On the Site and Mechanism of Action of β3-Adrenoceptor Agonists in the Bladder

Article information

Int Neurourol J. 2017;21(1):6-11
Publication date (electronic) : 2017 March 24
doi : https://doi.org/10.5213/inj.1734850.425
1Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Corresponding author: Karl Erik Andersson http://orcid.org/0000-0002-9637-6330 Department of Clinical Medicine, Aarhus University, Incuba/Skejby, bygning 2, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark E-mail: kea@aias.au.dk / Tel: +45-510-717-3765
Received 2017 March 8; Accepted 2017 March 10.


The clinical success of mirabegron as the first β3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β3-AR stimulation have still not been established. The recent demonstration of β3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β3-ARs can be found these structures. However, recent studies suggest that the β3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.


Mirabegron has been successfully introduced into clinical practice as the first selective β3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome [1-3], and its clinical success has resulted in an increased interest in the site and mechanism of action of β3-AR agonists. β-AR agonists, including mirabegron, have been suggested to relieve OAB symptoms through various mechanisms, e.g., direct relaxation of detrusor muscle by stimulation of cyclic AMP (cAMP) generation [4,5], opening of potassium channels [6,7], inhibition of spontaneous contractile activity in the bladder [8,9], and reduction in bladder afferent activity [9,10]. However, the site(s) and mechanism(s) of action of β3-AR agonists have not been established and has been the subject of several recent studies.


It seems reasonable to assume that there should be a relation between the distribution of adrenergic nerves and the location of β3-ARs. The sympathetic innervation to the urinary tract consists of short preganglionic neurons and long postganglionic neurons originating from the paravertebral and prevertebral ganglia [11]. Efferent sympathetic and parasympathetic fibres are conveyed to the genitourinary organs via the hypogastric and pelvic splanchnic nerves, respectively. The hypogastric and pelvic splanchnic nerves of either side meet and branch to form the pelvic plexus. The part of the plexus related to the urinary bladder—the vesical plexus—contains both sympathetic and parasympathetic neurons. The vesical plexus lies adjacent to the posterior and lateral walls of the urinary bladder. Similar mixed autonomic ganglia occur throughout all regions of the human bladder wall, both within and on the outer surface of the detrusor muscle with occasional ganglia being found in the lamina propria [11].

Bladder Body

The body of the human bladder receives a relatively sparse innervation by noradrenergic nerves [11], and Coelho et al. [12] observed that numerous smooth muscle areas were without any tyrosine-hydroxylase (key enzyme involved in noradrenaline synthesis) immunoreactive fibres. The density of noradrenergic nerves increases markedly toward the bladder neck, where the smooth muscle receives a dense noradrenergic nerve supply, particularly in the male [11]. Noradrenergic nerves can be found also in the lamina propria of the bladder, only some of which are related to the vascular supply [11,12].

The bladder and urethra form a functional unit, but the adrenergic nerves innervating these structures have different distribution and mediate different effects. It is generally considered, based on animal studies, that the activity in the adrenergic nerves keeps the bladder relaxed and the urethra contracted during filling [4,9]. However, the importance of the sympathetic input for human bladder function during the storage phase has not been established. Sympathectomy has no distinct effect on bladder filling in humans, and neither has blockade of β-ARs [13]. Furthermore, since patients with deficiency of dopamine β-hydroxylase, the enzyme that converts dopamine to noradrenaline, void normally [14], the sympathetic nervous system may not be essential for urine storage in humans. The density of noradrenergic nerves increases markedly towards the bladder neck, the majority of these nerves being intramuscular in location. The noradrenaline content of the bladder neck is higher than that of the bladder dome and the noradrenergic nerves have been shown to cause smooth muscle contraction and thus closure of the bladder neck. The trigone has a different embryological origin from the detrusor muscle and its pattern of innervation is readily distinguished from the bladder body. The superficial trigone receives a rich innervation by noradrenergic nerves although the precise function of this muscle layer is not established [11].

The effects of noradrenaline on structures in the bladder body are presumably mediated via β3-ARs (see below). However, the transmitter has different effects on different parts of the bladder and on the various structures in the bladder wall. Based on animal data, it has been assumed that there is a release of noradrenaline during filling. If this is the case also in humans, it is unclear how this affects the different structures in the bladder wall, e.g., the urothelium, interstitial cells, intramural ganglia, and bladder vasculature.


