Accepted Manuscript

Selective β3-Adrenoceptor Agonists in the Treatment of the Overactive Bladder

Karl-Erik Andersson, Nancy Martin, Victor Nitti

PII: S0022-5347(13)00380-7 DOI: 10.1016/j.juro.2013.02.104

Reference: JURO 9999

To appear in: The Journal of Urology Accepted date: 20 February 2013 Please cite this article as: Andersson, K.E., Martin, N., Nitti, V., Selective β3-Adrenoceptor Agonists in the Treatment of the Overactive Bladder, The Journal of Urology® (2013), doi: 10.1016/j.juro.2013.02.104. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

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February 28, 2013

Selective β3−Adrenoceptor Agonists in the Treatment

of the Overactive Bladder

Karl-Erik Andersson1, Nancy Martin2, Victor Nitti3

1Institute for Regenerative Medicine, Wake Forest University School of Medicine, NC,2Astellas Scientific and Medical Affairs, Northbrook, IL, 3New York University Urology Associates, New York, New York

Correspondence:

K-E Andersson, MD, PhD

Institute for Regenerative Medicine

Wake Forest University School of Medicine

Medical Center Boulevard

Winston Salem, NC 27157

Tel 336.713.1195

Fax 336.713.7290

e-mail: keanders@wfubmc.edu

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Key words: adrenoceptors, detrusor smooth muscle, urodynamics, controlled clinical trials

Abbreviations and Acronyms

OAB = overactive bladder

RCT = randomized controlled clinical trial

AR = adrenoceptor

DO = detrusor overactivity

RT -PCR = reverse transcription polymerase chain reaction

ATP = adenosine triphosphate

NO = nitric oxide

PG = prostaglandin

BKca = calcium activated big potassium channel

PKA = protein kinase A

cAMP = cyclic adenosine monophosphate

  

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Abstract

Background and Purpose. Bladder effects of isoprenaline and selective β1− and β2−adrenoceptor

(AR) agonists reported in early studies suggested that bladder β−ARs are "atypical". Since there

is a lack of alternatives to antimuscarinics in the treatment of overactive bladder (OAB)

symptoms, there has been an intensive search for new drug targets. The discovery of the β3−AR

with high expression in the bladder, suggested that this receptor, mediating detrusor relaxation,

could be a target for treatment of patients with OAB symptoms. Methods. An overview of

published literature on β−ARs and bladder (MEDLINE) was performed. The US Food and Drug

Administration web site, clinicaltrials.gov, and controlled-trials.com online trial registries were

searched for English-language articles containing the terms β3−ARs and β3−AR agonists. In

addition, abstracts from recent international scientific meetings were searched for randomised

controlled trials (RCTs) on β3−AR agonists. Results. Stimulation of β3-ARs relaxes detrusor

smooth muscle, decreases afferent signaling from the bladder, improves bladder compliance on

filling, and increases bladder capacity.  RCTs show that the selective β3-AR agonist,

mirabegron, for which most information is available and which is approved in Japan, USA, and

Europe, reduces the number of micturitions and incontinence episodes in a 24-h period

compared with placebo. The most common adverse effects recorded are dry mouth (placebo

level) and gastrointestinal disturbances rated as mild to moderate. Small rises in mean heart rate

(1 beat /minute) and blood pressure (1 mm Hg) have been demonstrated in OAB patients.

Conclusions. Available information suggests that β3−AR agonists may be a promising

alternative to antimuscarinics in the treatment of OAB. However, further clinical experiences

outside clinical trials, and information on the long-term use in terms of efficacy, safety, and

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tolerability are warranted to optimally characterize the position of β3−AR agonists in the

treatment algorithm for OAB.

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Background.

