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.

Henderson KA, Borders RB, Ross JB, Abdulalil A, Gibbs S, Skowronek AJ, Knostman K, Bailey J, Smith J, Vinci T, Wood B, Knopp MV, Roche BM
J Pharmacol Toxicol Methods 94 54-63 11/01/2018

Abstract

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 P

Full Text