiding contractions. These findings are in agreement with the lack of activity shown by tolterodine in the same model , whereas Kwak and Lee  reported a significant decrease of frequency and amplitude of the non voiding contractions in anesthetized rats after intraarterial administration of 1 mg/kg oxybutynin.
Although the mechanism of action of antimuscarinic agents used for the treatment of overactive bladder (such as oxybutynin and tolterodine) is thought to be due mainly to suppression of detrusor contraction through blockade of M3 muscarinic receptors on detrusor smooth muscle, an effect on central muscarinic receptors, located in the brain cannot be ruled out as both compounds pass into the central nervous system .
Effects on the lower urinary tract of drugs acting on central nervous system muscarinic receptors have been reported by several investigators [17, 33–35] Following i.c.v. or i.t. administration in conscious normal rats of oxotremorine methiodide, a muscarinic agonist, a dose-dependent increase of BVC was observed. The muscarinic antagonist atropine did not change BVC after i.t. administration, and increased BVC after i.c.v. administration only in very high doses . Both oxybutynin and tolterodine i.c.v. administered showed no (oxybutynin) or little (tolterodine) augmenting effect on BVC . On the other hand, several Authors reported that oral oxybutynin administered in conscious rats with lesions at the basal forebrain [11, 18], increases BVC. These findings seem to indicate that the inhibitory muscarinic mechanisms that can be activated by exogenously administered agonists seem to be inactive under normal conditions , but are working in lesioned animals. These considerations, therefore, can explain the lack of central activity on BVC of antimuscarinics tested in conscious normal rats.
Muscarinic receptors are also found on bladder urothelial cells, where their density may be even higher than in detrusor muscle. Evidence has been reported for a release of acetylcholine from urothelium and/or nerves during bladder filling, and acetylcholine may act directly on afferent nerves to initiate the micturition reflex or to enhance the myogenic contractile activity of the detrusor. If this is correct, blockade of muscarinic receptors should be expected to reduce bladder tone during storage and to increase bladder capacity. This effect is observed after treatment with antimuscarinics in normal individuals as well as in patients with detrusor overactivity . In conscious rats, however, infravescical administration of different concentrations of oxybutynin did not increased BVC, but significantly decreased MP . Furthermore, Kim et al.  recently showed that bladder infusion of different antimuscarinic agents (including oxybutynin) at concentrations equivalent to urine concentration in humans with oral application of these drugs, did not modified BVC when tested in normal rats but only inhibited bladder overactivity induced by intravesical instillation of carbachol.
Despite the different experimental conditions utilized, the main effect of the antimuscarinics tested on cystometrographic parameters in anesthetized and conscious rats is a decrease of MP, whereas BVC is hardly and, generally, non-significantly affected, suggesting that the block of bladder muscarinic receptors is the only mechanism that can be affected and evaluated after treatment with these compounds in this animal species.
Although urodynamic assessment showed significant comparable increases in bladder capacity following repeated treatment with oxybutynin and tolterodine in humans [6, 7], the published papers reporting the acute effect of these antimuscarinics in man are confusing, since oxybutynin seems devoid of effect , whereas tolterodine increased the volumes at which subjects experienced the first sensation of bladder filling and normal desire to void . It seems therefore difficult to reproduce in rats the cystometrographic effects observed in humans after chronic administration of these compounds. The effects observed in rats after acute administration (although obtained at doses about 10–100-fold higher than those used in ref. 39 and 40) seem more similar to those recorded in patients treated with a single dose, with the exception of the modification in symptoms that can not be recorded in animals.
The effects of the tested compounds on rats urodynamic parameters were evaluated by cystometrographic models in conscious and anesthetized animals. In anesthetized or obstructed animals (i.v. administration only) cystometry was performed on female rats (250–350 g b.w.). Conscious male rats (300–400 g b.w.) were used to evaluate the effect of tested compounds both after i.v. and oral administration.
Animals were housed with free access to food and water and maintained on a forced 12 hr light-dark cycle at 20–24°C for at least one week before the experiments were carried out. The animals were handled according to internationally accepted principles for the care and welfare of laboratory animals (E.E.C. Council Directive 86/609, O. J. no L358, 18/12/86).