In 1948, the existence of two broad subtypes of adrenoceptors (AR), α-ARs and β-ARs, were first

demonstrated.1 In the late 1960, two subtypes of β-ARs, β1 and β2, were identified and

characterized,2 while a third, β3, was isolated and cloned in 1989.3 β3-ARs are widely distributed in

the body, including adipose tissue, the heart and vascular system, and the urinary bladder, however,

the distribution is highly species dependent.4, 5 In isolated human bladder, non-subtype selective β-

AR agonists like isoprenaline have a pronounced inhibitory effect, and administration of such drugs

can increase bladder capacity in man.6 Early functional studies on bladders from animals (cat) and

humans suggested that such effects may be mediated by an "atypical' β-AR, since the β-ARs had

functional characteristics typical of neither β1-, nor β2- ARs.7, 8 Thus, the effects could be blocked by

propranolol (non-subtype selective), but not by practolol (β1) or metoprolol (β1) or butoxamine (β2).

Despite these functional data, it was suggested, based on receptor binding studies using subtype

selective ligands, that the β-ARs of the human detrusor were primarily of β2 subtype.6 Favourable

effects in patients with detrusor overactivity (DO) were reported in open studies with selective β2-

AR agonists such as terbutaline.9 However, further studies were unable to show that non-subtype or

β2-AR selective agonists represent an effective therapeutic principle in the treatment of the

overactive bladder (OAB).10

All three β-AR subtypes (β1, β2, and β3) have been identified in the detrusor of most species,

including humans.11 In addition, the human urothelium contains the three receptor subtypes,12

Studies using real-time RT-PCR have revealed a predominant expression of β3-AR mRNA in human

detrusor muscle.11, 13 As pointed out by Frazier et al.14 studies at the protein level have been difficult

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to interpret because none of the available radioligands is suited to detect β3-ARs. However, the

preclinical functional evidence for an important role of β3-ARs in both normal and neurogenic

bladders is convincing.15 The human detrusor also contains β2-ARs, and most probably both

receptors are involved in the physiological detrusor effects (relaxation) of noradrenaline.11

Rationale for use of selective β3-AR agonists in OAB. Several factors may contribute to OAB,

defined either based on symptoms (the OAB syndrome) or urodynamics (DO). Various theories

have been put forward and are discussed in detail elsewhere.16 OAB is a filling disorder, and

recent research has focused on afferent bladder function. Two signaling pathways by which

afferent information is generated and conveyed to the central nervous system, the myogenic and

the urothelial pathways, have been defined.17 (Figures 1 and 2)

It is well established that β-AR stimulation has relaxant effects on detrusor muscle, either from

basal tone or when contracted by KCl or various agonists.15 However, two types of detrusor

contraction can be observed. One is the voiding contraction, which is a well coordinated bladder

contraction caused by release of acetylcholine and other contractant transmitters (e.g., ATP)

from cholinergic nerves. This contraction requires parasympathetic output from the sacral spinal

cord. The other type of contraction is the spontaneous (autonomous) contractile activity

occurring during bladder filling, which can be demonstrated in vitro and in vivo, 21 Both

preclinical and clinical studies have shown that β3-AR agonists have no significant negative

effects on the voiding contraction,15 suggesting a more limited potential for urinary retention.

The normal stimulus for activation of the micturition reflex is considered to be distension of the

bladder, initiating activity in ‘‘in series’’-coupled, low-threshold mechanoreceptive (Aδ)

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afferents.19 It is obvious that if this response to distension is decreased by the detrusor muscle

being relaxed and more compliant, the afferent activity needed to initiate micturition will be

delayed and bladder capacity increased. Such an effect may be obtained by stimulating the β3-

ARs on the detrusor muscle. There are reasons to believe that the spontaneous contractile, phasic

activity of the detrusor smooth muscle during filling not only can create tone in the detrusor

muscle, but also generate afferent input (‘‘afferent noise’’), contributing to OAB/DO. In fact.

Aizawa et al.20 showed in rats that the β3-AR agonist, CL316,243, could inhibit filling-induced

activity not only in mechano-sensitive Aδ-fibers, but also in C-fiber primary bladder afferents

provided that these fibers were stimulated by prostaglandin (PG) E2. A more recent study from

the same group confirmed similar findings with mirabegron.21 β3-AR agonists have a

pronounced effect on spontaneous contractile activity in detrusor muscle in vitro (Figure 3),22

which may be an important basis for their clinical effects.

