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Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?

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Abstract

β3-Adrenoceptor agonists have recently been introduced for the symptomatic treatment of the overactive bladder syndrome. As such treatment is not curative, long-term treatment is anticipated to be required. As the susceptibility of β3-adrenoceptors to undergo agonist-induced desensitization is cell type- and tissue-dependent, we have explored whether pre-treatment with a β-adrenoceptor agonist will attenuate subsequent relaxation responses to freshly added agonist using rat urinary bladder as a model. We have used the prototypical β-adrenoceptor agonist isoprenaline, the β2-selective fenoterol and the β3-selective CL 316,243 and mirabegron as well as the receptor-independent bladder relaxant forskolin. We show that a 6-h pre-treatment with agonist can significantly reduce subsequent relaxation against KCl-induced smooth muscle tone, but agonist-induced desensitization was also observed with longer pre-treatments or against passive tension. The agonist-induced desensitization was prominent for the β2 component of rat bladder relaxation but much weaker or even absent for the β3 component. Moreover, β-adrenoceptor agonist pre-treatment reduced contractile responses to the muscarinic agonist carbachol and the receptor-independent stimulus KCl. Taken together these data do not support the hypothesis that the long-term clinical efficacy of β3-adrenoceptor agonists in the treatment of the overactive bladder syndrome will be limited by receptor desensitization. Rather they raise the possibility that such treatment may not only cause smooth muscle relaxation but also may attenuate hyper-contractility of the bladder.

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References

  • Andersson K-E (2011) Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol 59:377–386

    Article  CAS  PubMed  Google Scholar 

  • Baker JG (2005) The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br J Pharmacol 144:317–322

    Article  CAS  PubMed  Google Scholar 

  • Baker JG (2010) The selectivity of β-adrenoceptor agonists at human β1-, β2- and β3-adrenoceptors. Br J Pharmacol 160:1048–1061

    Article  CAS  PubMed  Google Scholar 

  • Barendrecht MM, Frazier EP, Vrydag W, Alewijnse AE, Peters SLM, Michel MC (2009) The effect of bladder outlet obstruction on α1- and β-adrenoceptor expression and function. Neurourol Urodyn 28:349–355

    Article  CAS  PubMed  Google Scholar 

  • Benes J, Varejkova E, Farar V, Novakova M, Myslivecek J (2012) Decrease in heart adrenoceptor gene expression and receptor number as compensatory tool for preserved heart function and biological rhythm in M2 KO animals. Naunyn-Schmiedeberg’s Arch Pharmacol 385:1161–1173

    Article  CAS  Google Scholar 

  • Bengtsson T, Redegren K, Strosberg AD, Nedergaard J, Cannon B (1996) Down-regulation of β3-adrenoceptor gene expression in brown fat cells is transient and recovery is dependent upon a short-lived protein factor. J Biol Chem 271:33366–33375

    Article  CAS  PubMed  Google Scholar 

  • Benner JS, Nichol MB, Rovner ES, Jumadilova Z, Alvir J, Huseein M, Fanning K, Trocio JN, Brubaker L (2010) Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 105:1276–1282

    Article  PubMed  Google Scholar 

  • Brubaker L, Fanning K, Goldberg EL, Benner JS, Trocio JN, Bavendam T, Jumadilova Z (2010) Predictors of discontinuing overactive bladder medications. BJU Int 105:1283–1290

    Article  PubMed  Google Scholar 

  • Budd DC, Challiss RAJ, Young KW, Tobin AB (1999) Cross talk between m3-muscarinic and β2-adrenergic receptors at the level of receptor phosphorylation and desensitization. Mol Pharmacol 56:813–823

    CAS  PubMed  Google Scholar 

  • Candelore MR, Deng L, Tota LM, Kelly LJ, Cascieri MA, Strader CD (1996) Pharmacological characterization of a recently described human β3-adrenergic receptor mutant. Endocrinol 137:2638–2641

    CAS  Google Scholar 

  • Carpene C, Galitzky J, Collon P, Esclapez F, Dauzats M, Lafontan M (1993) Desensitization of beta-1 and beta-2, but not beta-3 adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion. J Pharmacol Exp Ther 265:237–247

    CAS  PubMed  Google Scholar 

  • Chambers J, Park J, Cronk D, Chapman C, Kennedy FR, Wilson S, Milligan G (1994) β3-Adrenoceptor agonist-induced down-regulation of Gsα and functional desensitization in a Chinese hamster ovary cell line expressing a β3-adrenoceptor refractory to down-regulation. Biochem J 303:973–978

    CAS  PubMed  Google Scholar 

  • Chapple CR, Kaplan SA, Mitcheson D, Klecka J, Cummings J, Drogendijk T, Dorrepaal C, Martin N (2013) Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and effiaccy of mirabegron, a β3-adrenoceptor agonist, in overactive bladder. Eur Urol 63:296–305

