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Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder

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Abstract

We compared the density and function of M2 and M3 muscarinic acetylcholine receptor subtypes in the urinary bladder of young adult (3 months) and old (23 months) male Wistar rats. Old rats had a reduced density of muscarinic receptors (96±10 vs. 156±21 fmol/mg protein), but competition experiments with the M3-selective darifenacin did not indicate alterations in the relative roles of M2 and M3 receptors, with the former being more abundant. The amount of immunodetectable α-subunits of various G-proteins potentially linked to muscarinic receptor function was unchanged. The potency of carbachol to contract bladder strips was also unaltered; its maximum effects as well as those of a single KCl concentration were unchanged if raw data or those corrected for strip length were analysed, but somewhat reduced when those corrected for strip weight were analysed. Antagonistic effects of atropine, the M2-selective Ro 320–6206 and the M3-selective darifenacin were unchanged. Agonistic effects of the M3-sparing agonist 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-[1,4′]bipiperidinyl-1′-carboxylic acid ethyl ester were similarly poor in young and old rats. Additional experiments were concomitantly performed in submandibular glands from the same animals. While total muscarinic receptor density in submandibular glands was not significantly affected by age (56±5 vs. 61±4 fmol/mg protein), the relative contribution of M3 receptors significantly declined from 68±3% to 57±2% based upon darifenacin competition curves. We conclude that aged Wistar rats express fewer muscarinic receptors in their urinary bladder, but there is no change in the relative abundance of M2 and M3 receptors; this is accompanied by only minor if any alterations in receptor responsiveness. In contrast, submandibular gland expresses similar receptor numbers in young and old rats, but slightly fewer M3 receptors in old animals.

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References

  • Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A (2002) The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 21:167–178

    PubMed  Google Scholar 

  • Afiatpour P, Latifpour J, Takahashi W, Yono M, Foster HE Jr, Ikeda K, Pouresmail M, Weiss RM (2003) Developmental changes in the functional, biochemical and molecular properties of rat bladder endothelin receptors. Naunyn-Schmiedebergs Arch Pharmacol 367:462–472

    PubMed  Google Scholar 

  • Andersson K-E, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986

    PubMed  Google Scholar 

  • Borchert VE, Czyborra P, Fetscher C, Goepel M, Michel MC (2004) Extracts from Rhois aromatica and Solidaginis vigaurea inhibit rat and human bladder contraction. Naunyn-Schmiedebergs Arch Pharmacol 369:281–286

    PubMed  Google Scholar 

  • Brading AF (1997) A myogenic basis for the overactive bladder. Urology 50(Suppl 6A):57–67

    PubMed  Google Scholar 

  • Braverman AS, Ruggieri MR Sr (2003) Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol 285:R701–R708

    PubMed  Google Scholar 

  • Braverman AS, Luthin GR, Ruggieri MR (1998) M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol 275:R1654–R1660

    PubMed  Google Scholar 

  • Braverman AS, Legos JJ, Young W, Luthin G, Ruggieri MR (1999) M2 receptors in genito-urinary smooth muscle pathology. Life Sci 64:429–436

    PubMed  Google Scholar 

  • Derweesh IH, Wheeler MA, Weiss RM (2000) Alterations in G-proteins and β-adrenergic responsive adenylyl cyclase in rat urinary bladder during ageing. J Pharmacol Exp Ther 294:969–974

    PubMed  Google Scholar 

  • Elbadawi A, Diokno AC, Millard RJ (1998) The aging bladder: morphology and urodynamics. World J Urol 16(Suppl 1):S10–S34

    PubMed  Google Scholar 

  • Goepel M, Gronewald A, Krege S, Michel MC (1998) Muscarinic receptor subtypes in porcine detrusor: comparison with humans and regulation by bladder augmentation. Urol Res 26:149–154

    PubMed  Google Scholar 

  • Goepel M, Hoffmann J, Piro M, Rübben H, Michel MC (2002) Prevalence and physician awareness of symptoms of urinary bladder dysfunction. Eur Urol 41:234–239

