Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy
Abstract Aims Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosime...
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| Veröffentlicht in: | Cardiovascular research 2020-03, Vol.116 (3), p.576-591 |
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| creator | Efentakis, Panagiotis Varela, Aimilia Chavdoula, Evangelia Sigala, Fragiska Sanoudou, Despina Tenta, Roxane Gioti, Katerina Kostomitsopoulos, Nikolaos Papapetropoulos, Andreas Tasouli, Androniki Farmakis, Dimitrios Davos, Costantinos H Klinakis, Apostolos Suter, Thomas Cokkinos, Dennis V Iliodromitis, Efstathios K Wenzel, Philip Andreadou, Ioanna |
| description | Abstract
Aims
Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.
Methods and results
Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.
Conclusion
Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
Graphical Abstract
Graphical Abstract |
| doi_str_mv | 10.1093/cvr/cvz163 |
| format | Article |
| fullrecord | <record><control><sourceid>oup_pubme</sourceid><recordid>TN_cdi_pubmed_primary_31228183</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/cvr/cvz163</oup_id><sourcerecordid>10.1093/cvr/cvz163</sourcerecordid><originalsourceid>FETCH-LOGICAL-j237t-b558657419514c5284f6a360e2d6141e8bbbf30e8971ea921626a694a415310d3</originalsourceid><addsrcrecordid>eNo9kE1LAzEQhoMotlYv_gDJxWM0k6_d9SbFLyh40fOS3WQhpZuE7Aetv95I1cMwzMz7vgwPQtdA74BW_L6dU64vUPwELaGQknAm5ClaUkpLorjiC3QxDNs8SlmIc7TgwFgJJV-ieWPnMLjeeqM9jsnO1o8DNmEf0tS41nnivJlaa3Crk3FhDPu8HQ_YeTxmH8Ham6wfLDE25pjsx7323qYH7Pq4c60eXfAD7kLKpjCmEA-X6KzTu8Fe_fYV-nx--li_ks37y9v6cUO2jBcjaaQsVX4ZKgmilawUndJcUcuMAgG2bJqm49SWVQFWVwwUU1pVQguQHKjhK3RzzI1T01tTx-R6nQ71H4AsuD0KwhT_r0DrH7B1BlsfwfJvwMNryA</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Efentakis, Panagiotis ; Varela, Aimilia ; Chavdoula, Evangelia ; Sigala, Fragiska ; Sanoudou, Despina ; Tenta, Roxane ; Gioti, Katerina ; Kostomitsopoulos, Nikolaos ; Papapetropoulos, Andreas ; Tasouli, Androniki ; Farmakis, Dimitrios ; Davos, Costantinos H ; Klinakis, Apostolos ; Suter, Thomas ; Cokkinos, Dennis V ; Iliodromitis, Efstathios K ; Wenzel, Philip ; Andreadou, Ioanna</creator><creatorcontrib>Efentakis, Panagiotis ; Varela, Aimilia ; Chavdoula, Evangelia ; Sigala, Fragiska ; Sanoudou, Despina ; Tenta, Roxane ; Gioti, Katerina ; Kostomitsopoulos, Nikolaos ; Papapetropoulos, Andreas ; Tasouli, Androniki ; Farmakis, Dimitrios ; Davos, Costantinos H ; Klinakis, Apostolos ; Suter, Thomas ; Cokkinos, Dennis V ; Iliodromitis, Efstathios K ; Wenzel, Philip ; Andreadou, Ioanna</creatorcontrib><description>Abstract
Aims
Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.
Methods and results
Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.
Conclusion
Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvz163</identifier><identifier>PMID: 31228183</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><ispartof>Cardiovascular research, 2020-03, Vol.116 (3), p.576-591</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. 2019</rights><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-0321-7569 ; 0000-0002-5397-2781 ; 0000-0002-7605-5361 ; 0000-0003-4787-5106 ; 0000-0002-4867-6945 ; 0000-0002-4253-5930</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31228183$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Efentakis, Panagiotis</creatorcontrib><creatorcontrib>Varela, Aimilia</creatorcontrib><creatorcontrib>Chavdoula, Evangelia</creatorcontrib><creatorcontrib>Sigala, Fragiska</creatorcontrib><creatorcontrib>Sanoudou, Despina</creatorcontrib><creatorcontrib>Tenta, Roxane</creatorcontrib><creatorcontrib>Gioti, Katerina</creatorcontrib><creatorcontrib>Kostomitsopoulos, Nikolaos</creatorcontrib><creatorcontrib>Papapetropoulos, Andreas</creatorcontrib><creatorcontrib>Tasouli, Androniki</creatorcontrib><creatorcontrib>Farmakis, Dimitrios</creatorcontrib><creatorcontrib>Davos, Costantinos H</creatorcontrib><creatorcontrib>Klinakis, Apostolos</creatorcontrib><creatorcontrib>Suter, Thomas</creatorcontrib><creatorcontrib>Cokkinos, Dennis V</creatorcontrib><creatorcontrib>Iliodromitis, Efstathios K</creatorcontrib><creatorcontrib>Wenzel, Philip</creatorcontrib><creatorcontrib>Andreadou, Ioanna</creatorcontrib><title>Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Abstract
Aims
Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.
Methods and results
Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.
