title: Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol.
abstract: OBJECTIVE
  To investigate the effects of tissue stretch and muscarinic receptor stimulation on the spontaneous activity of the urothelium/lamina propria and identify the specific receptor subtype mediating these responses.
  
  
  METHODS
  Isolated strips of porcine urothelium with lamina propria were set up for in vitro recording of contractile activity. Muscarinic receptor subtype-selective antagonists were used to identify the receptors influencing the contractile rate responses to stretch and stimulation with carbachol.
  
  
  RESULTS
  Isolated strips of urothelium with lamina propria developed spontaneous contractions (3.7 cycles/min) that were unaffected by tetrodotoxin, Nω-nitro-L-arginine, or indomethacin. Carbachol (1 μM) increased the spontaneous contractile rate of these tissue strips by 122% ± 27% (P < .001). These responses were significantly depressed in the presence of the M3-selective muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (10-30 nM) but were not affected by the M1-selective antagonist pirenzepine (30-100 nM) or the M2-selective antagonist methoctramine (0.1-1 μM). Stretching of the tissue also caused an increase in the spontaneous contractile rate, and these responses were abolished by atropine (1 μM) and low concentrations of 4-diphenylacetoxy-N-methylpiperidine methiodide (10 nM). Darifenacin, oxybutynin, tolterodine, and solifenacin (1 μM) all significantly depressed the frequency responses to carbachol (1 μM).
  
  
  CONCLUSIONS
  The urothelium with the lamina propria exhibits a spontaneous contractile activity that is increased during stretch. The mechanism appears to involve endogenous acetylcholine release acting on M3 muscarinic receptors. Anticholinergic drugs used clinically depress the responses of these tissues, and this mechanism might represent an additional site of action for these drugs in the treatment of bladder overactivity.
authors: Department of Biomedical Science, Bond University Faculty of Health Sciences and Medicine, Queensland, Australia.
authors: Christian
authors: C
authors: Moro
authors: Jumpei
authors: J
authors: Uchiyama
authors: Russ
authors: R
authors: Chess-Williams
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D008333:Mandelic Acids / Q000494:pharmacology; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D010665:Phenylpropanolamine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D000069464:Solifenacin Succinate; D013314:Stress, Mechanical; D013552:Swine; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism*; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D003959:Diamines; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; D010890:Pirenzepine; D000068737:Tolterodine Tartrate; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate; C054938:methoctramine