There are well known anatomical differences between the male and female urethra, and this is also reflected in the innervation. In the human male, the smooth muscle surrounding the preprostatic part of the urethra is richly innervated by both cholinergic and adrenergic nerves [11]. This part is believed to serve as a sexual sphincter, contracting during ejaculation and thus preventing retrograde transport of sperm. The role of this structure in maintaining continence is unclear, but probably not essential. In the human female, there is no anatomical urethral smooth muscle sphincter, and the muscle bundles run obliquely or longitudinally along the length of the urethra. In the whole human female urethra, and in the human male urethra below the preprostatic part, there is a scarce supply of adrenergic nerves along the bundles of smooth muscle cells. Adrenergic terminals can also be found around blood vessels.


Human bladder tissue, taken from the anterior portion of the bladder dome of male patients undergoing radical cystectomy because of malignancy, predominantly expressed β3-AR mRNA (97% β3; 1.5% β1 and 1.4% β2, respectively) [15]. However, all 3 subtypes of β3-ARs (β1, β2, and β3) has been demonstrated in the detrusor muscle of most species [16], and also in the human urothelium [17].

The direct effect of noradrenaline on the detrusor, mediated mainly by β3-ARs, is inhibitory [4]. This does not exclude the possibility that released noradrenaline exerts an inhibitory effect on bladder function by other indirect mechanisms. β3-ARs can be found also in other bladder structures than detrusor and urothelium [12,18]. A recent study [12] demonstrated that β3-ARs are abundantly located in acetylcholine (ACh)-containing nerve fibres in the the mucosa and muscular layers of the human bladder. No β3-AR immunoreactivity was detected on urothelial, suburothelial interstitial cells or smooth muscle cells, which is in contrast to previous findings [17,18]. However, the authors did not exclude the possibility that the receptors on the urothelium or on smooth muscle cells were too few to be detected. Their findings thus suggest that the main site of action of β3-AR agonists may not be the detrusor, which is in support of findings in several functional studies [19-25].

The main effect of noradrenaline on the smooth muscle of the human urethra is to mediate contraction [4]. However, this action is mediated by β1-ARs [26,27], and the role of the urethral β3-ARs is unclear. Radioligand studies shown the presence of β3-ARs in the human external urethral sphincter [28], but the role of these receptors has not been established.


Activation of β3-ARs is associated with relaxation of the bladder during the storage phase of micturition [9,29,30]. The generally accepted mechanism by which β3-ARs induce direct detrusor relaxation in most species, is activation of adenylyl cyclase with the subsequent formation of cAMP [4]. However, studies with adenylyl cyclase or protein kinase A inhibitors have detected only a small, if any, role for this pathway in bladder relaxation [6]. There is compelling evidence suggesting that β-ARs can also stimulate large-conductance Ca2+-activated K+ (BKCa) channels in bladders from several animal species [31-34] and humans [7,35-37]. It is thus well established that these mechanisms can mediate relaxation of detrusor smooth muscle. However, the concentrations of the drugs needed to produce the effects are not always in the range obtained in the human plasma after administration of clinically used doses of e.g., mirabegron [20]. The plasma concentrations of therapeutic doses of mirabegron are in the order of 60–115 nM [38]. In this concentration range, little relaxation can be seen in carbachol-induced contractions in isolated strips of human bladder [39]. Experiments have also been done on isolated strips of the rat bladder demonstrating little or no effect of mirabegron [20,21]. β3-AR agonists have a conspicuous effect on spontaneous bladder contractions in isolated bladder strips from humans [8,9] and several animal species, and on nonvoiding contractions in animal models of increased bladder activity [20,21,24,40].