Changes in urothelial receptor function and neurotransmitter release, may lead to changes of

bladder contraction.23, 24 The urothelium interacts closely with underlying structures, e.g., the

interstitials cells and afferent nerves, and these structures appear to work together as a functional

unit.23, 24 The detrusor muscle, the urothelium, interstitial cells, and the afferent nerves all contain

β3-ARs, 12, 25, 26 which may be targeted and when stimulated may contribute to the effects of β3-

AR agonists. The possible role of urothelial β3-ARs in bladder relaxation has been investigated

by several investigators.12, 25 Murakami et al.25 found in human bladder strips that the presence of

urothelium caused a parallel rightward shift of the concentration-response curve to isoprenaline

and suggested that urothelial β3-AR stimulation could induce the release of a urothelium-derived

factor which inhibited the β3-AR agonist-induced relaxation of the detrusor smooth muscle.

However, to what extent a urothelial signaling pathway contributes in vitro and in vivo to the

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relaxant effects of β-AR agonists in general, and β3-AR agonists specifically, remains to be

elucidated.

The generally accepted molecular mechanism by which β-ARs mediate detrusor relaxation in most

species, is activation of adenylyl cyclase and subsequent formation of cAMP, which activates

protein kinase A (PKA). This enzyme, in turn, phosphorylates specific proteins resulting in detrusor

relaxation. However, there is evidence suggesting that in the bladder K+ channels, particularly BKCa

channels, may be more important in β3-AR mediated relaxation than cAMP.14, 27, 28 To what extent

each of these downstream signal cascade mechanisms contribute to the overall effect of the β-AR

agonists remains to be established.

The in vivo effects of β3-AR agonists on bladder function have been studied in several animal

models. It has been shown that compared with other agents (including antimuscarinics), β3-AR

agonists increase bladder capacity with no change in micturition pressure and the residual volume.17

For example, Hicks et al.29 studied the effects of the selective β3-AR agonist, GW427353

(solabegron), in the anesthetized dog and found that the β3−AR agonist evoked an increase in

bladder capacity under conditions of acid evoked bladder hyperactivity, without affecting voiding.

Effects of β3-ARs outside the bladder

Since the presence β3-ARs have been demonstrated in several tissues outside the bladder, such

as adipose tissues, heart, blood vessels, gastrointestinal, tract, prostate, brain, and near-term

myometrium,4 there is a consideration of "off target" effects of β3-AR stimulation when treating

OAB. Possible effects on the heart and vasculature have been the main concerns.

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There is evidence for expression of β3-AR mRNA in the human heart, but the receptor protein

does not seem to have been consistently demonstrated, and the functional role of β3-ARs has not

been established.30 In the normal heart, β3-ARs may mediate a moderate negative inotropic

effect, but in heart failure, it may protect against adverse effects of excessive catecholamine

stimulation by action on excitation-contraction coupling, electrophysiology, or remodeling.31 No

negative effects on cardiac contractility have been reported in the treatment of OAB patients.32

Cardiac electrophysiology has been extensively evaluated.31,33 There seems to be no evidence for

a direct effect of β3-AR agonists on the sinus node and consequent changes in heart rate.31

However, in a study on healthy volunteers,32 mirabegron increased heart rate in a dose-dependent

manner. Maximum mean increases in heart rate from baseline for the 50 mg, 100 mg, and 200

mg dose groups compared to placebo were 6.7 beats per minutes (bpm), 11 bpm, and 17 bpm,

respectively.32 However, in the clinical efficacy and safety studies, the change from baseline in

mean pulse rate for mirabegron 50 mg was approximately 1 bpm and reversible upon

discontinuation of treatment. Whether this discrepancy is dependent on the use of different

administration forms (rapid vs extended release) is unclear.

So far, there is no clinical evidence that β-AR agonists are causing QT-prolongation and

ventricular arrhythmia at therapeutic doses (see below).

