Doxorubicin-Induced Vascular Dysfunction and Its Attenuation by Exercise Preconditioning

Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide array of cancers. Its use is limited because of dose-dependent cardiovascular toxicity. Although exercise training has been shown to protect against DOX-induced cardiotoxicity, it is unclear as to whether exercise can attenuate DOX-induced vascular dysfunction. The purpose of this study was to determine if exercise training provides protection against the deleterious vascular effects of DOX treatment and if any changes in vascular function are related to the accumulation of DOX in vascular tissue. Male Sprague-Dawley rats remained sedentary (SED) or engaged in 14 weeks of voluntary wheel running (WR). After the 14-week period, animals received 15 mg DOX per kilogram of body mass or an equivalent volume of saline. Twenty-four hours after DOX/saline exposure, the aorta was isolated and was used to examine vascular function and aortic DOX accumulation. Aortic rings from WR + DOX animals contracted with significantly greater force and showed improved endothelium-independent relaxation when compared with rings from SED + DOX animals. In contrast, no significant differences in endothelium-dependent aortic function were noted between WR + DOX and SED + DOX. Furthermore, no significant differences in aortic DOX accumulation were observed between the DOX groups. These results suggest that chronic exercise attenuates vascular smooth muscle dysfunction associated with DOX treatment and seems to be independent of DOX accumulation in vascular tissue.