title: Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction.
abstract: OBJECTIVE
  This study examines whether M(2) receptors contribute to direct contraction of the detrusor in human neurogenic and idiopathic overactive bladders.
  
  
  METHODS
  Control detrusor muscle was obtained from patients undergoing cystectomy for bladder cancer, whilst overactive detrusor muscle was obtained from patients undergoing clam cystoplasty for idiopathic or neurogenic detrusor overactivity. The affinities of a range of subtype selective antagonists (DAMP, darifenacin, methoctramine R0-320-6206, and pirenzepine) were obtained in tissue bath experiments by using carbachol as the agonist. These affinity values were then compared with the known affinities for these antagonists at the muscarinic receptor subtypes.
  
  
  RESULTS
  An increased sensitivity to carbachol was observed in both the neurogenic and idiopathic overactive detrusors compared with the control human detrusor. The M(2)-selective antagonists (methoctramine, R0-320-6206) and M(1)-selective antagonist (pirenzepine) had low affinities, whilst the M(3)-selective antagonists (4-DAMP and darifenacin) had high affinities for the human detrusor muscarinic receptor in all three groups of tissues. The affinities (pK(B) values) for the five antagonists were consistent with antagonisms at the M(3) receptor in all three groups; Schild plot analysis indicated an action at this single receptor subtype.
  
  
  CONCLUSIONS
  Contraction mediated by muscarinic receptors is enhanced in idiopathic and neurogenic overactive detrusors compared with control detrusor. The direct contractile response to carbachol is mediated by the M(3) receptor in both human normal and overactive bladders, indicating no change in receptor subtype contribution to contraction in the disease state.
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Stevens
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chapple
authors.forename: Russ
authors.initials: R
authors.lastname: Chess-Williams
mesh_terms: D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects*; D001750:Urinary Bladder, Neurogenic / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000503:physiopathology*
chemical_list: D001572:Benzofurans; D003959:Diamines; D010880:Piperidines; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; C101207:darifenacin; C054938:methoctramine