Abstract
Doxorubicin is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. Angiotensin-converting enzyme inhibitors are commonly used as cardioprotective agents and have recently been shown in clinical studies to be efficacious in the prevention of anthracycline-induced heart failure. This study evaluated a mechanism for these protective effects by testing the ability of the angiotensin-converting enzyme inhibitor enalapril to preserve mitochondrial function in a model of chronic doxorubicin treatment in rats. Sprague Dawley rats were divided into 3 groups and followed for a total of 10 weeks: (1) control-untreated, (2) doxorubicin treated, and (3) doxorubicin+enalapril treated. Doxorubicin was administered via intraperitoneal injection at weekly intervals from weeks 2 to 7. Enalapril was administered in the drinking water of the doxorubicin+enalapril group for the study duration. Doxorubicin treatment produced a significant loss in left ventricular contractility (P<.05), decrease in mitochondrial function via impairment of state-3 respiration, decrease in the cytosolic fraction of adenosine triphosphate, and up-regulation of free radical production. Enalapril significantly attenuated the decrease in percent fractional shortening (P < .05) and prevented the doxorubicin-associated reduction in respiratory efficiency and cytosolic adenosine triphosphate content (P < .05). Enalapril also abolished the robust doxorubicin-induced increase in free radical formation. Administration of enalapril attenuates doxorubicin-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in doxorubicin-associated free radical generation.
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More From: The Journal of Thoracic and Cardiovascular Surgery
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