title: Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction.
abstract: 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 Ca(2+) transport and ATP levels. In this context, haloperidol treatment altered mitochondrial Ca(2+) 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 Ca(2+) mobilization, depleting ATP depletion from cardiomyocytes. These findings suggest a novel approach to mitigate haloperidol-related adverse effects in schizophrenia patients by ATP supplementation.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.affiliation: Department of Pathology and Translational Pathology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103, USA.
authors.forename: Md Shenuarin
authors.initials: MS
authors.lastname: Bhuiyan
authors.affiliation: Department of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan; Department of Electrical Engineering, Graduate School of Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan; Department of Electrical Engineering, Graduate School of Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanai
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001011:Aorta / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D003250:Constriction; D006220:Haloperidol / Q000494:pharmacology*; D006333:Heart Failure / Q000209:etiology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D000804:Angiotensin II; D000255:Adenosine Triphosphate; D006220:Haloperidol; D002118:Calcium
keywords: ATP; Angiotensin II (Ang II); Haloperidol; Myocardial hypertrophy; Sigma-1 receptor (σ(1)R)