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Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

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Abstract

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC50 of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pK B 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.

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References

  • Badawi JK, Uecelehan H, Hatzinger M, Michel MS, Haferkamp A, Bross S (2005) Relaxant effects of β-adrenergic agonists on porcine and human detrusor muscle. Acta Physiol Scand 185:151–159

    Article  PubMed  CAS  Google Scholar 

  • Badawi JK, Seja T, Uecelehan H, Honeck P, Kwon S-T, Bross S, Langbein S (2007) Relaxation of human detrusor muscle by selective beta-2 and beta-3 agonists and endogenous catecholamines. Urology 69:785–790

    Article  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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Belfer I, Buzas B, Evans C, Hipp H, Phillips G, Taubman J, Lorincz I, Lipsky RH, Enoch M-A, Max MB, Goldman D (2005) Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans. Eur J Hum Genet 13:341–351

    Article  PubMed  CAS  Google Scholar 

  • Biers SM, Reynard JM, Brading AF (2006) The effects of a new selective β3-adrenoceptor agonist (GW427353) on spontaneous activity and detrusor relaxation in human bladder. BJU Int 98:1310–1314

    Article  PubMed  CAS  Google Scholar 

  • Birder LA, Nealen ML, Kiss S, de Groat WC, Caterina MJ, Wang E, Apodaca G, Kanai AJ (2002) β-Adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 22:8063–8070

    PubMed  CAS  Google Scholar 

  • Fazier 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  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Frazier EP, Peters SLM, Braverman AS, Ruggieri MR, Michel MC (2008) Signal transduction underlying control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 377:449–462

    Article  CAS  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  PubMed  CAS  Google Scholar 

  • Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP (2007) GW427353 (solabegron), a novel, selective β3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. J Pharmacol Exp Ther 323:202–209

    Article  PubMed  CAS  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 

  • Honda K, Nomiya M, Shishido K, Yoshimura Y, Yamaguchi O (2006) Mutation of β3-adrenoceptor gene: a genetic marker for overactive bladder. Neurourol Urodyn 25:652

    Google Scholar 

  • Igawa Y, Yamazaki Y, Takeda H, Akahane M, Ajisawa Y, Yoneyama T, Nishizawa O (1998) Possible β3-adrenoceptor-mediated relaxation of the human detrusor. Acta Physiol Scand 164:117–118

    Article  PubMed  CAS  Google Scholar 

  • Igawa Y, Yamazaki Y, Takeda H, Hayakawa K, Akahane M, Ajisawa Y, Yoneyama T, Nishizawa O, Andersson KE (1999) Functional and molecular biological evidence for a possible β3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 126:819–825

    Article  PubMed  CAS  Google Scholar 

  • Igawa Y, Yamazaki Y, Takeda H, Kaidoh K, Akahane M, Ajisawa Y, Yoneyama T, Nishizawa O, Andersson KE (2001) Relaxant effects of isoproterenol and selective β3-adrenoceptor agonists on normal, low compliant and hyperreflexic human bladders. J Urol 165:240–244

    Article  PubMed  CAS  Google Scholar 

  • Klausner AP, Rourke KF, Miner AS, Ratz PH (2009) Potentiation of carbachol-induced detrusor smooth muscle contractions by β-adrenoceptor activation. Eur J Pharmacol 606:191–198

    Article  PubMed  CAS  Google Scholar 

  • Kullmann FA, Downs TR, Artim DE, Limberg BJ, Shah M, Contract D, de Groat WC, Rosenbaum JS (2011) Urothelial beta-3 adrenergic receptors in rat bladder. Neurourol Urodyn 30:144–160

    Article  PubMed  CAS  Google Scholar 

  • Li G, Li K, Wang P (2003) Age-dependent changes in β-adrenoceptor function in human detrusor and possible mechanisms. Chin Med J 116:1511–1514

    PubMed  CAS  Google Scholar 

  • Liang W, Lo WN (2011) β-Adrenoceptor-mediated differences in transverse and longitudinal strips from the rat detrusor. Int Urol Nephrol 43:99–107

    Article  PubMed  CAS  Google Scholar 

  • Maruyama I, Goi Y, Tatemichi S, Maruyama K, Hoyano Y, Yamazaki Y, Kusama H (2012) Bladder selectivity of the novel β3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-012-0755-x

  • 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  PubMed  CAS  Google Scholar 

  • Michel MC, Cernecka H, Ochodnicky P (2011a) Desirable properties of β3-adrenoceptor agonists: implications for the selection of drug development candidates. Eur J Pharmacol 657:1–3

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Morita T, Iizuka H, Iwata T, Kondo S (2000) Function and distribution of β3-adrenoceptors in rat, rabbit, and human urinary bladder and external urethral sphincter. J Smooth Muscle Res 36:21–32

    Article  PubMed  CAS  Google Scholar 

  • Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R (2007) The role of the urothelium in mediating bladder responses to isoprenaline. BJU Int 99:669–673

