Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction.
Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction.
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DOI：
10.1016/j.jphs.2016.05.012
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发表时间：
2016-07
影响因子：
3.5
通讯作者：
Yasuharu Shinoda;H. Tagashira;M. Bhuiyan;H. Hasegawa;H. Kanai;K. Fukunaga
中科院分区：
文献类型：
--
作者：
Yasuharu Shinoda;H. Tagashira;M. Bhuiyan;H. Hasegawa;H. Kanai;K. Fukunaga
氟哌啶醇是一种抗精神病药物，抑制多巴胺D2受体等。氟哌啶醇还结合σ-1受体（σ 1 R）并对其进行不可逆抑制。氟哌啶醇治疗精神分裂症患者的一个严重结局是因突发心力衰竭而死亡。虽然原因尚不清楚，但我们假设这些作用是由氟哌啶醇对心脏σ 1 R的慢性抑制介导的。为了验证这一点，我们用氟哌啶醇处理新生大鼠心肌细胞，将其暴露于血管紧张素II，并评估肥大、σ 1 R表达、线粒体Ca 2+转运和ATP水平。在这种情况下，氟哌啶醇处理改变了线粒体Ca 2+转运，通过灭活心脏σ 1 R和/或降低其表达导致ATP含量降低。我们还进行了横向主动脉缩窄术（TAC），然后用氟哌啶醇治疗小鼠。两周后，氟哌啶醇处理的小鼠显示出增强的心力衰竭，其特征在于心脏功能恶化、ATP产生减少和相对于仅TAC的小鼠死亡率增加。通过丙酮酸钠补充ATP挽救了氟哌啶醇处理的TAC小鼠中观察到的表型。我们的结论是，σ 1 R失活或下调氟哌啶醇治疗损害线粒体Ca 2+动员，消耗ATP消耗心肌细胞。这些研究结果表明，一种新的方法，以减轻氟哌啶醇相关的不良反应，精神分裂症患者的ATP补充剂。
Haloperidol is an antipsychotic drug that inhibits the dopamine D2 receptor among others. Haloperidol also binds the sigma-1 receptor (σ1R) and inhibits it irreversibly. A serious outcome of haloperidol treatment of schizophrenia patients is death due to sudden cardiac failure. Although the cause remains unclear, we hypothesized that these effects were mediated by chronic haloperidol inhibition of cardiac σ1R. To test this, we treated neonatal rat cardiomyocytes with haloperidol, exposed them to angiotensin II and assessed hypertrophy, σ1R expression, mitochondrial Ca2+transport and ATP levels. In this context, haloperidol treatment altered mitochondrial Ca2+transport resulting in decreased ATP content by inactivating cardiac σ1R and/or reducing its expression. We also performed transverse aortic constriction (TAC) and then treated mice with haloperidol. After two weeks, haloperidol-treated mice showed enhanced heart failure marked by deteriorated cardiac function, reduced ATP production and increasing mortality relative to TAC only mice. ATP supplementation via sodium pyruvate rescued phenotypes seen in haloperidol-treated TAC mice. We conclude that σ1R inactivation or downregulation in response to haloperidol treatment impairs mitochondrial Ca2+mobilization, depleting ATP depletion from cardiomyocytes. These findings suggest a novel approach to mitigate haloperidol-related adverse effects in schizophrenia patients by ATP supplementation.