Mucosa of human detrusor impairs contractionand β-adrenoceptor-mediated relaxationStefan Propping*, Melinda Wuest, Birgit Eichhorn, Manfred P. Wirth*,Alberto J. Kaumann† and Ursula RavensDepartments of Pharmacology and Toxicology and *Urology, Dresden University of Technology, Dresden, Germany,and †Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Objectives• To elucidate the impact of the mucosa on detrusor muscle

function by investigating force of contraction under variousstimulatory conditions and during subsequent relaxationusing catecholamines.

Patients and Methods• Detrusor tissue was obtained from patients who had

undergone cystectomy for bladder cancer and strips ofintact or mucosa-denuded muscle were set up for forcemeasurement. Preparations were precontracted with KCl,carbachol or electric-field stimulation (EFS).

• Precontracted strips were relaxed using increasingconcentrations of catecholamines in the absence andpresence of the subtype-selective β-adrenoceptor (AR)blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), andL-748,337 (β3-ARs).

Results• Force development in response to KCl (40 mM), carbachol

(1 μM) or EFS was larger in the absence of mucosathan in intact muscle strips. The force of contraction ofmucosa-denuded strips with detached urothelium incubatedin the same chamber was as low as in intact strips.

• Noradrenaline relaxed precontracted detrusor strips to asignificantly larger extent and at lower concentrations indenuded than in intact strips.

• CGP 20712A did not affect noradrenaline-inducedrelaxation of denuded and intact strips, and ICI 118,551 didnot influence noradrenaline-induced relaxation in denudedstrips, but abolished the difference between denuded andintact strips.

• The antagonism of the relaxant effects of noradrenaline byL-748,337 was slightly smaller in intact than denuded strips.

Conclusions• The mucosa of human detrusor strips impairs force

development when stimulated with KCl, carbachol or EFS.• The mucosa also blunts the relaxing effects of

catecholamines. The latter effect does not involve theactivation of β1-ARs but only of β2-ARs, whereas β3-ARsmediate the relaxation of human detrusor.

Keywordsdetrusor smooth muscle, relaxation, urothelium,β-adrenoceptors

Introduction

The urothelium of the urinary bladder not only serves as abarrier protecting the underlying smooth muscle againstirritating urine constituents, but also provides significantinhibitory effects on detrusor contractions in response tovarious stimulations. In the literature, there is good evidencefrom the detrusor muscle of several species that contractionselicited by tachykinins or muscarinic agonists are stronglyenhanced after removal of the urothelium [1–4]. Responses offeline and human detrusor to electric field stimulation (EFS)are enhanced in the absence of urothelium [5,6]; however,contractions elicited by KCl depolarization appear not to be

affected by the presence or absence of urothelium [5].Although it could be clearly shown that the relaxing effect ofthe urothelium is mediated by a diffusible factor, the chemicalnature of this ‘urothelium-derived relaxing factor’ [2] has notbeen resolved. Nevertheless, involvement of nitric oxide,cyclooxygenase products, purinergic P2Y receptors,TEA-sensitive K+ channels and small conductanceCa2+-activated K+ channels have been excluded [2,5]. Urinarybladder smooth muscle relaxes in response to catecholaminesvia activation of β-adrenoceptors (ARs) [1,7], and expressionof all β-AR subtypes at the mRNA-level has been found in ratand human detrusor [8–10]; however, the specific β-ARsubtype involved in detrusor relaxation seems to be quite

© 2013 The AuthorsBJU International © 2013 BJU International | doi:10.1111/bju.12267 BJU Int 2013; 112: 1215–1222Published by John Wiley & Sons Ltd. www.bjui.org wileyonlinelibrary.com

variable between different species [11–13]. For instance,β2-ARs mediate relaxation of detrusor smooth muscle inrabbits [14], β2-ARs and β3-ARs in pigs [15], or even all threesubtypes in rat detrusor [16], whereas in humans only β3-ARsare involved [14,15,17,18].

In the presence of urothelium, relaxation mediated by β-ARsis impaired [19]. Isoprenaline, for instance, is less effective inrelaxing carbachol-precontracted intact detrusor strips thanmucosa-denuded muscles. This finding would suggest thatthe urothelium plays a dual role: besides providing aurothelium-derived relaxing factor, it could also beassociated with a ‘contracting factor’ antagonizingcatecholamine-mediated relaxation [19,20].