    Article  CAS  PubMed  Google Scholar 

  • Chaudhry A, Granneman JG (1994) Influence of cell type upon the desensitization of the β3-adrenergic receptor. J Pharmacol Exp Ther 271:1253–1258

    CAS  PubMed  Google Scholar 

  • Curran PK, Fishman PH (1996) Endogenous β3- but not β1-adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells. Cell Signal 8:355–364

    Article  CAS  PubMed  Google Scholar 

  • Dhein S, von Salisch S, Michel MC (2013) Cross-regulation between cardiac muscarinic acetylcholine receptors and β-adrenoceptors: lessons for use of knock-out mice. Naunyn-Schmiedeberg’s Arch Pharmacol 386:1–3

    Article  CAS  Google Scholar 

  • Engelhardt S, Zieger W, Kassubek J, Michel MC, Lohse MJ, Brodde O-E (1997) Tocolytic therapy with fenoterol induces selective down-regulation of β-adrenergic receptors in human myometrium. J Clin Endocrinol Metab 82:1235–1242

    CAS  PubMed  Google Scholar 

  • Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ (2010) Ligand-directed signalling at β-adrenoceptors. Br J Pharmacol 159:1022–1038

    Article  CAS  PubMed  Google Scholar 

  • Evans BA, Hutchinson DS, Summers RJ (2013) β2-Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle — ligand-idrected signalling or a reflection of system complexity? Naunyn-Schmiedeberg’s Arch Pharmacol 386:757–760

    Article  CAS  Google Scholar 

  • Frazier EP, Mathy M-J, Peters SLM, Michel MC (2005) Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol? J Pharmacol Exp Ther 313:260–267

    Article  CAS  PubMed  Google Scholar 

  • Frazier EP, Schneider T, Michel MC (2006) Effects of gender, age and hypertension on β-adrenergic receptor function in rat urinary bladder. Naunyn-Schmiedeberg’s Arch Pharmacol 373:300–309

    Article  CAS  Google Scholar 

  • Frazier EP, Braverman AS, Peters SLM, Michel MC, Ruggieri MR Sr (2007) Does phospholipase C mediate muscarinic receptor-induced rat urinary bladder contraction? J Pharmacol Exp Ther 322:998–1002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frazier EP, Michel-Reher MB, van Loenen P, Sand C, Schneider T, Peters SLM, Michel MC (2011) Lack of evidence that nebivolol is a β3-adrenoceptor agonist. Eur J Pharmacol 654:86–91

    Article  CAS  PubMed  Google Scholar 

  • Granneman JG, Lahners KN (1992) Differential adrenergic regulation of β1- and β3-adrenoceptor messenger ribonucleic acids in adipose tissues. Endocrinol 130:109–114

    CAS  Google Scholar 

  • Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, Ueshima K, Sato S, Masuda N (2013a) Pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in cynomolgus monkeys. Naunyn-Schmiedeberg’s Arch Pharmacol 386:1001–1008

    Article  CAS  Google Scholar 

  • Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, Ueshima K, Sato S, Sasamata M (2013b) In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats. Naunyn-Schmiedeberg’s Arch Pharmacol 386:247–253

    Article  CAS  Google Scholar 

  • Hegde SS (2006) Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 147:S80–S87

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz K-N (2004) Comparative pharmacology of human β-adrenergic receptor subtypes — characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedeberg’s Arch Pharmacol 369:151–159

    Article  CAS  Google Scholar 

  • Hutchinson DS, Evans BA, Summers RJ (2000) β3-Adrenoceptor regulation and relaxation responses in mouse ileum. Br J Pharmacol 129:1251–1259

    Article  CAS  PubMed  Google Scholar 

  • Igawa Y, Michel MC (2013) Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome. Naunyn-Schmiedeberg’s Arch Pharmacol 386:177–183

    Article  CAS  Google Scholar 

  • Igawa Y, Schneider T, Yamazaki Y, Tatemichi S, Homma Y, Nishizawa O, Michel MC (2012) Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322. Naunyn-Schmiedeberg’s Arch Pharmacol 385:759–767

    Article  CAS  Google Scholar 

  • Irwin DE, Milsom I, Hunskaar S, Reillly K, Kopp Z, Herschorn S, Coyne K, Kelleher C, Hampel C, Artibani W, Abrams P (2006) Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1315

    Article  PubMed  Google Scholar 

  • Kanie S, Otsuka A, Yoshikawa S, Morimoto T, Hareyama N, Okazaki S, Kobayashi R, Hasebe K, Nakao K, Hayashi R, Mochizuki H, Matsumoto R, Ozono S (2012) Pharmacological effect of TRK-380, a novel selective human β3-adrenoceptor agonist, on mammailian detrusor strips. Urology 79:744.e1–744.e7