    PubMed  Google Scholar 

  • Goldsmith P, Gierschik P, Milligan G, Unson CG, Vinitsky R, Malech HL, Spiegel AM (1987) Antibodies directed against synthetic peptides distinguish between GTP-binding proteins in neutrophil and brain. J Biol Chem 262:14683–14688

    PubMed  Google Scholar 

  • Goldsmith P, Rossiter K, Carter A, Simonds WF, Unson CG, Vinitsky R, Spiegel AM (1988) Identification of the GTP-binding protein encoded by Gi3 complementary DNA. J Biol Chem 263:6476–6479

    PubMed  Google Scholar 

  • Hegde SS, Eglen RM (1999) Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci 64:419–428

    PubMed  Google Scholar 

  • Hegde SS, Mandel DA, Wilford MR, Briaud S, Ford APDW, Eglen RM (1998) Evidence for purinergic neurotransmission in the urinary bladder of pithed rats. Eur J Pharmacol 349:75–82

    PubMed  Google Scholar 

  • Herbison P, Hay-Smith J, Ellis G, Moore K (2003) Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. Br Med J 326:841–844

    Google Scholar 

  • Jasper JR, Pulido-Rios T, Stangeland E, Griffin JH, Horger B, Beattie D, Li G, Lee T-W, Steinfeld T, Mammen M, Hegde S (2002) Pharmacological characterization of a modified benzimidazolidinone, a potent muscarinic receptor agonist displaying selectivity for M2 and M4 receptor subtypes. Pharmacologist 44(Suppl 1):110.6

    Google Scholar 

  • Knezevic I, Borg C, Le Breton GC (1993) Identification of Gq as one of the G-proteins which copurify with human platelet thromboxane A2/prostaglandin H2 receptors. J Biol Chem 268:26011–26017

    PubMed  Google Scholar 

  • Kolta MG, Wallace LJ, Gerald MC (1984) Age-related changes in sensitivity of rat urinary bladder to autonomic agents. Mech Ageing Dev 27:183–188

    PubMed  Google Scholar 

  • Kories C, Czyborra C, Fetscher C, Schneider T, Krege S, Michel MC (2003) Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3? Naunyn-Schmiedebergs Arch Pharmacol 367:524–531

    PubMed  Google Scholar 

  • Latifpour J, Kondo S, O’Hollaren B, Morita T, Weiss RM (1990) Autonomic receptors in urinary tract: sex and age differences. J Pharmacol Exp Ther 253:661–667

    PubMed  Google Scholar 

  • Lepor H, Gup D, Shapiro E, Baumann M (1989) Muscarinic cholinergic receptors in the normal and neurogenic human bladder. J Urol 142:869–874

    PubMed  Google Scholar 

  • Lluel P, Palea S, Barras M, Grandadam F, Heudes D, Bruneval P, Corman B, Martin DJ (2000) Functional and morphological modifications of the urinary bladder in aging female rats. Am J Physiol 278:R964–R972

    Google Scholar 

  • Lluel P, Deplanne V, Heudes D, Bruneval P, Palea S (2003) Age-related changes in urethrovesical coordination in male rats: relationship with bladder instability? Am J Physiol 284:R1287–R1295

    Google Scholar 

  • MacKenzie AR, Cross PE (1991) Preparation of 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(phenalkyl)pyrrolidines as muscarinic antagonists. WO 1990-EP2043

  • Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E (2005) Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br J Pharmacol 144:1089–1099

    PubMed  Google Scholar 

  • Matsui M, Motomura D, Karasawa H, Fujikawa T, Jiang J, Komiya Y, Takahashi S, Taketo MM (2000) Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U S A 97:9579–9584

    PubMed  Google Scholar 

  • Meloy TD, Daniels DV, Hegde SS, Eglen RM, Ford APDW (2001) Functional characterization of rat submaxillary gland muscarinic receptors using microphysiometry. Br J Pharmacol 132:1606–1614

    PubMed  Google Scholar 

  • Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff JW, Wein AJ (2001) How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–766

    PubMed  Google Scholar 

  • Ordway GA, Esbenshade TA, Kolta MG, Gerald MC, Wallace LJ (1986a) Effect of age on cholinergic muscarinic responsiveness and receptors in the rat urinary bladder. J Urol 136:492–496

