Skip to main content

Advertisement

SpringerLink
Log in

In vivo characterization of muscarinic receptors in peripheral tissues: evaluation of bladder selectivity of anticholinergic agents to treat overactive bladder

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The present study was undertaken to characterize in vivo muscarinic receptors in peripheral tissues (urinary bladder, submaxillary gland, colon, stomach, heart) of mice, and further to evaluate bladder-selectivity of anticholinergic agents to treat overactive bladder. Following i.v. injection of [3H]QNB in mice, the radioactivity in peripheral tissues was exclusively detected as the unchanged form. The in vivo specific [3H]QNB binding in particulate fraction of tissue homogenates of mice showed a pharmacological specificity which characterized muscarinic receptors. Binding parameters (K d and B max) for in vivo specific [3H]QNB binding differed between mouse tissues. Oral administration of oxybutynin attenuated significantly in vivo specific [3H]QNB binding in all tissues of mice. From ratios of AUCurinary bladder/AUCother tissues of time-dependent muscarinic receptor occupancy, oral oxybutynin has been shown to exert little urinary bladder selectivity. Following oral administration of propiverine, there was a significant reduction of in vivo specific [3H]QNB binding in the urinary bladder, colon and submaxillary gland, but not in the stomach and heart. From the ratios of AUCurinary bladder to AUCsubmaxillary gland or AUC heart, it has been shown that oral propiverine exerts higher selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland and heart. Similarly, tolterodine displayed high selectivity to muscarinic receptors in the urinary bladder than in the submaxillary gland. Thus, the present study has demonstrated that [3H]QNB may be a useful ligand for in vivo characterization of muscarinic receptor binding of anticholinergic agents to treat overactive bladder. Propiverine and tolterodine have exhibited in vivo selectivity of muscarinic receptor in the mouse urinary bladder rather than in the submaxillary gland, and such receptor binding specificity may be the reason of lower incidence of dry mouth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

[3H]QNB:

quinuclidinyl benzilate L-[benzilic-4,4′-3H]

References

  • Abrams P, Freeman R, Anderström C, Mattiasson A (1998) Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 81:801–810

    PubMed  CAS  Google Scholar 

  • Andersson K-E (2004) Antimuscarinics for treatment of overactive bladder. The Lancet Neurol 3:46–53

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hirano K, Maruyama S, Kimura R, Kagawa Y, Yamada S (2004) In vivo identification and characterization of binding sites for selective serotonin reuptake inhibitors in mouse brain. Life Sci 75:2933–2945

    Article  PubMed  CAS  Google Scholar 

  • Hosoi R, Kobayashi K, Watanabe Y, Inoue O (1999) Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. J Neural Trans 106:583–592

    Article  CAS  Google Scholar 

  • Madersbacher H, Mürtz G (2001) Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol 19:324–335

    Article  PubMed  CAS  Google Scholar 

  • Madersbacher H, Halaska M, Voigt R, Alloussi S, Höfner K (1999) A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU International 84:646–651

    Article  PubMed  CAS  Google Scholar 

  • Michel MC, Hedge SS (2006) Treatment of the overactive bladder syndrome with muscarinic receptor antagonists-a matter of metabolites? Naunyn-Schmiedebergs Arch Pharmacol 374:79–85

    Article  PubMed  CAS  Google Scholar 

  • Mayuzumi K, Watanabe K, Tamaru K, Kasama T (1986) Effects of oxybutynin hydrochloride on the urinary bladder and urethra in in situ preparations. Nippon Yakurigaku Zasshi 87:557–571

    PubMed  CAS  Google Scholar 

  • Nilvebrant L, Andersson K-E, Gillberg PG, Stahl M, Sparf B (1997a) Tolterodine-a new bladder-selective antimuscarinic agent. Eur J Pharmacol 327:195–207

    Article  PubMed  CAS  Google Scholar 

  • Nilvebrant L, Gillberg PG, Sparf B (1997b) Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine. Pharmacol Toxicol 81:169–172

    Article  PubMed  CAS  Google Scholar 

  • Nomura N, Kaneko S, Hamakawa T, Nagai M, Iriki M (1989) Effects of propiverine hydrochloride (P-4) and its metabolites on urinary bladder function in anesthetized rats. Nippon Yakurigaku Zasshi 94:173–180

    PubMed  CAS  Google Scholar 

  • Oki T, Thoma A, Yamada S, Kimura R (2001) Muscarinic receptor binding characteristics in rat tissues after oral administration of oxybutynin and propiverine. Biol Pharam Bull 24:491–495

    Article  CAS  Google Scholar 

  • Oki T, Maruyama S, Takagi Y, Yamamura HI, Yamada S (2006) Characterization of muscarinic receptor binding and inhibition of salivation after oral administration of tolterodine in mice. Eur J Pharmacol 529:157–163

    Article  PubMed  CAS  Google Scholar 

  • Påhlman I, Gozzi P (1999) Serum protein binding of tolterodine and its major metabolites in humans and several animal species. Biopharm Drug Dispos 20:91–99