    Article  Google Scholar 

  • Khullar V, Amarenco G, Anuglo J, Cambronero J, Hoye K, Milsom I, Radziszewski P, Rechberger T, Boerrigter P, Drogendijk T, Wooning M, Chapple C (2013) Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonists, in patients with overactive bladder: results from a randomised European–Australian phase 3 trial. Eur Urol 63:283–295

    Article  CAS  PubMed  Google Scholar 

  • Lee NH, Fraser CM (1993) Cross-talk between m1 muscarinic actylcholine and β2-adrenergic receptors. cAMP and the third intracellular loop of m1 muscarinic receptors confer heterologous regulation. J Biol Chem 268:7949–7957

    CAS  PubMed  Google Scholar 

  • Longhurst PA, Levendusky M (1999) Pharmacological characterization of β-adrenoceptors mediating relaxation of the rat urinary bladder in vitro. Br J Pharmacol 127:1744–1750

    Article  CAS  PubMed  Google Scholar 

  • Maruyama I, Goi Y, Tatemichi S, Maruyama K, Hoyano Y, Yamazaki Y, Kusama H (2012) Bladder selectivity of ritobegron (KUC-7483), a novel β3-adrenoceptor agonist: on the in vitro and in vivo studies. Naunyn-Schmiedeberg’s Arch Pharmacol 385:845–852

    Article  CAS  Google Scholar 

  • Matsui M, Griffin MT, Shehnaz D, Taketo MM, Ehlert FJ (2003) Increased relaxant action of forskolin and isoproterenol against muscarinic agonist-induced contractions in smooth muscle from M2 receptor knockout mice. J Pharmacol Exp Ther 305:106–113

    Article  CAS  PubMed  Google Scholar 

  • Michel MC (2011) β-Adrenergic receptor subtypes in the urinary tract. In: Andersson K-E, Michel MC (eds) Urinary tract. Springer-Verlag, Berlin, pp 307–318

    Chapter  Google Scholar 

  • Michel MC, Barendrecht MM (2008) Physiological and pathological regulation of the autonomic control of urinary bladder contractility. Pharmacol Ther 117:297–312

    Article  CAS  PubMed  Google Scholar 

  • Michel MC, Sand C (2009) Effect of pre-contraction on β-adrenoceptor-mediated relaxation of rat urinary bladder. World J Urol 27:711–715

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michel MC, Vrydag W (2006) α1-, α2- and β-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147:S88–S119

    Article  CAS  PubMed  Google Scholar 

  • Michel MC, Ochodnicky P, Homma Y, Igawa Y (2011) β-Adrenoceptor agonist effects in experimental models of bladder dysfunction. Pharmacol Ther 131:40–49

    Article  CAS  PubMed  Google Scholar 

  • Michel-Reher MB, Michel MC (2013) Agonist-induced desensitization of human β3-adrenoceptors expressed in human embryonic kidney cells. Naunyn-Schmiedeberg’s Arch Pharmacol 386:843–851

    Article  CAS  Google Scholar 

  • Nantel F, Bonin H, Emorine LJ, Zelberfarb V, Strosberg AD, Bouvier M, Marullo S (1993) The human β3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol 43:548–555

    CAS  PubMed  Google Scholar 

  • Nantel F, Bouvier M, Strosberg AD, Marullo S (1995) Functional effects of long-term activation of human β2- and β3-adrenoceptor signalling. Br J Pharmacol 114:1045–1051

    Article  CAS  PubMed  Google Scholar 

  • Ngala RA, O’Dowd JF, Stocker CJ, Cawthorne MA, Arch JRS (2013) β2-adrenoceptor agonists can both stimulate and inhibit glucose uptake in mouse soleus muscle through ligand-directed signalling. Naunyn-Schmiedeberg’s Arch Pharmacol 386:761–773

    Article  CAS  Google Scholar 

  • Nishimoto T, Latifpour J, Wheeler MA, Yoshida M, Weiss RM (1995) Age-dependent alterations in β-adrenergic responsiveness of rat detrusor smooth muscle. J Urol 153:1701–1705

    Article  CAS  PubMed  Google Scholar 

  • Nitti V, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S (2013) Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 189:1388–1395

    Article  CAS  PubMed  Google Scholar 

  • Ochodnicky P, Uvelius B, Andersson K-E, Michel MC (2013) Autonomic nervous control of the urinary bladder. Acta Physiol 207:16–33

    Article  CAS  Google Scholar 

  • Ohlstein EH, von Keitz A, Michel MC (2012) A multicenter, double-blind, randomized, placebo controlled trial of the β3-adrenoceptor agonist solabegron for overactive bladder. Eur Urol 62:834–840

