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Am J Physiol Regul Integr Comp Physiol 282: R1443-R1449, 2002. First published January 17, 2002; doi:10.1152/ajpregu.00486.2001
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Vol. 282, Issue 5, R1443-R1449, May 2002

M3-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea

Peter W. Stengel1, Masahisa Yamada2, Jürgen Wess2, and Marlene L. Cohen1

1 Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285; and 2 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892-0810

Negative chronotropic and smooth muscle contractile responses to the nonselective muscarinic agonist carbamylcholine were compared in isolated tissues from M3-muscarinic receptor knockout and wild-type mice. Carbamylcholine (10-8-3.0 × 10-5 M) induced a concentration-dependent decrease in atrial rate that was similar in atria from M3-receptor knockout and wild-type mice, indicating that M3 receptors were not involved in muscarinic receptor-mediated atrial rate decreases. In contrast, the M3 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 M3-receptor involvement among the tissues. Contraction to carbamylcholine was virtually abolished in urinary bladder from M3-receptor knockout mice, suggesting that contraction was predominantly due to M3-receptor activation. However, ~50-60% maximal contraction to carbamylcholine occurred in stomach fundus and trachea from M3-receptor knockout mice, indicating that contraction in these tissues was also due to M2-receptor activation. High concentrations of carbamylcholine relaxed the stomach fundus from M3-receptor knockout mice by M1-receptor activation. Thus M3-receptor knockout mice provided unambiguous evidence that M3 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 M2 receptors in mouse stomach fundus and trachea.

atrial rate; negative chronotropy; smooth muscle contraction; carbamylcholine-mediated responses


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