In the present study, we aimed to investigate which β-ARsubtype is involved in blunting relaxation in intactprecontracted human detrusor strips. According to ourprevious studies [17], catecholamine-induced relaxation ismediated by β3-ARs, however, β2-ARs are responsible formucosa-induced impairment of relaxation.

Patients and MethodsAll patients donating tissue gave fully informed consent inaccordance with the Declaration of Helsinki and theregulation of the local ethics committee (approval No EK194092004). Specimens of human detrusor muscle wereobtained from the bladder dome of patients undergoingprimary radical cystectomy for the treatment of carcinomainvading bladder muscle. Patients who had receivedchemotherapy or radiotherapy were excluded. The mean (SD)age of the 62 patients was 69 (2) years.

Contraction of Human Detrusor

Care was taken to ensure that the muscle strips were obtainedfrom tissue free of macroscopic tumour or inflammation. Thetissue was transported in buffer solution to the laboratorywithin 15–30 min after excision. After careful removal of theserosa, four to eight longitudinal muscle strips (10–15 mm inlength and 4–6 mm in width) were cut from the tissue. Themucosa was removed from half of the preparations, butremained intact in the other half. In some bladder strips themucosa was removed and fixed close to the denuded stripwithin the organ bath.

Recording of Contractions

All preparations were mounted in 5-mL organ bathscontaining carbogen-gassed Tyrode’s solution at 37 °C.Isometric tension was measured with an isometricforce transducer (GM2; Föhr Medical Instruments,Seeheim/Ober-Beerbach, Germany), amplified and recordedwith Chart 4.0TM (AD Instruments, Sydney, Australia).Resting load was 10 mN. All experiments were carried out in

the presence of the α-AR antagonists phentolamine (3 μM)and prazosin (1 μM) to exclude any α-AR-mediated processes.During an equilibration period of 60 min, the bath solutionwas changed three times. The detrusor strips were exposed to40 mM KCl for 10 min, followed by washout. Muscle stripswere precontracted with 1 μM carbachol, 40 mM KCl or EFS(5-s long stimuli at 30 Hz every 2 min) and responses becamestable within 45 min. Detrusor contraction was measured asforce and expressed as mN/mg wet weight of each musclestrip. Relaxation was then induced by a stepwise increase ofthe concentration of (−)-noradrenaline or (−)-isoprenaline,until a maximum was reached. All relaxations wereexpressed in percent of maximum relaxation achievedwith 10 μM forskolin at the end of each experiment.Catecholamine-induced relaxation was either measuredwithout any β-AR blocker in the bath (time-matched controls)or in the presence of either one of the subtype-selective β-ARantagonists, i.e. CGP 20712A (300 nM) for β1-ARs, ICI118,551 (50 nM) for β2-ARs, and L-748,337 (100 nM–1 μM)for β3-ARs, added 45 min before catecholamine-inducedrelaxation.

Drugs and Solutions

The modified Ringer’s solution contained: 149 mM NaCl,2.7 mM KCl, 1.8 mM CaCl2, 0.1 mM NaH2HPO4 and 5.6 mMglucose. The Tyrode’s solution contained: 127 mM NaCl,5.4 mM KCl, 1.05 mM MgCl2, 1.8 mM CaCl2; 0.4 mMNaH2HPO4, 22 mM NaCO3, 0.04 mM EDTA, 0.2 mMascorbic acid and 5.6 mM glucose, pH 7.4, when equilibratedwith 95% O2 and 5% CO2. Drugs and chemicals wereobtained from Sigma (St. Louis, MO, USA) and TocrisBioscience (Bristol, UK). All drugs were dissolved in Milli-Qwater (Millipore, Billerica, MA, USA), with the exception of(−)-isoprenaline and (−)-noradrenaline, which were dissolvedin water containing 200 mM ascorbic acid and 0.04 mMEDTA. L-748,337 and forskolin were dissolved inDMSO and stock solutions were further diluted withMilli-Q water.

Data Analysis and Statistics

Concentration–response curves for catecholamines wereanalysed by nonlinear regression of each individualexperiment using GRAPHPAD 4.0 (GraphPad Prism SoftwareInc., San Diego, CA, USA). The negative logarithm of themolar concentration producing 50% of the maximum relaxingeffect (−logEC50) was calculated. Results are presented asmean −logEC50 (SEM) values from n muscle strips. Statisticaldifferences were evaluated using Student’s t-test (paired orunpaired) and ANOVA. A P value of <0.05 was considered toindicate statistical significance. Schild plot analysis was used toestimate apparent affinity values for L-748,337 [21].

