Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction

Yasuharu Shinoda, Hideaki Tagashira, Md Shenuarin Bhuiyan, Hideyuki Hasegawa, Hiroshi Kanai, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)172-183
Number of pages12
JournalJournal of Pharmacological Sciences
Issue number3
Publication statusPublished - 2016 Jul 1


  • ATP
  • Angiotensin II (Ang II)
  • Haloperidol
  • Myocardial hypertrophy
  • Sigma-1 receptor (σR)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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