title: M(3)-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea.
abstract: Negative chronotropic and smooth muscle contractile responses to the nonselective muscarinic agonist carbamylcholine were compared in isolated tissues from M(3)-muscarinic receptor knockout and wild-type mice. Carbamylcholine (10(-8)-3.0 x 10(-5) M) induced a concentration-dependent decrease in atrial rate that was similar in atria from M(3)-receptor knockout and wild-type mice, indicating that M(3) receptors were not involved in muscarinic receptor-mediated atrial rate decreases. In contrast, the M(3) receptor was a major muscarinic receptor involved in smooth muscle contraction of stomach fundus, urinary bladder, and trachea, although differences existed in the extent of M(3)-receptor involvement among the tissues. Contraction to carbamylcholine was virtually abolished in urinary bladder from M(3)-receptor knockout mice, suggesting that contraction was predominantly due to M(3)-receptor activation. However, approximately 50-60% maximal contraction to carbamylcholine occurred in stomach fundus and trachea from M(3)-receptor knockout mice, indicating that contraction in these tissues was also due to M(2)-receptor activation. High concentrations of carbamylcholine relaxed the stomach fundus from M(3)-receptor knockout mice by M(1)-receptor activation. Thus M(3)-receptor knockout mice provided unambiguous evidence that M(3) receptors 1) play no role in carbamylcholine-induced atrial rate reduction, 2) are the predominant receptor mediating carbamylcholine-induced urinary bladder contractility, and 3) share contractile responsibility with M(2) receptors in mouse stomach fundus and trachea.
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. stengel_peter_w@lilly.com
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stengel
authors.forename: Masahisa
authors.initials: M
authors.lastname: Yamada
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000818:Animals; D016275:Atrial Function / Q000187:drug effects; D001835:Body Weight / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D005748:Gastric Fundus / Q000187:drug effects / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000235:genetics / Q000502:physiology*; D012016:Reference Values; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D018679:Cholinergic Agonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D002217:Carbachol