Stimulation of cyclic AMP accumulation and phosphoinositide hydrolysis by M(3) muscarinic receptors in the rat peripheral lung
Stimulation of cyclic AMP accumulation and phosphoinositide hydrolysis by M(3) muscarinic receptors in the rat peripheral lung
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DOI：
10.1016/0006-2952(96)00339-5
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发表时间：
1996-08-23
影响因子：
5.8
通讯作者：
Ehlert, FJ
中科院分区：
文献类型：
--
作者：
Esqueda, EE;Gerstin, EH;Ehlert, FJ
本文研究了毒蕈碱激动剂氧代震颤素-M（oxo-M）对大鼠外周肺片环磷酸腺苷（cAMP）蓄积的影响。Oxo-M以浓度依赖性方式刺激cAMP积累，EC（50）值为4.2 μ M，最大效应为基础值的2.4 +/-0.39倍。在存在毛喉素（25 μ M）的情况下，oxo-M的最大作用增加到基础的14.1 +/-4.0倍。单独使用毛喉素导致cAMP相对于基础增加5.9 +/-2.2倍;因此，两种药物的组合超过了相加。oxo-M对cAMP积累的影响不受河豚毒素的影响，表明oxo-M的作用不是由神经递质的神经元释放介导的。氧-M有一个小的抑制作用，cAMP的匀浆制备，表明在肺切片中的氧-M的刺激反应是不是由于腺苷酸环化酶的直接刺激。使用不同的毒蕈碱拮抗剂对毛喉素刺激的cAMP蓄积的氧代-M增强作用进行表征，计算得到的pK（B）值与M（3）亚型的结合亲和力一致。Oxo-M引起肺中的磷酸肌醇水解，这种反应的拮抗作用的性质也与M介导的反应的预期一致。在oxo M（100 μ M）、毛喉素（12 μ M）或两种药物联合存在下，cAMP的积累被吲哚美辛（1 μ M）抑制。这些结果表明，M（3）受体刺激cAMP的积累和磷酸肌醇水解在大鼠外周肺，和cAMP刺激的机制可能涉及花生四烯酸代谢产物。
The effects of oxotremorine-M (oxo-M), a muscarinic agonist, on cyclic AMP (cAMP) accumulation in slices of the rat peripheral lung were investigated. Oxo-M stimulated cAMP accumulation in a concentration-dependent manner with an EC(50) value of 4.2 mu M and a maximal effect of 2.4 +/- 0.39-fold over basal. In the presence of forskolin (25 mu M), the maximal effect of oxo-M was increased to 14.1 +/- 4.0-fold over basal. Forskolin alone caused a 5.9 +/- 2.2-fold increase in cAMP relative to basal; therefore, the combination of both drugs was more than additive. The effects of oxo-M on cAMP accumulation were unaffected by tetrodotoxin, indicating that the action of oxo-M was not mediated by neuronal release of neurotransmitters. Oxo-M had a small inhibitory effect on cAMP in a homogenate preparation, indicating that the stimulatory response to oxo-M in slices of the lung is not due to direct stimulation of adenylyl cyclase. Characterization of the oxo-M potentiation of forskolin-stimulated cAMP accumulation using different muscarinic antagonists yielded calculated pK(B) values that agreed with binding affinities for the M(3) subtype. Oxo-M elicited phosphoinositide hydrolysis in the lung, and the nature of the antagonism of this response was also consistent with that expected for an M-mediated response. cAMP accumulation in the presence of oxo M (100 mu M), forskolin (12 mu M), or both drugs combined was inhibited by indomethacin (1 mu M). These results demonstrate that the M(3) receptor stimulates cAMP accumulation and phosphoinositide hydrolysis in the rat peripheral lung, and the mechanism for cAMP stimulation may involve arachidonic acid metabolites.