To obtain bladder outlet obstruction, female rats were anesthetized with intraperitoneal administration of 3 ml/kg of equithensin solution (pentobarbital g 1.215, chloral hydrate g 5.312, magnesium sulphate g 2.657, ethanol ml 12.5, propylene glycol ml 49.5, distilled water to 125 ml of final volume) and then the bladder and proximal urethra were exposed via a lower abdominal midline incision. A silk ligature was placed around the urethra and tied in the presence of an intraluminally placed indwelling polyethylene cannula with an outside diameter of 1.22 mm. After removing the polyethylene cannula, the abdominal wall was sutured and then antibiotic medication (penicillin G 200,000 I.U./kg and streptomycin 300,000 I.U./kg i.m.) was administered. Obstructed rats were utilized for cystometry 3 weeks after urethral ligature.
To insert the catheter into the bladder, female rats were anesthetized with subcutaneous injection of urethane 1.25 g/kg (5 ml/kg). Animals were then placed in a supine position and an approximately 10 mm midline incision was made in the shaved and cleaned abdominal wall. The urinary bladder was gently freed from adhering tissues, emptied and then cannulated, via an incision at the dome, with a polyethylene cannula (ID 0.58 mm, OD 0.96 mm), which was permanently sutured with silk thread. For i.v. injection, another polyethylene cannula with the same characteristics and filled with heparine (40 UI/ml) in physiological saline was inserted into the jugular vein.
Obstructed female or male rats utilized 1 or 5 days after surgery were anesthetized with i.p. injection of equithensin (3 ml/kg) and catheters implantation was performed as above.
In female rats utilized upon anesthesia, the cannulae were exteriorized through a subcutaneous tunnel in the breast-bone area. In male and female rats awake utilized, the cannulae were exteriorized in the retroscapular area, where they were connected with a plastic adapter, in order to avoid the risk of removal by the animal. In male rats submitted to discontinuous cystometry, the free end of bladder cannula was connected to a swivel at the top of the cage, thus allowing free movements to animals in a 20 × 25 cm size cage. A rigid fluid-filled tubing connected to the swivel provided undistorted transmission of the bladder pressure to the transducer, which was placed outside the cage, at a height corresponding to the position of rat bladder.
The free tip of the bladder cannula was connected by a T-shape tube to a pressure transducer and to a peristaltic pump for a constant rate continuous infusion of saline solution (at room temperature) into the urinary bladder.
In anesthetized female normal rats, the urodynamic parameters were recorded continuously using a MacLab/8SP interface with Chart Software v. 4.1.2. (AD Instrument). In conscious rats, the urodynamic parameters were obtained from the cystometrogram recorded on a chart poligraph (Rectigraph SAN-EI 8K).
In anesthetized female rats the following parameters were evaluated: bladder volume capacity (BVC), defined as the volume (in ml) of saline infused into the bladder and necessary to induce detrusor contraction followed by micturition; micturition pressure (MP, in mm Hg) defined as the maximal intravesical pressure induced by contraction of the detrusor during micturition; threshold pressure (TP, in mmHg) i.e. the difference between intraluminar basal pressure and pressure value recorded just before micturition; the number (n.HFO) and the amplitude (a.HFO, in mmHg) of high-frequency oscillations recorded in 1 sec at the middle of the expulsion time phase.
In conscious female obstructed rats, the number and the mean amplitude of the spontaneous bladder contractions, present during bladder filling but without urine emission and termed "non-voiding contractions" (NVC), were evaluated for the 2 min time prior to micturition. In addition, BVC, MP and micturition volume (MV) were evaluated.
In conscious normal male rats, only BVC and MP values (defined as above) were obtained from the cystometrograms.
Cystometric investigation in conscious normal rats
Rats were generally utilized one day after catheter implantation. Some experiments were carried out in rats utilized 5 days after surgery.
On the day of the experiment, conscious rats were placed in Bollman's cages and the recording of cystometrographic parameters started after a stabilization period of 20 min. Saline infusion into the bladder was generally at a constant rate of about 0.1 ml/min. Some experiments were performed decreasing the rate of saline infusion at 0.05 and 0.025 ml/min. Basal BVC and MP values were evaluated as the mean of two complete and reproducible cystometrograms during the pretreatment period (basal). Then the animals were treated intravenously or orally with the test compound (or vehicle) under continuous infusion of the bladder with saline, and changes in BVC and MP were evaluated for 60 or 300 min, respectively.
