Ballejo G, Calixto J B, Medeiros Y S
Br J Pharmacol. 1986 Nov;89(3):515-23. doi: 10.1111/j.1476-5381.1986.tb11151.x.
The inhibitory effects of nifedipine, verapamil, cinnarizine (calcium entry blockers), chlorpromazine (a putative calmodulin antagonist) and fenoterol (a beta 2-adrenoceptor agonist) on contractility in human isolated pregnant myometrium were studied. Spontaneous contractions (present in 93% of the preparations) were inhibited in a concentration-related manner by these compounds in the following order of potency: nifedipine greater than verapamil much greater than cinnarizine greater than chlorpromazine. Cinnarizine was effective only at a concentration greater than 100 microM. Fenoterol, at 10 microM, did not produce an inhibitory effect but decreased the frequency of spontaneous contractions. All drugs, except fenoterol, produced a concentration-dependent relaxation of K+-induced contractions in the following order of sensitivity: nifedipine greater than verapamil much greater than chlorpromazine. Cinnarizine produced only about 40% of relaxation. Under these conditions nifedipine and verapamil were about 80 and 5 fold more potent respectively than when tested against spontaneous contractions. The potencies of chlorpromazine and cinnarizine did not differ in the two experimental conditions. Both the spontaneous and K+-induced contractions were inhibited in a time-dependent manner in Ca2+-free media and the responses were almost completely abolished in 70-100 min. Calcium addition to the medium rapidly restored both spontaneous or K+-induced contractions. To investigate further the role of intracellular calcium, K+-depolarized preparations contracted by calcium 3 mM (40-60% of maximal contractions) were relaxed by these compounds. Nifedipine and verapamil showed a relaxation time course similar to that induced by calcium removal. Cinnarizine and fenoterol had no relaxant effect while chlorpromazine induced a slight and slow relaxation. 6 These findings suggest that calcium influx and calmodulin are involved in spontaneous contractions of pregnant human myometrium in vitro. Since nifedipine and verapamil were more potent against K+-induced than spontaneous contractions, calcium channels activated by these conditions could be different. Finally, fenoterol, a beta 2-adrenoceptor agonist, widely used as a tocolytic agent, blocked neither spontaneous nor K+-induced contractions.
研究了硝苯地平、维拉帕米、桂利嗪（钙通道阻滞剂）、氯丙嗪（一种假定的钙调蛋白拮抗剂）和非诺特罗（一种β2肾上腺素能受体激动剂）对人离体妊娠子宫肌层收缩性的抑制作用。这些化合物以浓度依赖的方式抑制自发收缩（93%的标本中有自发收缩），其效力顺序如下：硝苯地平＞维拉帕米＞＞桂利嗪＞氯丙嗪。桂利嗪仅在浓度大于100μM时才有效。非诺特罗在10μM时未产生抑制作用，但降低了自发收缩的频率。除非诺特罗外，所有药物均使K⁺诱导的收缩产生浓度依赖性舒张，其敏感性顺序如下：硝苯地平＞维拉帕米＞＞氯丙嗪。桂利嗪仅产生约40%的舒张。在这些条件下，硝苯地平和维拉帕米的效力分别比针对自发收缩测试时强约80倍和5倍。氯丙嗪和桂利嗪在两种实验条件下的效力没有差异。在无钙培养基中，自发收缩和K⁺诱导的收缩均以时间依赖的方式受到抑制，且反应在70 - 100分钟内几乎完全消失。向培养基中添加钙可迅速恢复自发或K⁺诱导的收缩。为了进一步研究细胞内钙的作用，用3 mM钙收缩（最大收缩的40 - 60%）的K⁺去极化标本被这些化合物舒张。硝苯地平和维拉帕米显示出与钙去除诱导的舒张相似的时间进程。桂利嗪和非诺特罗没有舒张作用，而氯丙嗪诱导轻微且缓慢的舒张。这些发现表明钙内流和钙调蛋白参与了体外妊娠人子宫肌层的自发收缩。由于硝苯地平和维拉帕米对K⁺诱导的收缩比对自发收缩更有效，这些条件激活的钙通道可能不同。最后，非诺特罗，一种广泛用作宫缩抑制剂的β2肾上腺素能受体激动剂，既不阻断自发收缩也不阻断K⁺诱导的收缩。
