Kitazawa T, Kubo O, Satoh M, Taneike T
Department of Pharmacology, Faculty of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan.
Br J Pharmacol. 1998 Jan;123(2):173-82. doi: 10.1038/sj.bjp.0701583.
1 5-Hydroxytryptamine (5-HT; 1 nM - 100 microM) concentration-dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68-84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3-1.44 microM) to 5-HT. To characterize the 5-HT receptor subtype responsible for inhibition of myometrial contractility, the effects of 5-HT receptor agonists on spontaneous contractions and of 5-HT receptor antagonists on inhibition by 5-HT were examined in circular muscle preparations. 2 Pretreatment with tetrodotoxin (1 microM), propranolol (1 microM), atropine (1 microM), guanethidine (10 microM) or L-NAME (100 microM) failed to change the inhibition by 5-HT, indicating that the inhibition was due to a direct action of 5-HT on the smooth muscle cells. 3 5-CT, 5-MeOT and 8-OH-DPAT mimicked the inhibitory response of 5-HT, and the rank order of the potency was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, alpha-methyl-5-HT, 2-methyl-5-HT, cisapride, BIMU-1, BIMU-8, ergotamine and dihydroergotamine had almost no effect on spontaneous contractions, even at 10-100 microM. 4 Inhibition by 5-HT was not decreased by either pindolol (1 microM), ketanserin (1 microM), tropisetron (10 microM), MDL72222 (1 microM) or GR113808 (10 microM), but was antagonized by the following compounds in a competitive manner (with pA2 values in parentheses): methiothepin (8.05), methysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7.06) and spiperone (6.86). 5 Ro 20-1724 (20 microM) and rolipram (10 microM) significantly enhanced the inhibitory response of 5-HT, but neither zaprinast (10 microM) nor dipyridamole (10 microM) altered the response of 5-HT. 6 5-HT (1 nM - 1 microM) caused a concentration-dependent accumulation of intracellular cyclic AMP in the circular muscle. 7 From the present results, the 5-HT receptor, which is functionally correlated with the 5-HT7 receptor, mediates the inhibitory effect of 5-HT on porcine myometrial contractility. This inhibitory response is probably due to an increase in intracellular cyclic AMP through the activation of adenylate cyclase that is positively coupled to 5-HT7 receptors.
5-羟色胺（5-HT；1 nM - 100 microM）浓度依赖性地抑制猪子宫肌层纵行肌和环行肌的自发收缩幅度和频率。环行肌（半数有效浓度EC50；68 - 84 nM）比纵行肌（EC50；1.3 - 1.44 microM）对5-HT更敏感。为了确定负责抑制子宫肌层收缩力的5-HT受体亚型，在环行肌制备物中研究了5-HT受体激动剂对自发收缩的影响以及5-HT受体拮抗剂对5-HT抑制作用的影响。
用河豚毒素（1 microM）、普萘洛尔（1 microM）、阿托品（1 microM）、胍乙啶（10 microM）或L-硝基精氨酸甲酯（L-NAME，100 microM）预处理未能改变5-HT的抑制作用，表明该抑制作用是由于5-HT对平滑肌细胞的直接作用。
5-羧色胺（5-CT）、5-甲氧基色胺（5-MeOT）和8-羟基-二丙基氨基四氢吡啶（8-OH-DPAT）模拟了5-HT的抑制反应，其效价顺序为5-CT>5-HT>5-MeOT>8-OH-DPAT。另一方面，奥昔麻黄碱、α-甲基-5-HT、2-甲基-5-HT、西沙必利、BIMU-1、BIMU-8、麦角胺和双氢麦角胺即使在10 - 100 microM时对自发收缩也几乎没有影响。
吲哚洛尔（1 microM）、酮色林（1 microM）、托烷司琼（10 microM）、MDL72222（1 microM）或GR113808（10 microM）均未降低5-HT的抑制作用，但以下化合物以竞争性方式拮抗该作用（括号内为pA2值）：甲硫噻吨（8.05）、麦角新碱（7.92）、美替拉酮（7.4）、米安色林（7.08）、氯氮平（7.06）和螺哌隆（6.86）。
罗吡丁酯（20 microM）和咯利普兰（10 microM）显著增强了5-HT的抑制反应，但扎普司特（10 microM）和双嘧达莫（10 microM）均未改变5-HT的反应。
5-HT（1 nM - 1 microM）导致环行肌细胞内环状AMP呈浓度依赖性积累。
根据目前的结果，与5-HT7受体功能相关的5-HT受体介导了5-HT对猪子宫肌层收缩力的抑制作用。这种抑制反应可能是由于通过与5-HT7受体正向偶联的腺苷酸环化酶的激活导致细胞内环状AMP增加所致。