The effect of the following treatments was evaluated:
- i.v. administration of tolterodine (0.03 – 0.1 and 0.3 mg/kg) and oxybutynin (0.1 and 0.3 mg/kg) in conscious rats utilized 1 day after catheter implantation;
- p.o. administration of tolterodine (1 – 3 and 10 mg/kg) and oxybutynin (1 and 3 mg/kg) in conscious rats utilized 1 day after catheter implantation;
- p.o. administration of oxybutynin (3 mg/kg) in conscious freely-moving rats upon discontinuous cystometry;
- p.o. administration of oxybutynin (1 mg/kg) in conscious rats utilized 1 day after catheter implantation and with saline infusion rate of 0.025 and 0.05 ml/min;
- p.o. administration of oxybutynin (3 mg/kg) in conscious rats utilized 1 day after catheter implantation and with suramine infusion into the bladder at 3 × 10-6 and 1 × 10-5 M concentration.
- i.v. administration of tolterodine (0.1 and 0.3 mg/kg) in conscious rats utilized 5 days after catheter implantation;
- p.o. administration of oxybutynin (1 mg/kg) in conscious rats utilized 5 days after catheter implantation;
Cystometric investigation in anesthetized normal rats
Rats were utilized on the day of catheter implantation. Saline infusion into the bladder was at a constant rate of about 0.1 ml/min. After stabilization, basal values of the considered parameters were evaluated as mean value from the second and third cystometrogram recorded after i.v. injection of vehicle. Then, the animals were treated with the compound tested (or again with vehicle for the control group) and changes induced by treatment were evaluated by considering the value of the cited parameters as mean of the second and third cystometrogram after treatment.
The effect of i.v. administration of oxybutynin 0.3 mg/kg was evaluated.
Cystometric investigation in rats with bladder infused with diluted acetic acid
In conscious rats utilized 1 day after catheter implantation, saline solution was infused into bladder until stabilization of cystometrograms was achieved. At this point, bladder infusion was switched from saline to 0.2% acetic acid solution. Infusion rate was always 0.1 ml/min. One hr after, the rats were injected intravenously with the test compound (or vehicle) and changes in BVC and MP were evaluated for the following 60 min under continuous infusion of acetic acid. The effect of i.v. administration of tolterodine (0.03 – 0.1 and 0.3 mg/kg) and oxybutynin (0.1 and 0.3 mg/kg) was evaluated.
Cystometric investigation in conscious obstructed rats
Rats were utilized two days after catheter implantation. Saline infusion into the bladder was at a constant rate of about 0.17 ml/min. From the cystometrograms of the obstructed rats, the number and the mean amplitude of the spontaneous bladder contractions, present during bladder filling without urine emission and termed "non-voiding contractions" (NVC) were evaluated for the 2 min time prior to micturition. In addition, BVC and micturition volume (MV) were evaluated. Values of the parameters reported above were expressed as mean values obtained from two similar cystometrograms recorded just before (basal values) and as mean of the second and third cystometrogram after treatment. Since the ligature around the urethra was not removed before cystometry, peak micturition pressure was not considered in these experiments.
The effect of i.v. administration of oxybutynin 0.3 mg/kg was evaluated.
Data were always expressed as mean ± S.E. of the mean.
Statistical significance of the change of the different parameters recorded in anesthetized normal rats and conscious obstructed rats (before vs after treatment) was evaluated by Student's t test for paired data.
Statistical analysis of data involving time-course of BVC and MP values was performed by S.A.S./STAT software, version 6.12. The difference between vehicle and active treatments effect at different times was evaluated on values (for each rat the value at considered time minus basal value) of BVC and MP, using the general linear model procedure, repeated measures ANOVA, a univariate test of hypotheses for within subjects effects and ANOVA of contrast variables.
BVC and MP values of each rat were also transformed in AUC data. Statistical significance was evaluated by ANOVA (and Dunnett's test) or by Student's t test.
Iris Simonazzi and Rita Cova provided excellent technical assistance.
Valuable criticism of the manuscript by D.E. Clarke, is also greatly appreciated.
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