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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 × 105 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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