Pataricza János, Krassói Irén, Höhn József, Kun Attila, Papp Julius Gyula
Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6701, Szeged, Dóm tér 12., Hungary.
Cardiovasc Drugs Ther. 2003 Mar;17(2):115-21. doi: 10.1023/a:1025331617233.
Levosimendan, a new type of inodilator drugs, is known to activate membrane adenosine 3',5'-triphosphate-sensitive potassium (KATP) channels in some vascular smooth muscles and causes vasorelaxation. The involvement of potassium channels in the mechanism of the coronary artery relaxing effect of the drug has not been established. In the present study performed in the porcine epicardial coronary artery, the effect of levosimendan (0.009-3.2 microM) was compared to cromakalim (0.0125-5 microM), the known activator of ATP-sensitive potassium (KATP) channels, in the presence of glibenclamide (GLI), an inhibitor of KATP channels and tetraethylammonium (TEA), the non-selective inhibitor of potassium channels. The interaction of levosimendan with the specific calcium-activated potassium channel (KCa) blocker, iberiotoxin (IBTX), and the voltage-sensitive potassium channel (KV) blocker, 4-aminopyridine (4-AP), was also studied. All the experiments were performed in the isometric tension of endothelium denuded porcine isolated epicardial coronary arteries precontracted with 20 mM potassium chloride. 1 microM GLI decreased the maximum of cromakalim-induced relaxation by 60% but did not affect the action of levosimendan. In contrast, 2 mM TEA decreased only the coronary artery relaxing effect of levosimendan. 100 nM IBTX suppressed the maximum effect of levosimendan by only 15% while 0.5 mM 4-AP significantly shifted the concentration-response curve of the inodilator to the right. 5 mM 4-AP caused a maximum of 33% decrease of levosimendan-induced relaxation. These results indicate that, in porcine isolated epicardial coronary artery, the vasorelaxing mechanism of levosimendan involves the activation of voltage-sensitive and, at large concentrations, calcium-activated potassium channels.
左西孟旦是一种新型的血管活性药物，已知其可激活某些血管平滑肌中的膜三磷酸腺苷（ATP）敏感性钾（KATP）通道并引起血管舒张。钾通道在该药物冠状动脉舒张作用机制中的参与情况尚未明确。在本研究中，在猪心外膜冠状动脉上进行实验，将左西孟旦（0.009 - 3.2微摩尔）的作用与已知的ATP敏感性钾（KATP）通道激活剂克罗卡林（0.0125 - 5微摩尔）在格列本脲（GLI，一种KATP通道抑制剂）和四乙铵（TEA，一种钾通道非选择性抑制剂）存在的情况下进行比较。还研究了左西孟旦与特异性钙激活钾通道（KCa）阻滞剂iberiotoxin（IBTX）和电压敏感性钾通道（KV）阻滞剂4 - 氨基吡啶（4 - AP）的相互作用。所有实验均在预先用20毫摩尔氯化钾预收缩的去内皮猪离体心外膜冠状动脉的等长张力条件下进行。1微摩尔GLI使克罗卡林诱导的最大舒张降低60%，但不影响左西孟旦的作用。相反，2毫摩尔TEA仅降低左西孟旦的冠状动脉舒张作用。100纳摩尔IBTX仅使左西孟旦的最大作用降低15%，而0.5毫摩尔4 - AP使该血管活性药物的浓度 - 反应曲线显著右移。5毫摩尔4 - AP使左西孟旦诱导的舒张最大降低33%。这些结果表明，在猪离体心外膜冠状动脉中，左西孟旦的血管舒张机制涉及电压敏感性钾通道以及在高浓度时钙激活钾通道的激活。
