Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction
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 re...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-07-01
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| Series: | Journal of Pharmacological Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861316300640 |
| _version_ | 1818310377504505856 |
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| author | Yasuharu Shinoda Hideaki Tagashira Md. Shenuarin Bhuiyan Hideyuki Hasegawa Hiroshi Kanai Kohji Fukunaga |
| author_facet | Yasuharu Shinoda Hideaki Tagashira Md. Shenuarin Bhuiyan Hideyuki Hasegawa Hiroshi Kanai Kohji Fukunaga |
| author_sort | Yasuharu Shinoda |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T07:45:06Z |
| format | Article |
| id | doaj.art-4675c017ceff4fbb8c18a15e9a78dead |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-13T07:45:06Z |
| publishDate | 2016-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-4675c017ceff4fbb8c18a15e9a78dead2022-12-21T23:54:52ZengElsevierJournal of Pharmacological Sciences1347-86132016-07-01131317218310.1016/j.jphs.2016.05.012Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunctionYasuharu Shinoda0Hideaki Tagashira1Md. Shenuarin Bhuiyan2Hideyuki Hasegawa3Hiroshi Kanai4Kohji Fukunaga5Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, JapanDepartment of Pathology and Translational Pathology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103, USADepartment of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, JapanDepartment of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, JapanDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, JapanHaloperidol 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.http://www.sciencedirect.com/science/article/pii/S1347861316300640Sigma-1 receptor (σ1R)HaloperidolAngiotensin II (Ang II)Myocardial hypertrophyATP |
| spellingShingle | Yasuharu Shinoda Hideaki Tagashira Md. Shenuarin Bhuiyan Hideyuki Hasegawa Hiroshi Kanai Kohji Fukunaga Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction Journal of Pharmacological Sciences Sigma-1 receptor (σ1R) Haloperidol Angiotensin II (Ang II) Myocardial hypertrophy ATP |
| title | Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction |
| title_full | Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction |
| title_fullStr | Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction |
| title_full_unstemmed | Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction |
| title_short | Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction |
| title_sort | haloperidol aggravates transverse aortic constriction induced heart failure via mitochondrial dysfunction |
| topic | Sigma-1 receptor (σ1R) Haloperidol Angiotensin II (Ang II) Myocardial hypertrophy ATP |
| url | http://www.sciencedirect.com/science/article/pii/S1347861316300640 |
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