Gillespie et al. [20,21] have questioned the accepted view on the mode and site of action of β3-AR agonists, and suggested that effects on neither spontaneous contractions, nor on nonvoiding contractions in e.g., obstructed rats, can fully explain the effects of β3-AR agonist stimulation (mirabegron). Since there is evidence that there is a release of ACh during bladder filling [41,42], the finding that activation of prejunctional β3-ARs can decrease ACh release resulting in an inhibitory control of parasympathetic activity may be of interest [22,23]. Electrical stimulation of nerves in the bladder releases ACh from the bladder cholinergic nerves, thus mimicking parasympathetic outflow from the spinal cord. However, during bladder filling, there is no parasympathetic outflow from the spinal cord, which means that the source of ACh, which may be neurogenic or nonneurogenic, is not known. The fact that antimuscarinics works during the filling phase in humans strongly favours that there in fact is a release. It may be speculated that small amounts of ACh are “leaking” from cholinergic nerves and that this amount is sufficient to enhance spontaneous, myogenic contractions and the generation of afferent activity (“afferent noise”). This release may be inhibited by β3-AR agonist stimulation, but it seems unlikely that the massive release of ACh that occurs in the detrusor during voiding can be prevented by the inhibitory action of β3-AR agonists on cholinergic nerve endings. This is in accordance with studies showing that the capacity of β3-AR agonists to inhibit electrically induced ACh release is only partial [22,23], and with the finding that β3-AR agonists have little or no effect on the voiding contraction in humans.


Since β3-ARs are present in the urothelium, their possible role in bladder relaxation has been investigated [17,43,44]. Murakami et al. [43] found that the relaxation responses of the detrusor were not influenced by the urothelium. However, isoprenaline was more potent at inhibiting carbachol contractions in the presence of the urothelium than in its absence. It was suggested that this might reflect the release of an inhibitory factor from the urothelium. Further support for this hypothesis was given by Otsuka et al. [17]. However, to what extent a urothelial signaling pathway contributes in vitro and in vivo to the relaxant effects of β-AR agonists in general, and β3-AR agonists specifically, remains to be elucidated. Birder et al. [45] showed that activation of β-AR by isoproterenol in rat urothelial cells can release nitric oxide through an increase in intracellular Ca2+ by cAMP accumulation. However, activation of urothelial cells also release a urothelial-derived factor that inhibits contractions induced by carbachol in the pig detrusor [43]. The β-AR involved in the release of a urothelial-derived inhibitory factor was shown to be a β3-AR [46]. However, the role of urothelial β3-ARs in bladder relaxation during filling is unclear and has to be established.


Mirabegron is a selective β3-AR agonist whose preclinical pharmacological profile has been well described in vitro and in vivo [5,47,48]. In animal models, mirabegron increases bladder capacity without decreasing the amplitude of the voiding contraction. It increases intervoid intervals, bladder compliance, and reduces nonmicturition contractions, while preserving active voiding function [9,48]. Mirabegron is by far the best investigated β3-AR agonist, and has been used as an important tool for elucidation of β3-AR mediated effects. However, the β3-AR selectivity of the drug has been questioned [49]. Alexandre et al. [50] showed that in addition to its major β3-AR agonistic effect, promoting urethral relaxation in mice, mirabegron exhibited selective α1A- and α1D-AR antagonistic actions that could be expected to contribute to this relaxation. The importance of this additional effect of mirabegron is unclear. The study findings seem to have little, if any, clinical relevance for the effects of mirabegron on the human lower urinary tract, or the use of the drug for the treatment of OAB [51].

β3-AR agonists, including mirabegron, are an alternative therapeutic option for the treatment of urgency and their clinical efficacy (mirabegron) is well documented. β3-AR agonists have a different mode of action from antimuscarinic agents, but both classes of drugs decrease bladder afferent activity, which would make combination therapy an attractive approach for treatment of OAB [52].


The location(s) of β3-ARs in different structures within the bladder wall, and the mode(s) of action of β3-AR stimulation have still not been established. The recent demonstration of β3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies and has to be confirmed. Functional studies strongly suggest that β3-ARs can be found on the detrusor muscle and on the urothelium. With respect to the mode of action of β3-ARs in the mediation of bladder relaxation during filling and decreasing afferent output, recent data suggest that the receptors on detrusor smooth muscle may not be the functionally most relevant. The assumption that β3-AR activation during bladder filling inhibits ACh release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exlude that other mechanisms may be contributing, and supports combined approches to reduce afferent activity for treatment of the OAB syndrome.


Conflict of Interest

No potential conflict of interest relevant to this article was reported.


