M2 and M4 Receptor Knockout Mice: Muscarinic Receptor Function in Cardiac and Smooth Muscle In Vitro
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 M 2 and M 4 muscarinic receptor knockout mice an...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 292; no. 3; p. 877 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.03.2000
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Online Access | Get full text |
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Summary: | 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 M 2 and M 4 muscarinic receptor knockout mice and their wild-type littermates. Carbamylcholine (1 Ã 10 â8 -3 Ã 10 â5 M) produced similar concentration-dependent bradycardia in spontaneously beating atria from M 4 receptor knockout and wild-type control mice. In contrast, carbamylcholine did not produce bradycardia in atria derived from
M 2 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 M 4 receptor knockout mice and their wild-type littermates for each tissue (âlogEC 50 values ranging from 6.20 ± 0.10 to 6.76 ± 0.08), suggesting that M 4 receptors do not participate in smooth muscle contraction in these tissues. In contrast, â¼2-fold higher carbamylcholine concentration
was required for contraction of stomach fundus, urinary bladder, and trachea from M 2 receptor knockout mice (âlogEC 50 = 6.39 ± 0.05, 6.07 ± 0.06, and 6.27 ± 0.12, respectively) than from wild-type littermates (âlogEC 50 = 6.68 ± 0.07, 6.27 ± 0.07, and 6.56 ± 0.06, respectively). Furthermore, the affinity of the M 2 âselectiveâ receptor antagonist AF-DX116 in inhibiting carbamylcholine-induced smooth muscle contraction was significantly
reduced in M 2 receptor knockout mice compared with tissues from wild-type littermates. Collectively, these results provide direct and unambiguous
evidence that M 2 receptors mediate muscarinic receptor-induced bradycardia and play a role in smooth muscle contractility, whereas M 4 receptors are not involved in stomach fundus, urinary bladder, or tracheal contractility. |
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ISSN: | 0022-3565 1521-0103 |