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Vol. 292, Issue 3, 877-885, March 2000
Eli Lilly and Company, Lilly Research Laboratories, Neuroscience
Research, Lilly Corporate Center, Indianapolis, Indiana
Peripheral muscarinic receptors play key roles in the control of heart
rate and smooth muscle activity. In this study, bradycardic and smooth
muscle contractile responses to the muscarinic agonist carbamylcholine
were compared in isolated tissues from M2 and M4 muscarinic receptor knockout mice and their wild-type
littermates. Carbamylcholine (1 × 10
8-3 × 105 M) produced similar concentration-dependent
bradycardia in spontaneously beating atria from M4 receptor
knockout and wild-type control mice. In contrast, carbamylcholine did
not produce bradycardia in atria derived from M2 receptor
knockout mice, whereas such atria were responsive to adenosine-induced
bradycardia. Carbamylcholine-induced contractile responses were similar
in stomach fundus, urinary bladder, and tracheal preparations from
M4 receptor knockout mice and their wild-type littermates
for each tissue (
logEC50 values ranging from 6.20 ± 0.10 to 6.76 ± 0.08), suggesting that M4 receptors do
not participate in smooth muscle contraction in these tissues. In
contrast, ~2-fold higher carbamylcholine concentration was required
for contraction of stomach fundus, urinary bladder, and trachea from
M2 receptor knockout mice (logEC50 = 6.39 ± 0.05, 6.07 ± 0.06, and 6.27 ± 0.12, respectively) than from wild-type littermates
(logEC50 = 6.68 ± 0.07, 6.27 ± 0.07, and
6.56 ± 0.06, respectively). Furthermore, the affinity of the
M2 "selective" receptor antagonist AF-DX116 in
inhibiting carbamylcholine-induced smooth muscle contraction was
significantly reduced in M2 receptor knockout mice compared
with tissues from wild-type littermates. Collectively, these results
provide direct and unambiguous evidence that M2 receptors
mediate muscarinic receptor-induced bradycardia and play a role in
smooth muscle contractility, whereas M4 receptors are not
involved in stomach fundus, urinary bladder, or tracheal contractility.
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