Propping et al.

© 2013 The Authors1216 BJU International © 2013 BJU International

ResultsActivation of urothelium-denuded and intact human detrusorstrips, with 40 mM KCl, 1 μM carbachol or with EFS, yieldedtransient increases in force of contraction (Fig. 1) that turnedinto a constant steady-state force development within 30 min.Peak tension resulting from each mode of stimulation wassignificantly higher in urothelium-denuded than in intactpreparations, but this difference was no longer significant atsteady-state (Fig. 2). Interestingly, when detached urotheliumwas placed into the organ bath close to the denuded strip,contraction amplitudes in response to KCl or carbacholresembled those of intact strips (Fig. 2). These findings areconsistent with previous reports of the existence of aurothelium-derived factor inhibiting contraction [2,5].Precontracted detrusor strips were then relaxed withcumulatively increasing concentrations of (−)-isoprenaline or(−)-noradrenaline (Fig. 3). Maximum relaxation obtainedwith either catecholamine was smaller than with forskolin.(−)-isoprenaline was equally potent and slightly moreefficacious in denuded than in intact strips, although thedifference was nonsignificant (Table 1). By contrast,(−)-noradrenaline was more potent and efficacious in denudedthan in intact strips, irrespective of the precontracting agentused (Table 1). Denuded strips tested with the detachedurothelium fixed closed to them exhibited intermediateresponses to (−)-noradrenaline. After EFS, the presence or

absence of urothelium did not significantly affect(−)-isoprenaline- or (−)-noradrenaline-induced relaxationbecause of the large scatter between values from individualstrips; nevertheless, there was a trend for more relaxation indenuded than in intact strips (Table 1). Taken together, theseresults suggest that the intact urothelium may counteractrelaxation induced by (−)-noradrenaline but not by(−)-isoprenaline.

Next, we examined whether activation of specific β-ARsubtypes might contribute to the differences in(−)-noradrenaline responses between denuded and intactdetrusor strips. For this purpose, concentration–responsecurves were repeated in the presence of subtype-selectiveβ-AR antagonists. The β1-AR blocker CGP 20712A (300 nM)did not alter mean -logEC50 or maximum effect of(−)-noradrenaline in intact or denuded strips (Fig. 4A,Table 1). The β2-AR blocker ICI 118,557 (50 nM) enhancedthe potency and efficacy of (−)-noradrenaline in intact but notin denuded detrusor strips, so that the difference betweendenuded and intact muscle was abolished (Fig. 4B, Table 1).This finding suggests that urothelial β2-ARs are involved inmediating the effect that opposes (−)-noradrenaline-induceddetrusor relaxation. It should be noted that ICI 118,551 doesnot antagonize the effects of (−)-noradrenaline in denudedstrips (Fig. 4, left and middle bottom panels), ruling out aparticipation of β2-ARs in (−)-noradrenaline-evoked

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Fig. 1 Original recordings of force of

contraction in detrusor strips with intact or

denuded urothelium from a male patient with

a muscle-invasive urothelial carcinoma. Muscle

strips were precontracted with 40 mM KCl,

1 μM carbachol (CCh) or EFS followed by

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(−)-noradrenaline (increments in half log

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10 μM forskolin at the end of each experiment.

Impact of mucosa on detrusor muscle function

© 2013 The AuthorsBJU International © 2013 BJU International 1217

Fig. 2 Peak (left set of columns) and

steady-state force of contraction (45 min, right

set of columns ) induced by KCl, carbachol

(CCh) or EFS in human detrusor with intact,

detached or denuded urothelium. Force

expressed as mean (SEM) from n investigated

patients. n.s., not significant; *P < 0.05;

**P < 0.01.

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Fig. 3 Concentration–response curves for the effects of (−)-isoprenaline and (−)-noradrenaline on KCl-, carbachol- (CCh) or EFS-induced contractions

in intact or denuded urothelium human detrusor. Data are expressed in % of maximum relaxation induced by 10 μM forskolin (= 100%) and mean (SEM)

from n investigated strips.

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Propping et al.

© 2013 The Authors1218 BJU International © 2013 BJU International

relaxation. When stimulating KCl- and carbachol-precontracted, denuded and intact detrusor strips with theβ2-AR selective agonist salbutamol, relaxation was observedonly at very high concentrations, at which β3-ARs are alsoactivated (Fig. 4C).