In some vascular beds β-AR stimulation has been demonstrated to cause dilatation both directly

and via release of NO,31, 34 which could be expected to reduce blood pressure. This is in contrast

to what has been observed clinically. In healthy subjects, mirabegron (50-300 mg/day for 10

days) increased blood pressure dose-dependently.32 However, in the studies on OAB patients the

mean increases (compared to placebo) in systolic/diastolic blood pressure after therapeutic doses

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of mirabegron once daily was approximately 0.5 - 1 mmHg and reversible upon discontinuation

of treatment.32 Again, whether this discrepancy is dependent on the use of different

administration forms is unclear.

Pharmacology of selective β3-adrenoceptor agonists.

The selective β3-AR agonist, mirabegron,35 has been approved for treatment of OAB in Japan

(Betanis®), USA (Myrbetriq®), and Europe (Betmiga®). There are proof of concept studies for

other β3-AR selective agonists such as and solabegron and ritobegron.36 However, the

development of ritobegron has been ceased since in failed to reach the primary efficacy endpoint

in phase III studies. Other agents, e.g., TRK-380, 37 is in pre-clinical development for the

treatment of OAB.

Mirabegron. Takusagawa et al. found that mirabegron was rapidly absorbed after oral

administration. It circulates in the plasma as the unchanged form, its glucuronic acid conjugates

and other metabolites, the metabolites being inactive.38 Of the administered dose, 55% is

excreted in urine, mainly as the unchanged form, and 34% is recovered in feces, almost entirely

as the unchanged form. Mirabegron is highly lipophilic and is metabolized in the liver via

multiple pathways, mainly by cytochrome P450 3A4 and 2D6 (CYP2D6).39, 40 In a Phase I

pharmacokinetic study, sixteen healthy volunteers, phenotyped as either poor or extensive

metabolizers of CYP2D6 were enrolled. The volunteers received a 160 mg single oral dose after

overnight fasting. Poor metabolizers excreted a slightly higher urinary fraction of mirabegron

(15.4±4.2%) than extensive metabolizers (11.7±3.0%). Tmax in both extensive and poor

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metabolizers was about 2 hours and the terminal elimination half-life (t1/2) approximately 23-25

hours.41,42

The cardiac safety of mirabegron was evaluated in a thorough QT/QTc (heart rate (HR)-

corrected QT interval) study, including supratherapeutic doses. This was a randomized, placebo-

and active- controlled (moxifloxacin 400 mg) four-treatment-arm parallel crossover study 43 and

the design followed the recommendations of The International Conference on Harmonisation

(ICH). The effect of multiple doses of mirabegron 50 mg, 100 mg and 200 mg once daily on

QTc interval was studied, and according to ICH E14 criteria, mirabegron did not cause QTcI

prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex.

Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95%

CI >10 ms) in females, but not in males.

Clinical experiences with mirabegron. Chapple et al.44 reported the results of a phase IIA trial of

mirabegron in patients with OAB - the "Blossom trial", which was conducted in several

European countries, as a proof of concept study. It enrolled 314 patients with OAB symptoms -

262 patients were randomly assigned to 4 groups: placebo, mirabegron 100 mg bid, mirabegron

150 mg bid, and tolterodine 4 mg qd for a 4-week treatment period. The primary endpoint was

efficacy, and the primary efficacy variable was the change in the mean number of micturitions

per 24 hours as recorded on a frequency/volume chart. In both mirabegron groups significant

improvements in the mean number of micturitions per 24 hours were found compared with the

placebo group (−2.19 and −2.21 vs. −1.18, respectively). Mean volume voided was dose-

dependently increased in the mirabegron groups, and the change reach significance in the

mirabegron 150 mg group. Urgency episodes per 24 hours decreased significantly in both

