Muscarinic Agonist-Mediated Heterologous Desensitization in Isolated Ileum Requires Activation of Both Muscarinic M2 and

We investigated the subtypes of the muscarinic receptor me-diating short-term heterologous desensitization in the isolated ileum. Treatment of the ileum from C57BL/6 mice with acetyl-choline (30 M) for 20 min caused a subsequent decrease in contractile sensitivity to both prostaglandin F2 (PGF2) and the muscarinic agonist, oxotremorine-M. This subsensitivity was characterized by 7- and 3-fold increases in the EC50 values of the agonists, respectively, with no significant effect on the maximal response. The subsensitivity to PGF2 was prevented in both M2 and M3 muscarinic receptor knockout mice. Simi-larly, the subsensitivity to oxotremorine-M was prevented in M2 knockout mice. Acetylcholine-mediated desensitization of his-tamine-induced contractions in the guinea pig ileum was inhib-ited by both M2- and M3-selective muscarinic antagonists wit