title: Exogenous activation of muscarinic receptors decreases subsequent non-muscarinic bladder contractions in vivo in the female rat.
abstract: OBJECTIVE
  To determine if the muscarinic agonist, bethanechol, inhibits the non-cholinergic, atropine-resistant (i.e. putatively purinergic) component of naturally occurring (i.e. reflexogenic) bladder contractions in vivo in the rat, as previously described in vitro. Our second aim was to determine if elevation of endogenous acetylcholine (ACh) with distigmine, an acetylcholine esterase (AChE) inhibitor, could also inhibit non-cholinergic component of reflexogenic bladder contractions.
  
  
  METHODS
  Cystometry was performed in urethane anesthetized adult female Sprague Dawley rats. The nonselective muscarinic receptor (mAChR) antagonist, atropine, was administered intravenously (i.v.) before and after i.v. administration of the non-selective mAChR agonist, bethanechol, the AChE inhibitor, distigmine or the neurokinin receptor 2 agonist, [βAla(8)]-Neurokinin A(4-10). Intermicturition interval (IMI), bladder contraction amplitude (BCA), postvoid bladder pressure (PVBP), and voiding efficiency (VE) were measured.
  
  
  RESULTS
  Atropine (0.4 mg/kg; n=11 rats) delivered as the first drug, had insignificant effects on BCA (~15% reduction) or PVBP (~15% increase) and weakly reduced IMI and VE by ~40% (p<0.05) relative to vehicle. Bethanechol and distigmine on their own produced excitatory effects on bladder activity, consistent with mAChR activation. Unexpectedly atropine, administered after bethanechol or after distigmine but not after [βAla(8)]-Neurokinin A(4-10), completely blocked bladder activity for 3-10 min. Partial recovery of bladder activity occurred after that time, but BCA, IMI, and VE remained significantly reduced and PVBP remained significantly increased.
  
  
  CONCLUSIONS
  Activation of mAChRs by an exogenous agonist or elevation of endogenous ACh levels by an AChE inhibitor inhibits the non-cholinergic, atropine-resistant, component of reflexogenic bladder contractions in vivo.
authors: Urogenix Inc./Astellas, 801 Capitola Dr., Durham, NC, USA. aura240@yahoo.com
authors: F Aura
authors: FA
authors: Kullmann
authors: Grace I
authors: GI
authors: Wells
authors: David G
authors: DG
authors: McKenna
authors: Karl B
authors: KB
authors: Thor
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018723:Bethanechol / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005260:Female; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D018723:Bethanechol; D001285:Atropine; D000109:Acetylcholine; C084645:distigmine