Integration of cardiac energetics, function and histology from isolated rat hearts perfused with doxorubicin and doxorubicin-ol; a model for use in drug safety evaluations
| Autor: | Brandon Wood, R. Brandon Borders, John Ross, Seth Gibbs, Amir Abdulalil, Anthony J. Skowronek, Jeremy Smith, Katherine A. B. Knostman, Jay Bailey, Kim Henderson, Tom Vinci, Michael V. Knopp, Brian Roche |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cardiac function curve Male Magnetic Resonance Spectroscopy Metabolite Heart Ventricles Pharmacology Toxicology Phosphocreatine Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Heart Rate Toxicity Tests polycyclic compounds medicine Animals Doxorubicin Cardiotoxicity medicine.diagnostic_test Myocardium Cardiac stress test Histology Heart Isolated Heart Preparation Rats Perfusion 030104 developmental biology chemistry 030220 oncology & carcinogenesis Toxicity medicine.drug |
| Zdroj: | Journal of pharmacological and toxicological methods. 94(Pt 2) |
| ISSN: | 1873-488X |
| Popis: | The isolated rat heart (Langendorff) assay combined with NMR spectroscopy and histology were used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Doxorubicin blood concentrations and pharmacokinetic parameters were assessed following a clinically relevant dose of 2 mg/kg in order to select concentrations for isolated heart perfusions. Isolated rat hearts were exposed to 1 or 10 μM of doxorubicin or 0.3 μM dox-ol for at least 60 min using the Langendorff perfusion method. Effects on heart function were monitored using ECGs, left ventricular contraction parameters, and microscopic histology. Cardiac energetics (PCr, ATP, and Pi) were evaluated before, during, and after exposure to doxorubicin/dox-ol in perfused hearts using NMR spectroscopy. Cardiac effects were evident following clinically relevant concentrations of doxorubicin and dox-ol in isolated rat hearts demonstrated by altered heart function, energetic reserve, and microscopic lesions. A cardiac stress test utilizing isoproterenol resulted in enhanced functional response and reductions in PCr in doxorubicin versus vehicle treated hearts indicating possible alterations in the isoproterenol mediated pathway. Dox-ol treated hearts were similar to control with regard to function, but exhibited histologic findings. The use of combined Langendorff/NMR/histology methodologies allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters. Short abstract The isolated rat heart assay combined with NMR spectroscopy and histology was used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Heart function was altered and microscopic signs of toxicity were evident with dox and dox-ol exposures. The use of combined Langendorff/NMR/histology assays allowed for comparison of multiple indices of cardiac function at one time in which cardiac effects were evident in multiple parameters. |
| Databáze: | OpenAIRE |
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