title: Chronic administration of anticholinergics in rats induces a shift from muscarinic to purinergic transmission in the bladder wall.
abstract: BACKGROUND
  First-line pharmacotherapy for overactive bladder consists of anticholinergics. However, patient compliance is exceptionally low, which may be due to progressive loss of effectiveness.
  
  
  OBJECTIVE
  To decipher the involved molecular mechanisms and to evaluate the effects of chronic systemic administration of anticholinergics on bladder function and on muscarinic and purinergic receptors expression in rats.
  
  
  METHODS
  Female Wistar rats were implanted with an osmotic pump that chronically administered vehicle (Vehc), 0.36 mg/kg per day oxybutynin (Oxyc), or 0.19 mg/kg per day fesoterodine (Fesoc) for 28 d.
  
  
  METHODS
  For cystometry experiments, a small catheter was implanted in the bladder.
  
  
  METHODS
  Urologic phenotype was evaluated by the analysis of the micturition pattern and urodynamics. Expression of muscarinic and purinergic receptors was assessed by Western blot analysis of detrusor membrane protein. Functional responses to carbachol and adenosine triphosphate (ATP) were evaluated using muscle-strip contractility experiments.
  
  
  CONCLUSIONS
  The number of voided spots was transiently decreased in Oxyc rats. In Oxyc rats, the effect of an acute high dose of oxybutynin (1mg/kg intraperitoneally [IP]) on the intermicturition interval was abolished. Expression experiments revealed a decrease of muscarinic acetylcholine receptors M2 (mAChR2) and M3 (mAChR3), whereas the purinergic receptor P2X, ligand-gated ion channel, 1 (P2X1) was enhanced in Oxyc and Fesoc rats compared to Vehc rats. In concordance with the modification of the expression pattern in Oxyc rats, the force generated by carbachol and ATP in muscle-strip contractility experiments was, respectively, lower and higher. Urodynamics revealed that the effects of systemic administration of the purinergic blocker pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (50mg/kg IP) were enhanced in Oxyc rats. As rat bladder physiology is different from that of humans, it is difficult to directly extrapolate our findings to human patients.
  
  
  CONCLUSIONS
  Chronic administration of anticholinergics in rats induces receptor loss of efficiency and a shift from muscarinic to purinergic transmission.
authors.affiliation: Department of Development and Regeneration, Laboratory of Experimental Urology, Campus Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Uvin
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boudes
authors.forename: Aurélie
authors.initials: A
authors.lastname: Menigoz
authors.forename: Jan
authors.initials: J
authors.lastname: Franken
authors.forename: Sílvia
authors.initials: S
authors.lastname: Pinto
authors.forename: Thomas
authors.initials: T
authors.lastname: Gevaert
authors.forename: Ruth
authors.initials: R
authors.lastname: Verplaetse
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Dirk
authors.initials: D
authors.lastname: De Ridder
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D018679:Cholinergic Agonists / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000008:administration & dosage*; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015918:Infusion Pumps, Implantable; D008333:Mandelic Acids / Q000008:administration & dosage*; D009119:Muscle Contraction / Q000187:drug effects; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011687:Purines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D058474:Receptors, Purinergic P2X1 / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D001743:Urinary Bladder / Q000294:innervation*; D014546:Urinary Catheterization; D014554:Urination / Q000187:drug effects; D014563:Urodynamics / Q000187:drug effects; D064804:Urological Agents / Q000008:administration & dosage*
chemical_list: D001559:Benzhydryl Compounds; D018679:Cholinergic Agonists; D018680:Cholinergic Antagonists; D008333:Mandelic Acids; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D011687:Purines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D058474:Receptors, Purinergic P2X1; D064804:Urological Agents; C526675:fesoterodine; C005419:oxybutynin
keywords: Anticholinergics; Antimuscarinics; Fesoterodine; Muscarinic receptor; Oxybutynin; Purinergic receptor; Rats