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mirabegron groups compared with the placebo group. No severe adverse events were reported

and treatment was generally well tolerated. A mean increase in pulse rate with mirabegron 150

mg (5 beats per minute) was demonstrated, but this was not associated with a clinically

significant increase in adverse events such as tachycardia and palpitations. The effect of

mirabegron was numerically better than that of tolterodine, but the study was not powered for a

direct comparison. This successful phase IIA study was followed by a phase IIB trial in OAB

patients carried out in Europe.45 This trial was a dose-ranging study of once-daily mirabegron (an

extended release formula of mirabegron) with multiple arms (placebo, mirabegron 25 mg, 100

mg, 150 mg, and 200 mg qd, for a 12-week treatment period), and the primary endpoint was to

evaluate the dose-response relationship on efficacy. The mean number of micturitions per 24

hours decreased dose-dependently, and the decreases were statistically significant with

mirabegron 50, 150 and 200 mg compared with placebo. The mean volume voided per

micturition increased dose-dependently, and the increases were significant with mirabegron 50

mg and more. Adverse events were experienced by 45.2% of the patients - the incidence of

adverse events was similar among all treatment groups (placebo 43.2% vs. mirabegron 43.8-

47.9%). The overall discontinuation rate owing to adverse events was 3.2% (placebo 3.0% vs.

mirabegron 2.4-5.3%). The most commonly reported adverse events considered treatment-related

was gastrointestinal disorders, including constipation, dry mouth, dyspepsia, and nausea. There

was no patient-reported acute retention. No significant difference in ECG parameters between

the groups was demonstrated. However, a small but significant increase in mean pulse rate was

observed after mirabegron 100 and 200 mg (1.6 and 4.1 beats per minute, respectively), although

this was not associated with an increase in cardiovascular adverse events in this study.

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Three pivotal phase III studies have been performed.46-48 Nitti et al.46 reported on a phase III

multicenter, randomized, double-blind, parallel-group, placebo-controlled trial of mirabegron in

North America. They enrolled 1329 patients ≥18 years with OAB symptoms for ≥3 months.

Patients who completed a 2-week, single-blind, placebo run-in and had ≥8 micturitions/24 h and

≥3 urgency episodes/72 h (with or without incontinence) during a 3-day micturition diary period,

were randomized to receive placebo, or mirabegron 50 or 100 mg once daily for 12 weeks. Co-

primary endpoints were change from baseline to final visit (study end) in the mean number of

incontinence episodes/24 h and micturitions/24 h. Efficacy was assessed according to patient

micturition diaries and safety assessments included adverse event reporting. Patients were

randomized and received study drug (placebo: n=453; mirabegron 50 mg: n=443; mirabegron

100 mg: n=433). Mean age was 60.1 years, 74.3% were female, 29.7% had urgency

incontinence, 38.3% had mixed stress/urgency incontinence with urgency predominant and

32.2% had frequency without incontinence. At the final visit, mirabegron 50 and 100 mg showed

statistically significant improvements in the co-primary efficacy endpoints and mean volume

voided/micturition compared with placebo. Statistically significant benefits were achieved at the

first-measured time point of week 4. The incidence of adverse effects was similar across the

placebo and mirabegron 50 and 100 mg groups (50.1, 51.6 and 46.9%, respectively). The most

common (≥3%) adverse effects in any treatment group were hypertension (6.6, 6.1 and 4.9%,

respectively), urinary tract infection (1.8, 2.7 and 3.7%), headache (2.0, 3.2 and 3.0%) and

nasopharyngitis (2.9, 3.4 and 2.5%).

Khullar et al.47 performed a similarly designed study in Europe and Australia, enrolling 1978

patients, which included a fourth arm in which tolterodine SR 4 mg was used as a comparator.

Like the American study, Khullar et al. found that mirabegron caused a statistically significant

14  

improvements from baseline compared with placebo in the number of urgency incontinence

episodes and number of micturitions per 24 hours. Mirabegron 50 and 100 mg was statistically

superior to placebo, whereas tolterodine was not, in these two key OAB symptoms, but the

study was not powered for head-to-head evaluation. Mirabegron 50 and 100 mg was well

tolerated. In particular, the incidence of hypertension or UTI were generally similar across

treatments within this study. In contrast with tolterodine, no increased dry mouth incidence was

observed with mirabegron relative to placebo.