    Article  PubMed  CAS  Google Scholar 

  • Nergardh A, Boreus LO, Naglo AS (1978) Characterization of the adrenergic β-receptor in the urinary bladder of man and cat. Acta Pharmacol Toxicol 40:14–21

    Article  Google Scholar 

  • Niclauß N, Michel-Reher MB, Alewijnse AE, Michel MC (2006) Comparison of three radioligands for the labelling of human β-adrenoceptor subtypes. Naunyn-Schmiedeberg’s Arch Pharmacol 374:99–105

    Article  Google Scholar 

  • Nomiya M, Yamaguchi O (2003) A quantitative analysis of mRNA expression of α1 and β-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol 170:649–653

    Article  PubMed  CAS  Google Scholar 

  • Norlen L, Sundin T, Waagstein F (1978) β-Adrenoceptor stimulation of the human urinary bladder in vivo. Acta Pharmacol Toxicol 43:26–30

    Article  CAS  Google Scholar 

  • Otsuka A, Shinbo H, Hasebe K, Matsumoto R, Ozono S (2008a) 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  PubMed  CAS  Google Scholar 

  • Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S (2008b) Expression and functional role of β-adrenoceptors in the human urinary bladder. Naunyn-Schmiedeberg’s Arch Pharmacol 377:473–481

    Article  CAS  Google Scholar 

  • Propping S, Wuest M, Eichorn B, Grimm M, Wirth M, Kaumann A, Ravens U (2009) Role of urothelium on β3-adrenoceptor mediated relaxation in human detrusor muscle. Neurourol Urodyn 28:870–871

    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  PubMed  CAS  Google Scholar 

  • Sato M, Horinouchi T, Hutchinson DS, Evans BA, Summers RJ (2007) Ligand-directed signaling at the β3-adrenoceptor produced by SR59230A relative to receptor agonists. Mol Pharmacol 74:1359–1368

    Article  Google Scholar 

  • Schneider T, Fetscher C, Krege S, Michel MC (2004) Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther 309:1148–1153

    Article  PubMed  CAS  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. Frontiers Pharmacol 2:11

    CAS  Google Scholar 

  • Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (2007) Effect of (R)-2-(2-aminothiazol-4-yl)-4′-2-[(2-hydroxy-2-phenylethyl)amino]ethyl acetanilide (YM178), a novel selective β3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647

    Article  PubMed  CAS  Google Scholar 

  • Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T, Hatano A, Takahashi K, Nomura S (1999) Evidence for β3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 288:1367–1373

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Walton J, Silver K, Bogardus C, Knowler WC, Celi FS, Austin S, Manning B, Strosberg AD, Stern MP, Raben N, Sorkin JD, Roth J, Shuldiner AR (1995) Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic receptor gene. New Engl J Med 333:343–347

    Article  Google Scholar 

  • Wuest M, Hecht J, Christ T, Braeter M, Schoeberl C, Hakenberg OW, Wirth MP, Ravens U (2005) Pharmacodynamics of propiverine and three of its metabolites on detrusor contraction. Br J Pharmacol 145:608–619

    Article  PubMed  CAS  Google Scholar 

  • Yamanishi T, Yasuda K, Kitahara S, Nakai H, K-i Y, Iizuka H (2006) Effects of 138-355, a β3-adrenoceptor selective agonist, on relaxation of the human detrusor muscle in vitro. Neurourol Urodyn 25:815–819

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The current studies were supported by a Grant-in-Aid for Scientific Research (YI; grant no. 40159588) from the Ministry of Education, Culture, Sport, Science, and Technology of the Japanese Government and funded in part by grants from Kissei Pharmaceutical and Boehringer Ingelheim and through Coordination Theme 1 (Health) of the European Community’s FP7, grant agreement number HEALTH-F2-2008-223234. YI has been a consultant for Astellas and Pfizer and received research funds and lecture honoraria from Kissei and Astellas. TS has been a consultant for Pfizer, Astellas, Bayer, and Takeda. YH has been a consultant for Astellas and Pfizer and received research funds and lecture honoraria from Kissei and Astellas. MCM has been a consultant for AltheRx and Astellas and after completion of the present study became an employee of Boehringer Ingelheim.

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Authors and Affiliations

  1. Department of Continence Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yasuhiko Igawa

  2. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yukio Homma

  3. Department of Urology, University of Duisburg-Essen, Essen, Germany

    Tim Schneider

  4. Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan

    Osamu Nishizawa

  5. Pharmacology Research, R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan

    Yoshinobu Yamazaki & Satoshi Tatemichi

  6. Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany

    Martin C. Michel

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  1. Yasuhiko Igawa
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  3. Yoshinobu Yamazaki
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  4. Satoshi Tatemichi
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  6. Osamu Nishizawa
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  7. Martin C. Michel
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Correspondence to Yasuhiko Igawa.

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Igawa, Y., Schneider, T., Yamazaki, Y. et al. 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 (2012). https://doi.org/10.1007/s00210-012-0763-x

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