1. Chapple CR, Cardozo L, Nitti VW, Siddiqui E, Michel MC. Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability. Neurourol Urodyn 2014;33:17–30.
2. Robinson D, Thiagamoorthy G, Cardozo L. A drug safety evaluation of mirabegron in the management of overactive bladder. Expert Opin Drug Saf 2016;15:689–96.
3. Warren K, Burden H, Abrams P. Mirabegron in overactive bladder patients: efficacy review and update on drug safety. Ther Adv Drug Saf 2016;7:204–16.
4. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 2004;84:935–86.
5. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 2007;321:642–7.
6. Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC. Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 2008;377:449–62.
7. Petkov GV. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol 2014;307:R571–84.
8. Biers SM, Reynard JM, Brading AF. The effects of a new selective beta3-adrenoceptor agonist (GW427353) on spontaneous activity and detrusor relaxation in human bladder. BJU Int 2006;98:1310–4.
9. Igawa Y, Michel MC. Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome. Naunyn Schmiedebergs Arch Pharmacol 2013;386:177–83.
10. Aizawa N, Homma Y, Igawa Y. Effects of mirabegron, a novel β3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. Eur Urol 2012;62:1165–73.
11. Gosling JA, Dixon JS, Jen PY. The distribution of noradrenergic nerves in the human lower urinary tract. A review. Eur Urol 1999;36 Suppl 1:23–30.
12. Coelho A, Antunes-Lopes T, Gillespie J, Cruz F. Beta-3 adrenergic receptor is expressed in acetylcholine-containing nerve fibers of the human urinary bladder: An immunohistochemical study. Neurourol Urodyn 2017;Feb. 10. [Epub]. https://doi.org/10.1002/nau.23224.
13. Andersson KE. Clinical relevance of some findings in neuro-anatomy and neurophysiology of the lower urinary tract. Clin Sci (Lond) 1986;70 Suppl 14:21s–32s.
14. Gary T, Robertson D. Lessons learned from dopamine b-hydroxylase deficiency in humans. Physiology 1994;9:35–9.
15. Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol 2003;170(2 Pt 1):649–53.
16. Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006;147 Suppl 2:S88–119.
17. Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 2008;377:473–81.
18. Limberg BJ, Andersson KE, Aura Kullmann F, Burmer G, de Groat WC, Rosenbaum JS. β-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder. Cell Tissue Res 2010;342:295–306.
19. Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 2012;110(2 Pt 2):E132–42.
20. Gillespie JI, Rouget C, Palea S, Granato C, Korstanje C. Beta adrenergic modulation of spontaneous microcontractions and electrical field-stimulated contractions in isolated strips of rat urinary bladder from normal animals and animals with partial bladder outflow obstruction. Naunyn Schmiedebergs Arch Pharmacol 2015;388:719–26.
21. Gillespie JI, Rouget C, Palea S, Granato C, Birder L, Korstanje C. The characteristics of intrinsic complex micro-contractile activity in isolated strips of the rat bladder. Naunyn Schmiedebergs Arch Pharmacol 2015;388:709–18.
22. Rouget C, Rekik M, Camparo P, Botto H, Rischmann P, Lluel P, et al. Modulation of nerve-evoked contractions by β3-adrenoceptor agonism in human and rat isolated urinary bladder. Pharmacol Res 2014;80:14–20.
23. D’ Agostino G, Maria Condino A, Calvi P. Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor. Eur J Pharmacol 2015;758:115–22.
24. Granato C, Korstanje C, Guilloteau V, Rouget C, Palea S, Gillespie JI. Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro. Naunyn Schmiedebergs Arch Pharmacol 2015;388:727–35.
25. Eastham J, Stephenson C, Korstanje K, Gillespie JI. The expression of β3-adrenoceptor and muscarinic type 3 receptor immuno-reactivity in the major pelvic ganglion of the rat. Naunyn Schmiedebergs Arch Pharmacol 2015;388:695–708.
26. Taki N, Taniguchi T, Okada K, Moriyama N, Muramatsu I. Evidence for predominant mediation of alpha1-adrenoceptor in the tonus of entire urethra of women. J Urol 1999;162:1829–32.
27. Andersson KE, Gratzke C. Pharmacology of alpha1-adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol 2007;4:368–78.
28. Morita T, Iizuka H, Iwata T, Kondo S. Function and distribution of beta3-adrenoceptors in rat, rabbit and human urinary bladder and external urethral sphincter. J Smooth Muscle Res 2000;36:21–32.
