Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy

Detalhes bibliográficos
Autor(a) principal: Santos, D. L.
Data de Publicação: 2002
Outros Autores: Moreno, A. J. M., Leino, R. L., Froberg, M. K., Wallace, K. B.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/5412
https://doi.org/10.1006/taap.2002.9532
Resumo: Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective [beta]-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 ± 26 versus 425 ± 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 ± 0.6 versus 5.8 ± 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 ± 0.9 versus 5.6 ± 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca2+ loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.
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spelling Carvedilol Protects against Doxorubicin-Induced Mitochondrial CardiomyopathyAdriamycinAdrenergicToxicityMitochondriaSeveral cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective [beta]-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 ± 26 versus 425 ± 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 ± 0.6 versus 5.8 ± 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 ± 0.9 versus 5.6 ± 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca2+ loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.http://www.sciencedirect.com/science/article/B6WXH-47G34FR-7/1/591ea3d1072dcf2971b640191c05679a2002info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5412http://hdl.handle.net/10316/5412https://doi.org/10.1006/taap.2002.9532engToxicology and Applied Pharmacology. 185:3 (2002) 218-227Santos, D. L.Moreno, A. J. M.Leino, R. L.Froberg, M. K.Wallace, K. B.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2021-11-10T11:25:14Zoai:estudogeral.uc.pt:10316/5412Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:55:31.595493Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
title Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
spellingShingle Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
Santos, D. L.
Adriamycin
Adrenergic
Toxicity
Mitochondria
title_short Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
title_full Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
title_fullStr Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
title_full_unstemmed Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
title_sort Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy
author Santos, D. L.
author_facet Santos, D. L.
Moreno, A. J. M.
Leino, R. L.
Froberg, M. K.
Wallace, K. B.
author_role author
author2 Moreno, A. J. M.
Leino, R. L.
Froberg, M. K.
Wallace, K. B.
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Santos, D. L.
Moreno, A. J. M.
Leino, R. L.
Froberg, M. K.
Wallace, K. B.
dc.subject.por.fl_str_mv Adriamycin
Adrenergic
Toxicity
Mitochondria
topic Adriamycin
Adrenergic
Toxicity
Mitochondria
description Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective [beta]-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 ± 26 versus 425 ± 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 ± 0.6 versus 5.8 ± 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 ± 0.9 versus 5.6 ± 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca2+ loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.
publishDate 2002
dc.date.none.fl_str_mv 2002
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/5412
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https://doi.org/10.1006/taap.2002.9532
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https://doi.org/10.1006/taap.2002.9532
dc.language.iso.fl_str_mv eng
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dc.relation.none.fl_str_mv Toxicology and Applied Pharmacology. 185:3 (2002) 218-227
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