Department of Vegetative Physiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Anesth Analg. 2010 Sep;111(3):638-46. doi: 10.1213/ANE.0b013e3181e41996. Epub 2010 Jul 2.
Droperidol is a highly potent butyrophenone used for the therapy of postoperative nausea and vomiting. Its cardiac safety in cardiovascular-healthy patients and those with long QT (LQT) syndrome is a matter of debate. In this study, we investigated whether droperidol has subtype-specific effects in cellular and computational models of LQT syndrome.
Left ventricular cardiac myocytes were isolated from adult guinea pig hearts. LQT1-like behavior was pharmacologically induced by chromanol 293B (10 micromol/L) and LQT2-like states by E4031 (10 micromol/L). Computational analysis was performed using the Luo-Rudy dynamic model. Data are given as mean + or - SEM.
In control myocytes, droperidol lengthened action potentials in a concentration-dependent manner with a maximal prolongation of 37% + or - 13% (n = 4) at a concentration of 0.6 micromol/L. In LQT1-like myocytes, droperidol (0.6 micromol/L) further prolonged action potentials by 31% + or - 6% (n = 6) but shortened action potentials of LQT2-like myocytes by 11% + or - 2% (n = 8). Computational modeling supported the concept that droperidol, in addition to the rapid component of the delayed K(+) current, blocks depolarizing targets, such as the L-type Ca(2+) current, the Na(+)-Ca(2+) exchanger, and the Na(+)-K(+) adenosine triphosphatase.
Droperidol has more detrimental effects on cardiac repolarization of LQT1-like than of LQT2-like myocytes suggesting subtype-specific cardiotoxic effects in patients with LQT syndrome. The subtype specificity of droperidol seems to be caused by a complex interaction of droperidol with several different molecular targets. This interaction deserves further investigation to establish the feasibility of a subtype-directed approach in the perioperative management of patients with LQT syndrome.
氟哌利多是一种强效丁酰苯类药物，用于治疗术后恶心和呕吐。其在心血管健康患者和长 QT （LQT）综合征患者中的心脏安全性存在争议。在这项研究中，我们研究了氟哌利多是否在 LQT 综合征的细胞和计算模型中具有亚型特异性作用。
从成年豚鼠心脏中分离出左心室心肌细胞。用色烷 293B（10 μmol/L）诱导 LQT1 样行为，用 E4031（10 μmol/L）诱导 LQT2 样状态。使用 Luo-Rudy 动力学模型进行计算分析。数据表示为均值±SEM。
在对照心肌细胞中，氟哌利多呈浓度依赖性延长动作电位，在 0.6 μmol/L 浓度下最大延长 37%±13%（n=4）。在 LQT1 样心肌细胞中，氟哌利多（0.6 μmol/L）进一步延长动作电位 31%±6%（n=6），但缩短 LQT2 样心肌细胞的动作电位 11%±2%（n=8）。计算模型支持这样的概念，即除了延迟 K+电流的快速成分外，氟哌利多还阻断去极化靶标，如 L 型 Ca2+电流、Na+-Ca2+交换体和 Na+-K+三磷酸腺苷酶。
氟哌利多对 LQT1 样心肌细胞的心脏复极产生比 LQT2 样心肌细胞更有害的影响，提示 LQT 综合征患者存在亚型特异性心脏毒性作用。氟哌利多的亚型特异性似乎是由于氟哌利多与几个不同的分子靶标复杂相互作用的结果。这种相互作用值得进一步研究，以确定在 LQT 综合征患者围手术期管理中采用亚型定向方法的可行性。
