Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue
Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue
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DOI：
10.1007/s00395-014-0436-7
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发表时间：
2014-11-01
影响因子：
9.5
通讯作者：
Eschenhagen, Thomas
中科院分区：
文献类型：
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作者：
Eder, Alexandra;Hansen, Arne;Eschenhagen, Thomas
对药物的致敏风险的评估仍然具有挑战性。目的评价大鼠工程化心脏组织（EHT）用于预防性实验的可行性。我们监测药物对自发收缩活动的影响，在选定的情况下，对动作电位（锐微电极）和钙瞬变（Fura-2）和电起搏下的收缩。I-受体阻滞剂抑制剂4-氨基吡啶增加动作电位时程和T2，并引起后收缩，这被兰尼碱受体（RyR 2; JTV-519）或钠钙交换剂（NCX; SEA 0400）抑制剂消除。然后在1-10- 100倍游离治疗血浆浓度（FTPC）下测试77种药物。I-Kr、I-Ks、I-to抑制剂、抗心律失常药（8）、因尖端扭转型室性心动过速而退出市场的药物（TdP，5）、具有可测量（7）或孤立TdP发生率（13）的药物、认为安全的药物（14）、28种新化学实体（NCE）I-Kr或I-Ks抑制剂单独无作用，但在高浓度下联合使用时可显著延长舒张时间（T2）。15/33种与TdP相关的药物和6/14种被认为非致室性心动过速的药物（环苯唑啉、地尔硫卓、依巴斯汀、酮康唑、阿托沙星和苯妥英）诱导浓度依赖性T2间期延长（10- 100 x FTPC）。苄普地尔、地昔帕明、丙咪嗪、硫利达嗪和红霉素引起不规则搏动。3例NCE延长T2，1例力降低。抑制复极的药物延长大鼠EHT的舒张，并引起涉及RyR 2和NCX的后收缩。对I-Kr抑制剂不敏感使得大鼠EHT不适合作为一般的致心律失常筛选，但有利于检测对I-to、I-Ks + I-to或I-Ks + I-Kr的作用。筛选大量药物表明，除了I-Kr外，对这些电流的影响比预期的更常见。
The assessment of proarrhythmic risks of drugs remains challenging. To evaluate the suitability of rat engineered heart tissue (EHT) for detecting proarrhythmic effects. We monitored drug effects on spontaneous contractile activity and, in selected cases, on action potentials (sharp microelectrode) and Ca2+ transients (Fura-2) and contraction under electrical pacing. The I-to-blocker inhibitor 4-aminopyridine increased action potential duration and T2 and caused aftercontractions, which were abolished by inhibitors of ryanodine receptors (RyR2; JTV-519) or sodium calcium exchanger (NCX; SEA0400). 77 Drugs were then tested at 1-10-100x free therapeutic plasma concentrations (FTPC). Inhibitors of I-Kr, I-Ks, I-to, antiarrhythmics (8), drugs withdrawn from market for torsades des pointes arrhythmias (TdP, 5), drugs with measurable (7) or isolated TdP incidence (13), drugs considered safe (14), 28 new chemical entities (NCE) Inhibitors of I-Kr or I-Ks had no effect alone, but substantially prolonged relaxation time (T2) when combined at high concentration. 15/33 drugs associated with TdP and 6/14 drugs considered non-torsadogenic (cibenzoline, diltiazem, ebastine, ketoconazole, moxifloxacin, and phenytoin) induced concentration-dependent T2 prolongations (10-100x FTPC). Bepridil, desipramine, imipramine, thioridazine, and erythromycin induced irregular beating. Three NCE prolonged T2, one reduced force. Drugs inhibiting repolarization prolong relaxation in rat EHTs and cause aftercontractions involving RyR2 and NCX. Insensitivity to I-Kr inhibitors makes rat EHTs unsuitable as general proarrhythmia screen, but favors detection of effects on I-to, I-Ks + I-to or I-Ks + I-Kr. Screening a large panel of drugs suggests that effects on these currents, in addition to I-Kr, are more common than anticipated.