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.

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.

Embryonal rhabdomyosarcoma in an immature Baird's tapir (Tapirus bairdii).

An immature Baird's tapir (Tapirus bairdii) with a history of seizure-like episodes developed signs of respiratory disease. The initial clinical diagnosis was pneumonia, and antibiotic therapy was started. The animal failed to improve after 14 days of therapy and developed unilateral, bloody nasal discharge. Endoscopic examination and radiography revealed a soft tissue mass in the nasopharynx depressing the soft palate. The tapir died 32 days after initial presentation. Histologic examination of the mass demonstrated a mesenchymal tumor composed of spindle cells with elongate nuclei forming densely packed fascicles. The neoplastic spindle cells showed prominent cross-striations. Immunohistochemistry revealed the cells to be positive for desmin and myoglobin, but negative for smooth muscle actin, confirming diagnosis of rhabdomyosarcoma. Embryonal rhabdomyosarcoma is the most common nasopharyngeal soft tissue tumor of humans, and it has been reported infrequently in dogs, horses, and pigs. Neoplasia should be a differential diagnosis in cases of unilateral nasal discharge and inspiratory stridor, even in young animals.