Acetylcholine-Induced Desensitization of the Contractile Response to Histamine in Guinea Pig Ileum Is Prevented by Either Pertussis Toxin Treatment or by Selective Inactivation of Muscarinic M_3 Receptors

摘要

We have studied the role of M2 and M3 muscarinic receptors in acetylcholine-mediated desensitization of the contractile re- sponse to histamine in the guinea pig ileum. Treatment of the isolated ileum with acetylcholine (30 ILM) for 20 min caused a marked desensitization of the contractile response to hista- mine. When measured 5 min after washout of acetylcholine, the ECso value of histamine increased 5.8-fold compared with that estimated before acetylcholine treatment, whereas the maximal response was unaffected. This shift in the ECso value of hista- mine was maximal at the earliest time measured after acetyl- choline treatment (5 min), and normal sensitivity recovered in approximately 20 min. Acetylcholine-induced desensitization was prevented by uncoupling of M2 receptors from Gj with pertussis toxin or by selective inactivation of M3 receptors with N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP mus- tard). The shifts in the EC5o values of histamine measured 5 min after acetylcholine treatment were only 2.0- and 1.8-fold in pertussis toxin- and 4-DAMP mustard-treated ilea, respec- tively. Both pertussis toxin- and 4-DAMP mustard-treatment had little or no effect on histamine-induced contractions in control ileum. Measurement of histamine-stimulated inositol phosphate accumulation in the longitudinal muscle of the ileum showed little or no inhibitory effect of prior exposure to acetyl- choline, indicating that the majority of the heterologous desen- sitization occurs downstream from phospholipase Cf3 activa- tion. Collectively, our results suggest that activation of both M2 and M3 receptors is required for heterologous desensitization of histamine-mediated contractions in the guinea pig ileum.