Jafferji S S, Michell R H
Biochem J. 1976 Nov 15;160(2):163-9. doi: 10.1042/bj1600163.
A number of drugs classed as calcium antagonists, spasmolytics, non-specific receptor antagonists or receptor antagonists with multiple sites of action were tested to determine whether they prevent the stimulation of phosphatidylinositol turnover caused in various tissues by the activation of receptors which increase cell-surface Ca2+ permeability. The experiments were done with fragments of longitudinal smooth muscle from guinea-pig ileum; these were incubated in vitro with 32Pi and either 100 muM-carbamoylcholine or 100 muM-histamine, in the presence of antagonistic drugs at concentrations at least sufficient to cause complete blockade of smooth-muscle contraction. The phosphatidylinositol response to carbamoylcholine was not changed by cinchocaine, papaverine, nifedipine, dibenamine, amethocaine, cinnarizine, lidoflazine, methoxyverapamil, prenylamine or two antimuscarinic alkane-bis-ammonium compounds, and the response to histamine was unaffected by the first four drugs. In contrast, phenoxybenzamine prevented the increase in phosphatidylinositol labelling caused by either carbamoylcholine or histamine. The insensitivity of the phosphatidylinositol response to most of the drugs provides further experimental support for the conclusion that the receptor-stimulated phosphatidylinositol breakdown which initiates the increase in phosphatidylinositol turnover is not caused by an increase in intracellular Ca2+. The simplest interpretation of the available information appears to be that phosphatidylinositol breakdown plays a role in the coupling between the receptor-agonist interaction and the opening of cell-surface Ca2+ gates [Michell, R. H. (1975) Biochim. Biophys. Acta 415, 81-147]. If this is correct, then phenoxybenzamine must exert its inhibitory effects on phosphatidylinositol breakdown early in this sequence of events, but the drugs must act at a stage later than phosphatidylinositol breakdown. The unexpected difference in the effects of dibenamine and phenoxybenzamine, which are chemically very similar, may provide a useful experimental tool with which to explore the way in which activated receptors provoke the opening of cell-surface Ca2+ gates.
对一些归类为钙拮抗剂、解痉剂、非特异性受体拮抗剂或具有多个作用位点的受体拮抗剂的药物进行了测试，以确定它们是否能阻止因增加细胞表面Ca2+通透性的受体激活而在各种组织中引起的磷脂酰肌醇周转率的刺激。实验采用豚鼠回肠纵行平滑肌片段进行；将这些片段在体外与32Pi以及100μM氨甲酰胆碱或100μM组胺一起孵育，同时存在浓度至少足以完全阻断平滑肌收缩的拮抗药物。辛可卡因、罂粟碱、硝苯地平、二苯胺、丁卡因、桂利嗪、利多氟嗪、甲氧基维拉帕米、普尼拉明或两种抗毒蕈碱链烷双铵化合物对氨甲酰胆碱的磷脂酰肌醇反应没有影响，前四种药物对组胺的反应也未产生影响。相比之下，苯氧苄胺可阻止氨甲酰胆碱或组胺引起的磷脂酰肌醇标记增加。磷脂酰肌醇反应对大多数药物不敏感，这为以下结论提供了进一步的实验支持：引发磷脂酰肌醇周转率增加的受体刺激的磷脂酰肌醇分解不是由细胞内Ca2+增加引起的。对现有信息的最简单解释似乎是，磷脂酰肌醇分解在受体 - 激动剂相互作用与细胞表面Ca2+通道开放之间的偶联中起作用[米歇尔，R. H.（1975年）《生物化学与生物物理学报》415，81 - 147]。如果这是正确的，那么苯氧苄胺必须在这一系列事件的早期对磷脂酰肌醇分解发挥其抑制作用，但这些药物的作用阶段必须晚于磷脂酰肌醇分解。化学结构非常相似的二苯胺和苯氧苄胺在作用上的意外差异，可能提供一个有用的实验工具，用于探索激活的受体引发细胞表面Ca2+通道开放的方式。