    PubMed  Google Scholar 

  • Ordway GA, Kolta MG, Gerald MC, Wallace LJ (1986b) Age-related change in α-adrenergic responsiveness of the urinary bladder of the rat is regionally specific. Neuropharmacology 25:1335–1340

    PubMed  Google Scholar 

  • Pagala MK, Tetsoti L, Nagpal D, Wise GJ (2001) Aging effects on contractility of longitudinal and circular detrusor and trigone of rat bladder. J Urol 166:721–727

    PubMed  Google Scholar 

  • Sawaki K, Baum BJ, Roth GS, Ambudkar IS (1995) Decreased m3-muscarinic and α1-adrenergic receptor stimulation of PIP2 hydrolysis in parotid gland membranes from aged rats: defect in activation of G alpha/q11. Arch Biochem Biophys 322:319–326

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Schneider T, Hein P, Michel MC (2004b) Signal transduction underlying carbachol-induced contraction of rat urinary bladder. I. Phospholipases and Ca2+ sources. J Pharmacol Exp Ther 308:47–53

    PubMed  Google Scholar 

  • Schneider T, Hein P, Bai J, Michel MC (2005) A role for muscarinic receptors or rho-kinase in hypertension-associated rat bladder dysfunction? J Urol 173:2178–2181

    PubMed  Google Scholar 

  • Simonds WF, Goldsmith PK, Woodard CJ, Unson CG, Spiegel AM (1989) Receptor and effector interactions of Gs. Functional studies with antibodies to the αs carboxyl-terminal decapeptide. FEBS Lett 249:189–194

    PubMed  Google Scholar 

  • Stewart WF, van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–336

    PubMed  Google Scholar 

  • Wuest M, Morgenstern K, Graf E-M, Braeter M, Hakenberg OW, Wirth MP, Ravens U (2005) Cholinergic and purinergic responses in isolated human detrusor in relation to age. J Urol 173:2182–2189

    PubMed  Google Scholar 

  • Wyndaele JJ (2001) The overactive bladder. BJU Int 88:135–140

    PubMed  Google Scholar 

  • Yamakawa T, Ando M, Koito S, Ohwaki K, Kimura T, Saeki T, Miyaji M, Iwahori Y, Fujikawa T, Otake N, Noguchi K (2001) Substituted imidazolidinone derivatives. WO2000JP07133 20001013

  • Yoshida M, Homma Y, Inadome A, Yono M, Seshita H, Miyamoto Y, Murakami S, Kawabe K, Ueda S (2001) Age-related changes in cholinergic and purinergic neurotransmission in human isolated bladder smooth muscles. Exp Gerontol 36:99–109

    PubMed  Google Scholar 

  • Yu H-J, Wein AJ, Levin RM (1997) Contractile responses and calcium mobilization induced by muscarinic agonists in the rat urinary bladder: effects of age. Gen Pharmacol 28:623–628

    PubMed  Google Scholar 

  • Zhao S-H, Berger J, Miller AK, Flippin LA, Clark RD, Maag H, Stepan G, Watson N, Shetty SG, Cefalu JS, Dawson MW, Rocha C (2001) Novel 2-benzyl-piperidine derivatives as selective M2 muscarinic receptor antagonists. Am Chem Soc Proc 221:ORGN-597

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (Mi 294/7-1) and Theravance Inc. TS was recipient of a training fellowship from the intramural grant programme of the University of Essen Medical School (IFORES). The skilful technical assistance of Ms. Charlotte Fetscher is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Urology, University of Essen, Essen, Germany

    Tim Schneider

  2. Department of Medicine, University of Essen, Essen, Germany

    Tim Schneider & Peter Hein

  3. Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

    Martina B. Michel-Reher & Martin C. Michel

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  1. Tim Schneider
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  2. Peter Hein
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Correspondence to Martin C. Michel.

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Schneider, T., Hein, P., Michel-Reher, M.B. et al. Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder. Naunyn Schmied Arch Pharmacol 372, 71–78 (2005). https://doi.org/10.1007/s00210-005-1084-0

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  • DOI: https://doi.org/10.1007/s00210-005-1084-0

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