Allen S L, Foster R W, Morgan G P, Small R C
Br J Pharmacol. 1986 Jan;87(1):117-27. doi: 10.1111/j.1476-5381.1986.tb10163.x.
Nicorandil (1-1000 mumol l-1) caused concentration-dependent relaxation of guinea-pig isolated trachealis. Propranolol (1 mumol l-1) did not modify the relaxant action of nicorandil but antagonized isoprenaline. Among K+-channel inhibitors tested, apamin (0.1 mumol l-1) and procaine (5 mmol l-1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol l-1) caused five fold antagonism. Trachealis exposed to K+-rich (120 mmol l-1) Krebs solution developed near-maximal tension. Nicorandil relaxed the K+-depolarized tissue though its concentration-effect curve was shifted markedly to the right. In tissues in which tone was induced by histamine, methylene blue (100 mumol l-1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. Intracellular electrophysiological recording showed that nicorandil (1 mumol l-1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10-1000 mumol l-1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. TEA (8 mmol l-1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. Procaine (5 mmol l-1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, nicorandil (1000 mumol l-1) increased the efflux rate constant, whereas isoprenaline (1 mumol l-1) was without effect. It is concluded that nicorandil-induced relaxation does not involve the activation of beta-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.
尼可地尔（1 - 1000 μmol·l⁻¹）可引起豚鼠离体气管平滑肌浓度依赖性舒张。普萘洛尔（1 μmol·l⁻¹）不改变尼可地尔的舒张作用，但拮抗异丙肾上腺素。在所测试的钾通道抑制剂中，蜂毒明肽（0.1 μmol·l⁻¹）和普鲁卡因（5 mmol·l⁻¹）不改变尼可地尔的舒张作用。相反，四乙铵（TEA，8 mmol·l⁻¹）引起五倍的拮抗作用。暴露于富含钾（120 mmol·l⁻¹）的克雷布斯溶液中的气管平滑肌产生接近最大张力。尼可地尔可使钾去极化的组织舒张，尽管其浓度 - 效应曲线明显右移。在由组胺诱导张力的组织中，亚甲蓝（100 μmol·l⁻¹）拮抗尼可地尔和硝普钠，但不改变氨茶碱的舒张作用。细胞内电生理记录显示，尼可地尔（1 μmol·l⁻¹）在无电变化时可引起一定舒张。较高浓度（10 - 1000 μmol·l⁻¹）降低自发电慢波的幅度和频率。尼可地尔还引起浓度依赖性超极化和舒张。当超极化足够明显时，慢波活动消失。TEA（8 mmol·l⁻¹）诱导慢波，其后跟随一个锋电位。TEA略微降低尼可地尔诱导的最大超极化，并增加尼可地尔消除慢波放电所需的时间。普鲁卡因（5 mmol·l⁻¹）诱导频率相对较低的慢波。有时其后跟随一个锋电位。普鲁卡因显著降低尼可地尔诱导的超极化，并增加消除慢波所需的时间。在对富含肌肉的气管条带中⁸⁶Rb⁺外流的研究中，尼可地尔（1000 μmol·l⁻¹）增加外流速率常数，而异丙肾上腺素（1 μmol·l⁻¹）无作用。结论是，尼可地尔诱导的舒张不涉及β - 肾上腺素能受体的激活，部分归因于其分子结构中硝酸盐部分形成一氧化氮。尼可地尔在无膜电位变化时可引起舒张，但在其有效浓度范围上限附近，尼可地尔增加膜钾电导，从而引起气管平滑肌细胞超极化。尼可地尔打开的钾通道对⁸⁶Rb通透，对蜂毒明肽和TEA不敏感，但可能被普鲁卡因抑制。
