M3-receptor knockout mice:: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea

Negative chronotropic and smooth muscle contractile responses to the nonselective muscarinic agonist carbamylcholine were compared in isolated tissues from M-3-muscarinic receptor knockout and wild-type mice. Carbamylcholine (10(-8)-3.0 x 10(-5) M) induced a concentration-dependent decrease in atrial rate that was similar in atria from M-3-receptor knockout and wild-type mice, indicating that M-3 receptors were not involved in muscarinic receptor-mediated atrial rate decreases. In contrast, the M-3 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 M-3-receptor involvement among the tissues. Contraction to carbamylcholine was virtually abolished in urinary bladder from M-3-receptor knockout mice, suggesting that contraction was predominantly due to M-3-receptor activation. However, similar to50-60% maximal contraction to carbamylcholine occurred in stomach fundus and trachea from M-3-receptor knockout mice, indicating that contraction in these tissues was also due to M-2- receptor activation. High concentrations of carbamylcholine relaxed the stomach fundus from M-3-receptor knockout mice by M-1-receptor activation. Thus M-3-receptor knockout mice provided unambiguous evidence that M-3 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 M-2 receptors in mouse stomach fundus and trachea.