The selective β3-AR antagonist L-748,337 at 100 nM shiftedsignificantly more to the right the concentration–response

curve of noradrenaline in denuded than intact strips (Fig. 5,Table 1). The joint administration of 50 nM ICI 118,551 plus100 nM L-748,337 increased the antagonism compared withL-748,337 alone (Fig. 5). Higher concentrations of L-748,337(300 nM–1 μM) shifted the concentration–response curvefor (−)-noradrenaline-induced relaxation in carbachol-precontracted detrusor strips systematically to higherconcentrations without affecting maximum relaxation

Table 1 Relaxing effects of catecholamines in human detrusor strips with intact and denuded urothelium and their modulation by subtype selectiveβ-AR blockers.

Precontraction, KCl 40 mMMean ± SEM

Precontraction, carbachol 1 μMMean ± SEM

EFSMean ± SEM

β-AR agonist β-AR blocker Urothelium −logEC50, M Emax, % n −logEC50, M Emax, % n −logEC50, M Emax, % n

Isoprenaline None Intact 6.73 ± 0.25 50 ± 5 7 6.73 ± 0.12 51 ± 5 7 6.27 ± 0.34 44 ± 8 5None Denuded 6.74 ± 0.17 64 ± 5 11 6.67 ± 0.07 64 ± 2 9 5.95 ± 0.28 64 ± 6 5

Noradrenaline None Detached 6.19 ± 0.01** 6.19 ± 0.01** 9 6.19 ± 0.01** 68 ± 7 6 n.d. n.d.None Intact 6.20 ± 0.07** 6.20 ± 0.07** 8 6.20 ± 0.07** 55 ± 3*** 12 6.07 ± 0.96 30 ± 10 6None Denuded 6.57 ± 0.08 84 ± 3 9 6.41 ± 0.09 70 ± 3 24 6.48 ± 0.31 55 ± 8 7CGP20712A; 300 nM Intact 5.80 ± 0.39 69 ± 1* 4 6.01 ± 0.12 60 ± 4* 4

Denuded 6.33 ± 0.25 80 ± 4 3 6.46 ± 0.39 80 ± 5 4ICI118,551; 50 nM Intact 6.52 ± 0.03 73 ± 7 3 6.39 ± 0.16 72 ± 1 4

Denuded 6.80 ± 0.16 88 ± 3 3 6.60 ± 0.23 79 ± 5 4L-748,337; 100 nM Intact 5.81 ± 0.12 78 ± 2 7 5.15 ± 0.20 68 ± 2 8

Denuded 5.57 ± 0.18 66 ± 4 11 5.44 ± 0.12 73 ± 2 6ICI 118.551, 50 nM and

L-748,337, 100 nMIntact 5.14 ± 0.10 58 ± 4** 6Denuded 5.20 ± 0.11 77 ± 5 8

Emax, maximum response in % of response to 10 μM forskolin (=100%). Significant difference when compared with respective values for urothelium-denuded detrusor strips *P < 0.05;**P < 0.01; ***P < 0.001.

Fig. 4 Concentration–response curves for (−)-noradrenaline-evoked relaxation of KCl- or carbachol-precontracted human detrusor strips with intact or

denuded urothelium. Effects of the subtype-selective β1-AR blocker CGP 20712A, 300 nM (A), the β2-AR blocker ICI 118,551, 50 nM (B) and the β2-AR

agonist salbutamol (C) on KCl- and carbachol-(CCh)-induced contractions. Data are expressed in % of maximum relaxation induced by 10 μM

forskolin (=100%) and mean (SEM) from n investigated strips.

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Impact of mucosa on detrusor muscle function

© 2013 The AuthorsBJU International © 2013 BJU International 1219

regardless of the presence or absence of urothelium(Fig. 5).

Schild plot analysis revealed that slopes were not significantlysteeper than those with data from intact and denuded strips.The affinity estimate for L-748,337 was larger for β3-ARs ofdenuded than intact detrusor with mean (SEM) apparentaffinity values of 8.01 (0.05) and 7.61 (0.08) [Fig. 5].

DiscussionThe aim of the present study was to characterize the influenceof the urothelium on human detrusor smooth muscle function.The major novel findings were: (i) the presence of anintact urothelium reduced the potency and efficacy of(−)-noradrenaline-induced relaxation; (ii) blockade of β1-ARs didnot affect (−)-noradrenaline-induced relaxation of denuded andintact strips, whereas blockade of β2-ARs abolished the differenceso that intact strips responded like denuded strips; and (iii) theβ3-AR blocker L-748,337 antagonized the (−)-noradrenaline-evoked relaxation more in urothelium-denuded than in intactstrips.