In a third phase 3 study48, evaluating the effects of 25 and 50 mg mirabegron, both doses were

associated with significant improvements in efficacy measures of incontinence episodes and

micturition frequency. In mirabegron-treated patients, the overall incidence/severity of adverse

effects was similar to that of placebo.

In a 12-month study to assess safety and efficacy of mirabegron, Chapple et al.49 randomized a

total of 812, 820, and 812 patients to receive mirabegron 50 mg, mirabegron 100 mg, and

tolterodine ER 4 mg, respectively. The primary variable was incidence and severity of treatment-

emergent adverse, and secondary variables were change from baseline at months 1, 3, 6, 9, and

12 in key OAB symptoms. The study had no placebo control. It was found that mirabegron and

the active control, tolterodine, improved key OAB symptoms from the first measured time point

of 4 wk, and efficacy was maintained throughout the 12-mo treatment period.

Clinical experiences with solabegron. Ohlstein et al.50 evaluated the efficacy and tolerability of

solabegron in a clinical proof-of-concept study in 258 incontinent (one or more 24-h

incontinence episodes and eight or more average 24-h micturitions) women with OAB

symptoms. The study was randomized, and double-blinded and the patients were given

15  

solabegron 50 mg (n = 88), 125 mg (n = 85), or placebo (n = 85) twice daily. The primary

efficacy parameter was percentage change from baseline by week 8 in the number of

incontinence episodes over 24 h. Secondary end points included actual change in micturitions

and urgency episodes per 24 h, and volume voided per micturition. Solabegron 125 mg produced

a statistically significant difference in percent change from baseline by week 8 in incontinence

episodes over 24 h when compared with placebo (p = 0.025), and showed statistically significant

reductions from baseline by weeks 4 and 8 in micturitions over 24 h and a statistically significant

increase from baseline to week 8 in urine volume voided. The drug was well tolerated, with a

similar incidence of adverse effects in each treatment group. Systolic blood pressure, diastolic

blood pressure, mean arterial pressure, or heart rate during the 24-h ambulatory measurement,

were not reported as significantly changed.

The promise of selective β3−adrenoceptor agonists in the treatment of OAB

The published evidence for mirabegron and solabegron appears to favor selective β3-AR agonists

as a new effective and well-tolerated class of drug for patients with OAB symptoms. In

comparison with antimuscarinics, only a relatively small number of patients have been studied so

far. In view of its pharmacokinetics, mirabegron has the potential for adverse drug interactions

with other CYP2D6 substrates with narrow therapeutic index. This, in addition to the effect on

the cardiovascular system, needs careful evaluation, especially in the elderly population.

Prospective evaluation of co-administration of β3-AR agonists with antimuscarinics seems

attractive for treatment of the OAB syndrome and is reasonable to examine. However, such

information is not yet available. Although available long-term data are limited, β3-AR agonists

as a class can be considered an attractive alternative to antimuscarinics for treatment of OAB.

16  

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22  

Legends to figures

Figure 1

When activated by mechanical or chemical stimuli, the urothelium generates and releases

different agents (e.g., ATP: adenosine triphosphate, ACh: acetylcholine; PGs: prostanoids; NO:

nitric oxide) with stimulating (+) or inhibitory (-) effects on underlying structures, resulting in

modification of the activity in the afferent nerves

Figure 2

During bladder filling, there is no activity in the parasympathetic outflow from the bladder.

However, the myocytes have a spontaneous (autonomous) contractile activity that generates

afferent nerve activity (C-fibers and Aδ-fibers).

Figure 3

The effect on resting tone of solabegron(GW427353; 10−6 M) in a human detrusor strip showing

spontaneous activity (A), and in a ‘normal’ human detrusor strip (B). Values are expressed as the

mean (SEM) percentage of the control tone. ***P < 0.001. (from reference 22)