School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (A.A., D.F.v.H., D.R.L.); Bosch Institute, Discipline of Anatomy, University of Sydney, Sydney, New South Wales, Australia (C.d.R.); School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (P.M.); and Northside Clinical School of Medicine, University of Queensland, Cardio-vascular Molecular & Therapeutics Translational Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia (P.M.).
School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, New South Wales, Australia (A.A., D.F.v.H., D.R.L.); Bosch Institute, Discipline of Anatomy, University of Sydney, Sydney, New South Wales, Australia (C.d.R.); School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia (P.M.); and Northside Clinical School of Medicine, University of Queensland, Cardio-vascular Molecular & Therapeutics Translational Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia (P.M.)
Mol Pharmacol. 2020 Apr;97(4):250-258. doi: 10.1124/mol.119.117721. Epub 2020 Feb 3.
Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca release during systole or affecting Ca release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca] but not at Ca levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca in a manner paralleling that of dantrolene. Moreover, the IC of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT: We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.
苯妥英是一种乙内酰脲衍生物，临床上用于治疗癫痫，据报道对心脏具有抗心律失常作用。在衰竭的心脏中，升高的肌浆网舒张 Ca 泄漏可以通过肌质网 Ca 释放通道 2（RyR2）抑制剂丹曲林钠得到正常化，而不会抑制收缩期的 Ca 释放或影响正常健康心脏的 Ca 释放。不幸的是，丹曲林钠具有肝毒性，不适合长期慢性给药。因为苯妥英和丹曲林钠都属于乙内酰脲类化合物，所以我们使用 RyR2 的人工脂质双层的单通道记录来测试丹曲林钠和苯妥英对 RyR2 具有相似抑制作用的假设。苯妥英对来自绵羊和人类衰竭心脏的 RyR2 通道产生可逆抑制作用。它遵循双曲线剂量反应，最大抑制率约为 50%，Hill 系数约为 1，IC 范围为 10 至 20µM。它在舒张细胞质[Ca]时引起抑制，但在收缩期时在二联体裂隙中的 Ca 水平时不引起抑制。值得注意的是，苯妥英抑制来自衰竭的人类心脏的 RyR2，但不抑制来自健康心脏的 RyR2，表明苯妥英可能选择性地靶向人类的有缺陷的 RyR2 通道。我们得出结论，苯妥英可以有效地抑制 RyR2 介导的 Ca 释放，其方式与丹曲林钠相似。此外，苯妥英在 RyR2 中的 IC 至少比其他离子通道和临床使用的血清水平低三倍，这表明苯妥英作为一种针对心力衰竭和心律失常的治疗方法，比丹曲林钠更安全。意义：我们表明，苯妥英，一种临床上用于治疗癫痫的钠通道阻滞剂，是一种在低于其当前治疗水平三倍的剂量下，对心脏钙释放通道（肌质网 Ca 释放通道 2（RyR2））的舒张抑制剂。苯妥英抑制来自衰竭的人类心脏的 RyR2，但不抑制来自健康心脏的 RyR2，表明苯妥英可能选择性地靶向人类的有缺陷的 RyR2 通道，并指出苯妥英作为一种针对心力衰竭和心律失常的治疗方法，比丹曲林钠更安全。
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