    Article  PubMed  Google Scholar 

  • Påhlman I, D’Argy R, Nilvebrant L (2001) Tissue distribution of tolterodine, a muscarinic receptor antagonist, and transfer into fetus and milk in mice. Arzneim Forsch/Drug Res 51:125–133

    Google Scholar 

  • Pelham RW, Munsat TL (1979) Identification of direct competition for, and indirect influences on, striatal muscarinic cholinergic receptors: in vivo [3H]quinuclidinyl benzilate binding in rats. Brain Res 171:473–480

    Article  PubMed  CAS  Google Scholar 

  • Postlind H, Danielson A, Lindgren A, Andersson SH (1998) Tolterodine: a new muscarinic receptor antagonist, is metabolized by cytochrome P450 2D6 and 3A4 in human liver microsomes. Drug Metab Disp 26:289–293

    CAS  Google Scholar 

  • Terai T, Deguchi Y, Ohtsuka M, Kumada S (1991) Effects of the anticholinergic drug prifinium bromide on urinary bladder contractions in rat in vivo and in guinea-pig in vitro. Arzneimittelforschung 41:417–420

    PubMed  CAS  Google Scholar 

  • Todorova A, Vonderheid-Guth B, Dimpfel W (2001) Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol 41:636–644

    Article  PubMed  CAS  Google Scholar 

  • Uchida S, Yamada S, Nagai K, Deguchi Y, Kimura R (1997) Brain pharmacokinetics and in vivo receptor binding of 1,4-dihydropyridine calcium channel antagonists. Life Sci 61:2083–2090

    Article  PubMed  CAS  Google Scholar 

  • Uchida S, Yamada S, Deguchi Y, Yamamoto M, Kimura R (2000) In vivo specific binding characteristics and pharmacokinetics of a 1,4-dihydropyridine calcium channel antagonist in the senescent mouse brain. Pharm Res 17:844–850

    Article  PubMed  CAS  Google Scholar 

  • Uchida S, Kurosawa S, Fujino (Oki) T, Kato Y, Nanri M, Yoshida K, Yamada S (2007) Binding activities by propiverine and its N-oxide metabolites of L-type calcium channel antagonist receptors in the rat bladder and brain. Life Sci 80:2454–2460

    Article  PubMed  CAS  Google Scholar 

  • Weizman R, Weifman A, Kook KA, Vocci F, Deutsh SI, Paul SM (1989) Repeated swim stress alters brain benzodiazepine receptors measured in vivo. J Pharmacol Exp Ther 249:701–707

    PubMed  CAS  Google Scholar 

  • Wuest M, Weiss A, Waelbroeck M, Braeter M, Kelly LU, Hakenberg OW, Ravens U (2006) Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction. Naunyn-Schmiedebergs Arch Pharmacol 374:87–97

    Article  PubMed  CAS  Google Scholar 

  • Yamada S, Ohkura T, Deguchi Y, Kimura R (1999) In vivo measurement by [3H]tamsulosin of α1 adrenoceptors of in tissues in relation to the pharmacokinetics. J Pharmacol Exp Ther 289:1575–1583

    PubMed  CAS  Google Scholar 

  • Yamada S, Ohkura T, Deguchi Y, Kimura R (2001) In vivo demonstration of α1-adrenoceptor subtype selectivity of KMD-3213 in rat tissues. J Pharmacol Exp Ther 296:160–167

    PubMed  CAS  Google Scholar 

  • Yamada S, Nakajima M, Kusaka T, Uchida S, Kimura R (2002) In vivo receptor binding of benidipine and amlodipine in mesenteric arteries other tissues of spontaneously hypertensive rats. Life Sci 70:1999–2011

    Article  PubMed  CAS  Google Scholar 

  • Yamada S, Maruyama S, Takagi Y, Uchida S, Oki T (2006) In vivo demonstration of M3 muscarinic receptor subtype selectivity of darifenacin in mice. Life Sci 80:127–132

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto Y, Tsuda M, Uda K, Matsushita H, Shindo T, Kawaguchi Y (1995) Pharmacokinetic studies on propiverine hydrochloride. Metabolites in urinary bladder, other tissues and urine of rats. Xenobiotic Metabol Dispos 10:205–210

    CAS  Google Scholar 

  • Yamamura HI, Kuhar MJ, Snyder SH (1974) In vivo identification of muscarinic cholinergic receptor binding in rat brain. Brain Res 80:170–176

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Miss Yukiko Takagi for her excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (2) (No. 18590237) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information

Authors and Affiliations

  1. Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Shuji Maruyama, Naoki Hasuike, Kazuhiro Suzuki & Shizuo Yamada

  2. Department of Biopharmaceutical Sciences and Global COE Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Shizuo Yamada

Authors
  1. Shuji Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoki Hasuike
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuhiro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shizuo Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shizuo Yamada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maruyama, S., Hasuike, N., Suzuki, K. et al. In vivo characterization of muscarinic receptors in peripheral tissues: evaluation of bladder selectivity of anticholinergic agents to treat overactive bladder. Naunyn-Schmied Arch Pharmacol 377, 463–471 (2008). https://doi.org/10.1007/s00210-007-0207-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-007-0207-1

Keywords

Search

Navigation