Using a large number of detrusor strips we have confirmedour previous data, showing that the presence of urotheliumsignificantly attenuated contractile responses to high KCl andcarbachol [22], although lower KCl concentrations (40 mM)were used in the present study, and also reduced responses toEFS. Assuming that the urothelium accounts for the differences

in responses to contracting agents between intact and denudedstrips, it could decrease drug responses by reducing access forthe drug to smooth muscle [3], by causing drug degradation[23] or by releasing a urothelium-derived inhibitory factor [2].Detached mucosa placed close to the smooth muscle suppressedcontractile responses almost as effectively as in intacturothelium strips. In addition, differences in force ofcontraction with and without urothelium faded away with time(45 min). These findings support the idea that the urotheliumreleases a diffusible factor upon muscarinic stimulation, eitherdirectly or by depolarization, and that this urothelium-derivedinhibitory factor may not be stable over time. It has beenproposed that the factor may modulate pressure changes duringfilling of the bladder [2]. In addition, the effects caused by theurothelium-derived inhibitory factor are not influenced by anyof the following factors: inhibition of nitric oxide synthase,cyclooxygenase products, adenosine, purinergic receptors orpotassium channels [2,5].

The situation was reversed when detrusor strips were relaxedby stimulation of β-ARs. Urothelium-denuded strips relaxedmore completely than intact muscle strips and required lowerconcentrations of (−)-noradrenaline for relaxation, but therewere no differences for (−)-isoprenaline. Others have reportedthat passively stretched human detrusor was relaxed morepotently by isoprenaline in the absence than in the presence ofurothelium [19]. In other species, such as pig, relaxationresponses attributable to isoprenaline appeared not to be

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Fig. 5 Concentration–response curves for

(−)-noradrenaline-evoked relaxation in the

presence of increasing contractions the

selective β3-AR antagonist L-748,337.

Carbachol-(CCh) precontracted detrusor strips

without urothelium (‘denuded’, top left) and

intact urothelium (bottom left). Right: Schild

plots for L-748,337. Data are expressed in % of

maximum relaxation induced by 10 μM

forskolin (=100%), and mean (SEM) from ninvestigated strips.

Propping et al.

© 2013 The Authors1220 BJU International © 2013 BJU International

affected by the urothelium [20], although the former studyused different carbachol concentrations to induce stable andsimilar size precontractions in intact and denuded strips.Because of these conflicting results, the role of the urotheliumin the relaxant effect of (−)-isoprenaline cannot be resolved atpresent.

All three β-AR subtypes are expressed at the mRNA level indetrusor tissue [12,24] and also in urothelium [10,19] fromvarious species. Nomiya and Yamaguchi [9] reported that themRNA of β3-AR would represent ∼94% of mRNA from allAR subtypes detected in the human bladder. Also, infunctional studies, β3-ARs have been shown to be thepredominant subtype for the relaxation responses in humanurinary bladder with minor [12,14,15,17,24,25] or noinvolvement of β1-ARs or β2-ARs [17].

As the presence of urothelium significantly inhibitedrelaxation attributable to (−)-noradrenaline, we investigatedwhich β-AR subtype might be involved in the catecholamine-stimulated urothelium-mediated modulation of relaxationwith the natural neurotransmitter (−)-noradrenaline ratherthan with (−)- isoprenaline. Selective β1-AR blockade withCGP 20712A did not influence (−)-noradrenaline-induceddetrusor relaxation, irrespective of the presence or absence ofmucosa. Interestingly, the β2-AR antagonist ICI 118,551abolished the differences in potency and efficacy of(−)-noradrenaline between denuded and intact strips, byshifting the concentration–response curve for intact strips tothat for denuded strips; therefore, activation of β2-AR in theurothelium appears to be responsible for the reduced efficacyand potency of (−)-noradrenaline in intact strips. In analogyto the urothelium-derived relaxing factor released bycontractile stimuli such as carbachol and high KCl,impairment of relaxation could be mediated by aurothelium-derived contractile factor released bystimulation of β2-ARs.

