RT Journal Article
SR Electronic
T1 M<sub>2</sub> and M<sub>4</sub> Receptor Knockout Mice: Muscarinic Receptor Function in Cardiac and Smooth Muscle In Vitro
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 877
OP 885
VO 292
IS 3
A1 Peter W. Stengel
A1 Jesus Gomeza
A1 Jurgen Wess
A1 Marlene L. Cohen
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/877.abstract
AB 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 × 10−5 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. The American Society for Pharmacology and Experimental Therapeutics