    Article  CAS  PubMed  Google Scholar 

  • Otsuka A, Shinbo H, Hasebe K, Matsumoto R, Ozono S (2008) Effects of a novel β3-adrenoceptor agonist, AJ-9677, on relaxation of the detrusor muscle: an in vitro study. Int J Urol 15:1072–1076

    Article  CAS  PubMed  Google Scholar 

  • Palea S, Rekik M, Rouget C, Camparo P, Botto H, Rischman P, Lluel P, Westfall TD (2012) Fenoterol functionally activates the β3-adrenoceptor in human urinary bladder, a comparison with rat and mouse: implications for drug discovery. Eur J Pharmacol 690:202–206

    Article  CAS  PubMed  Google Scholar 

  • Penn RB (2008) Embracing emerging paradigms of G protein-coupled receptor agonism and signaling to address airway smooth muscle pathobiology in asthma. Naunyn-Schmiedeberg’s Arch Pharmacol 378:149–169

    Article  CAS  Google Scholar 

  • Rapp DE, Lyon MB, Bales GT, Cook SP (2005) A role for the P2X receptor in urinary tract physiology and in the pathophysiology of urinary dysfunction. Eur Urol 48:303–308

    Article  CAS  PubMed  Google Scholar 

  • Scarpace PJ, Matheny M, Thümer N (1999) Differential down-regulation of β3-adrenergic receptor mRNA and signal transduction by cold exposure in brown adipose tissue of young and senescent rats. Pflugers Arch 437:479–483

    Article  CAS  PubMed  Google Scholar 

  • Schneider T, Fetscher C, Michel MC (2011) Human urinary bladder strip relaxation by the β-adrenoceptor agonist isoprenaline: methodological considerations and effects of gender and age. Front Pharmacol 2:11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Seamon KB, Daly JW (1986) Forskolin: its biological and chemical properties. Adv Cyclic Nucleotide Protein Phosphorylation Res 20:1–150

    CAS  PubMed  Google Scholar 

  • Seifert R (2013) A door opener for future research: agonist-induced β3-adrenoceptor desensitization in HEK cells but not CHO cells. Naunyn-Schmiedeberg’s Arch Pharmacol 386:841–842

    Article  CAS  Google Scholar 

  • Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maryama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (2007) Effect of YM178, a novel selective β3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647

    Article  CAS  PubMed  Google Scholar 

  • Takeda H, Matsuzawa A, Igawa Y, Yamazaki Y, Kaidoh K, Akahane S, Kojima M, Miyata H, Akahane M, Nishizawa O (2003) Functional characterization of β-adrenoceptor subtypes in the canine and rat lower urinary tract. J Urol 170:654–658

    Article  CAS  PubMed  Google Scholar 

  • Vaughan CP, Johnson TM II, Ala-Lipasti MA, Cartwright R, Tammela TLJ, Taari K, Auvinen A, Tikkinen KAO (2011) The prevalence of clinically meaningful overactive bladder: bother and quality of life results from the population-based FINNO study. Eur Urol 59:629–636

    Article  PubMed  Google Scholar 

  • Vrydag W, Alewijnse AE, Michel MC (2009) Do gene polymorphisms alone or in combination affect the function of human β3-adrenoceptors? Br J Pharmacol 156:127–134

    Article  CAS  PubMed  Google Scholar 

  • Witte LPW, de Haas N, Mammen M, Stangeland EL, Steinfeld T, Aiyar J, Michel MC (2011) Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation. Naunyn-Schmiedeberg’s Arch Pharmacol 384:555–563

    Article  CAS  Google Scholar 

  • Yamaguchi O, Chapple CR (2007) β3-Adrenoceptors in urinary bladder. Neurourol Urodyn 26:752–756

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants from Astellas Europe B.V. and through Coordination Theme 1 (Health) of the European Community’s FP7, Grant agreement number HEALTH-F2-2008-223234.

Conflict of interest

In the past 5 years, MCM has received research support and/or consultancy honoraria in the β3-adrenoceptor field from AltheRX and Astellas. After completion of the experiments, he became an employee of Boehringer Ingelheim.

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  1. Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Str. 67, 51101, Mainz, Germany

    Martin C. Michel

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  1. Martin C. Michel
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Correspondence to Martin C. Michel.

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The experiments reported in this manuscript were largely performed by Mr. Wim Vrydag at the Academic Medical Center (Amsterdam, The Netherlands). As the department has been unable to contact him for a considerable period of time despite considerable efforts, he could not participate in the final data analysis or the writing of the manuscript. Therefore, upon consultation with the institutional ombudsman, it was decided not to list him as author despite his valuable contribution to this study.

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Michel, M.C. Do β-adrenoceptor agonists induce homologous or heterologous desensitization in rat urinary bladder?. Naunyn-Schmiedeberg's Arch Pharmacol 387, 215–224 (2014). https://doi.org/10.1007/s00210-013-0936-2

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