By contrast to (−)-noradrenaline, (−)-isoprenaline andsalbutamol did not facilitate detrusor relaxation inurothelium-denuded preparations. This is puzzling becausethe affinity of (−)-noradrenaline for recombinant β2-ARsis seventeenfold and fourfold lower than the affinity of(−)-isoprenaline and salbutamol, respectively, and its efficacyis only half that of these agonists [26]. We would haveexpected at least a similar potency difference between intactand denuded detrusor with (−)-isoprenaline and salbutamol,as found with (−)-noradrenaline but there was no differenceat all. It would appear, therefore, that the β2-ARs of theurothelium, when activated by (−)-noradrenaline, but not by(−)-isoprenaline or salbutamol, selectively blunt the(−)-noradrenaline-evoked detrusor relaxation mediatedthrough β3-ARs.

Interestingly, blockade of β2-ARs with ICI 118,551 sensitizedthe intact detrusor to the relaxant effects of (−)-noradrenaline

(Fig. 4). In addition ICI118.551-induced blockade of β2-ARsalso appeared to increase the antagonism by 100 nML-748,337 of the relaxant effects of (−)-noradrenaline atβ3-ARs in intact strips (precontracted with 40 mM KCl),compared with antagonism in the absence of ICI 118551(Fig. 5A,B). L-748,337 100 nM, and to a smaller extent thehigher concentrations of 300 nM and 1 μM, antagonize lessthe detrusor relaxation caused by (−)-noradrenaline in intactthan denuded strips. L-748,337 has also a moderate affinity forhuman β2-ARs with pKD of 6.69 [27]. Thus, it is plausible thathigh concentrations of L-748,337 could block also urothelialβ2-ARs, as did ICI 118,551, thereby enhancing the blockade ofβ3-ARs, as observed with ICI 118,551 (Fig. 4C). The relaxationelicited by (−)-isoprenaline and salbutamol is consistent withmediation through β3-ARs. At recombinant β3-ARs theaffinity of (−)-isoprenaline and (−)-noradrenaline is similarand the affinity of salbutamol approximately thirtyfold lower,but the efficacy of the three agonists is similar [26]. Theseproperties are consistent with the lower relaxant potency ofsalbutamol, compared with (−)-isoprenaline and(−)-noradrenaline.

Since ICI 118,551 only enhances both the relaxation to(−)-noradrenaline and blockade by 100 nM L-748,337 in intactbut not denuded strips, we assume that urothelial β2-ARsblunt the interaction of (−)-noradrenaline and L-748,337 withthe detrusor β3-AR system. The mechanism of the controlof detrusor β3-AR function by urothelial β2-ARs is stillunknown. It may be speculated that urothelial β2-ARs releasea factor from the urothelium that reduces the affinity of(−)-noradrenaline and L-748,337 for β3-ARs. The differentβ-AR subtypes involved in the relaxing effect ofcatecholamines in human detrusor could also be altered bypathology. β3-ARs might be overexpressed in obstructed ordiseased human bladder [9]; however, this issue cannot beresolved because detrusor tissue from healthy humanprobands is not available.

Our findings could also have some clinical implications. Itmay be speculated, that highly selective β3-AR agonists, suchas the recently approved mirabegron [28], may exhibit theirgood clinical efficacy in overactive bladder because they donot blunt relaxation via urothelial β2-AR stimulation as docatecholamines. Conversely, adding a selective β2-ARantagonist might even further improve β3-AR mediatedrelaxation.

In conclusion, the presence of urothelium in human detrusorhas dual effects: the mucosa impairs force development uponstimulation with KCl, carbachol or EFS, but also blunts therelaxing effects of catecholamines. Whilst β3-ARs mediatehuman detrusor relaxation, the blunting effect of theurothelium on this relaxation involves activation of β2-ARs.These findings may explain the good clinical efficacy ofselective β3-AR agonist as compared with non-selective β-ARagonists.

Impact of mucosa on detrusor muscle function

© 2013 The AuthorsBJU International © 2013 BJU International 1221

AcknowledgementsWe thank Maria Feilmeier for her excellent technical help.

Conflict of InterestNone declared.

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Correspondence: Ursula Ravens, Institut für Pharmakologieund Toxikologie Fetscherstrasse 74, 01307 Dresden, Germany.

e-mail: ravens@rcs.urz.tu-dresden.de

Abbreviations: EFS, electric field stimulation; AR,adrenoceptor; -logEC50, negative logarithm of the molarconcentration producing 50% of the maximum relaxing effect.

Propping et al.

© 2013 The Authors1222 BJU International © 2013 BJU International