29. Igawa Y, Aizawa N, Homma Y. Beta3-adrenoceptor agonists: possible role in the treatment of overactive bladder. Korean J Urol 2010;51:811–8.
30. Andersson KE, Martin N, Nitti V. Selective β3-adrenoceptor agonists for the treatment of overactive bladder. J Urol 2013;190:1173–80.
31. Petkov GV, Nelson MT. Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in guinea pig urinary bladder smooth muscle. Am J Physiol Cell Physiol 2005;288:C1255–63.
32. Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV. Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels. Am J Physiol Cell Physiol 2008;295:C1344–53.
33. Uchida H, Shishido K, Nomiya M, Yamaguchi O. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 2005;518:195–202.
34. Brown SM, Bentcheva-Petkova LM, Liu L, Hristov KL, Chen M, Kellett WF, et al. Beta-adrenergic relaxation of mouse urinary bladder smooth muscle in the absence of large-conductance Ca2+-activated K+ channel. Am J Physiol Renal Physiol 2008;295:F1149–57.
35. Hristov KL, Chen M, Kellett WF, Rovner ES, Petkov GV. Large-conductance voltage- and Ca2+-activated K+ channels regulate human detrusor smooth muscle function. Am J Physiol Cell Physiol 2011;301:C903–12.
36. Afeli SA, Rovner ES, Petkov GV. BRL37344, a β3-adrenergic receptor agonist, decreases nerve-evoked contractions in human detrusor smooth muscle isolated strips: role of BK channels. Urology 2013;82:744. e1-7.
37. Cernecka H, Kersten K, Maarsingh H, Elzinga CR, de Jong IJ, Korstanje C, et al. β3-Adrenoceptor-mediated relaxation of rat and human urinary bladder: roles of BKCa channels and Rho kinase. Naunyn Schmiedebergs Arch Pharmacol 2015;388:749–59.
38. Krauwinkel W, van Dijk J, Schaddelee M, Eltink C, Meijer J, Strabach G, et al. Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin Ther 2012;34:2144–60.
39. Svalø J, Nordling J, Bouchelouche K, Andersson KE, Korstanje C, Bouchelouche P. The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity. Eur J Pharmacol 2013;699:101–5.
40. Drake MJ, Kanai A, Bijos DA, Ikeda Y, Zabbarova I, Vahabi B, et al. The potential role of unregulated autonomous bladder micromotions in urinary storage and voiding dysfunction; overactive bladder and detrusor underactivity. BJU Int 2017;119:22–9.
41. Yossepowitch O, Gillon G, Baniel J, Engelstein D, Livne PM. The effect of cholinergic enhancement during filling cystometry: can edrophonium chloride be used as a provocative test for overactive bladder? J Urol 2001;165:1441–5.
42. Andersson KE. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol 2011;59:377–86.
43. Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R. The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int 2007;99:669–73.
44. Tyagi P, Thomas CA, Yoshimura N, Chancellor MB. Investigations into the presence of functional Beta1, Beta2 and Beta3-adrenoceptors in urothelium and detrusor of human bladder. Int Braz J Urol 2009;35:76–83.
45. Birder LA, Nealen ML, Kiss S, de Groat WC, Caterina MJ, Wang E, et al. Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 2002;22:8063–70.
46. Masunaga K, Chapple CR, McKay NG, Yoshida M, Sellers DJ. The β3-adrenoceptor mediates the inhibitory effects of β-adrenoceptor agonists via the urothelium in pig bladder dome. Neurourol Urodyn 2010;29:1320–5.
47. Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, et al. In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats. Naunyn Schmiedebergs Arch Pharmacol 2013;386:247–53.
48. Sadananda P, Drake MJ, Paton JF, Pickering AE. A functional analysis of the influence of β3-adrenoceptors on the rat micturition cycle. J Pharmacol Exp Ther 2013;347:506–15.
49. Michel MC. How β3 -adrenoceptor-selective is mirabegron? Br J Pharmacol 2016;173:429–30.
50. Alexandre EC, Kiguti LR, Calmasini FB, Silva FH, da Silva KP, Ferreira R, et al. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3 -adrenoceptor activation and α1 -adrenoceptor blockade. Br J Pharmacol 2016;173:415–28.
51. Andersson KE. Pharmacology: On the mode of action of mirabegron. Nat Rev Urol 2016;13:131–2.
52. Hood B, Andersson KE. Common theme for drugs effective in overactive bladder treatment: inhibition of afferent signaling from the bladder. Int J Urol 2013;20:21–7.

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