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Articles in PresS, published online ahead of print January 17, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00486.2001
Submitted on August 14, 2001
Accepted on January 15, 2002
1 Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA
2 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: stengel_peter_w{at}lilly.com.
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 (10-8-3.0x10-5M) 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, approximately 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.
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