Conclusion
Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
Graphical Abstract
Graphical Abstract</description><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNo9kE1LAzEQhoMotlYv_gDJxWM0k6_d9SbFLyh40fOS3WQhpZuE7Aetv95I1cMwzMz7vgwPQtdA74BW_L6dU64vUPwELaGQknAm5ClaUkpLorjiC3QxDNs8SlmIc7TgwFgJJV-ieWPnMLjeeqM9jsnO1o8DNmEf0tS41nnivJlaa3Crk3FhDPu8HQ_YeTxmH8Ham6wfLDE25pjsx7323qYH7Pq4c60eXfAD7kLKpjCmEA-X6KzTu8Fe_fYV-nx--li_ks37y9v6cUO2jBcjaaQsVX4ZKgmilawUndJcUcuMAgG2bJqm49SWVQFWVwwUU1pVQguQHKjhK3RzzI1T01tTx-R6nQ71H4AsuD0KwhT_r0DrH7B1BlsfwfJvwMNryA</recordid><startdate>20200301</startdate><enddate>20200301</enddate><creator>Efentakis, Panagiotis</creator><creator>Varela, Aimilia</creator><creator>Chavdoula, Evangelia</creator><creator>Sigala, Fragiska</creator><creator>Sanoudou, Despina</creator><creator>Tenta, Roxane</creator><creator>Gioti, Katerina</creator><creator>Kostomitsopoulos, Nikolaos</creator><creator>Papapetropoulos, Andreas</creator><creator>Tasouli, Androniki</creator><creator>Farmakis, Dimitrios</creator><creator>Davos, Costantinos H</creator><creator>Klinakis, Apostolos</creator><creator>Suter, Thomas</creator><creator>Cokkinos, Dennis V</creator><creator>Iliodromitis, Efstathios K</creator><creator>Wenzel, Philip</creator><creator>Andreadou, Ioanna</creator><general>Oxford University Press</general><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-0321-7569</orcidid><orcidid>https://orcid.org/0000-0002-5397-2781</orcidid><orcidid>https://orcid.org/0000-0002-7605-5361</orcidid><orcidid>https://orcid.org/0000-0003-4787-5106</orcidid><orcidid>https://orcid.org/0000-0002-4867-6945</orcidid><orcidid>https://orcid.org/0000-0002-4253-5930</orcidid></search><sort><creationdate>20200301</creationdate><title>Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy</title><author>Efentakis, Panagiotis ; Varela, Aimilia ; Chavdoula, Evangelia ; Sigala, Fragiska ; Sanoudou, Despina ; Tenta, Roxane ; Gioti, Katerina ; Kostomitsopoulos, Nikolaos ; Papapetropoulos, Andreas ; Tasouli, Androniki ; Farmakis, Dimitrios ; Davos, Costantinos H ; Klinakis, Apostolos ; Suter, Thomas ; Cokkinos, Dennis V ; Iliodromitis, Efstathios K ; Wenzel, Philip ; Andreadou, Ioanna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j237t-b558657419514c5284f6a360e2d6141e8bbbf30e8971ea921626a694a415310d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Efentakis, Panagiotis</creatorcontrib><creatorcontrib>Varela, Aimilia</creatorcontrib><creatorcontrib>Chavdoula, Evangelia</creatorcontrib><creatorcontrib>Sigala, Fragiska</creatorcontrib><creatorcontrib>Sanoudou, Despina</creatorcontrib><creatorcontrib>Tenta, Roxane</creatorcontrib><creatorcontrib>Gioti, Katerina</creatorcontrib><creatorcontrib>Kostomitsopoulos, Nikolaos</creatorcontrib><creatorcontrib>Papapetropoulos, Andreas</creatorcontrib><creatorcontrib>Tasouli, Androniki</creatorcontrib><creatorcontrib>Farmakis, Dimitrios</creatorcontrib><creatorcontrib>Davos, Costantinos H</creatorcontrib><creatorcontrib>Klinakis, Apostolos</creatorcontrib><creatorcontrib>Suter, Thomas</creatorcontrib><creatorcontrib>Cokkinos, Dennis V</creatorcontrib><creatorcontrib>Iliodromitis, Efstathios K</creatorcontrib><creatorcontrib>Wenzel, Philip</creatorcontrib><creatorcontrib>Andreadou, Ioanna</creatorcontrib><collection>PubMed</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Efentakis, Panagiotis</au><au>Varela, Aimilia</au><au>Chavdoula, Evangelia</au><au>Sigala, Fragiska</au><au>Sanoudou, Despina</au><au>Tenta, Roxane</au><au>Gioti, Katerina</au><au>Kostomitsopoulos, Nikolaos</au><au>Papapetropoulos, Andreas</au><au>Tasouli, Androniki</au><au>Farmakis, Dimitrios</au><au>Davos, Costantinos H</au><au>Klinakis, Apostolos</au><au>Suter, Thomas</au><au>Cokkinos, Dennis V</au><au>Iliodromitis, Efstathios K</au><au>Wenzel, Philip</au><au>Andreadou, Ioanna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>116</volume><issue>3</issue><spage>576</spage><epage>591</epage><pages>576-591</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>Abstract
Aims
Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.
Methods and results
Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.
Conclusion
Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31228183</pmid><doi>10.1093/cvr/cvz163</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-0321-7569</orcidid><orcidid>https://orcid.org/0000-0002-5397-2781</orcidid><orcidid>https://orcid.org/0000-0002-7605-5361</orcidid><orcidid>https://orcid.org/0000-0003-4787-5106</orcidid><orcidid>https://orcid.org/0000-0002-4867-6945</orcidid><orcidid>https://orcid.org/0000-0002-4253-5930</orcidid></addata></record> |
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| title | Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy |
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