Hemodynamic Assessment and In vivo Catabolism of Adenosine 5’-triphosphate in Doxorubicin or Isoproterenol-induced Cardiovascular Toxicity

Abstract

Purpose: Previous studies have shown that catabolism of adenosine 5’-triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity. We compared the acute toxicity of high doses of doxorubicin (DOX) and isoproterenol (ISO) on hemodynamics and ATP catabolism in the systemic circulation. Methods: sprague Dawley (SD) rats (n = 8 - 11) were each given either a single dose of 30 mg/kg ISO, or a twice-daily dose of 10 mg/kg of DOX or 4 doses of normal saline (control) by subcutaneous injection. Blood samples were collected up to 6 hours for measuring concentrations of ATP and its catabolites. Hemodynamics was recorded continuously. The difference was considered significant at p < 0.05 (ANOVA). Results: Mortality was 1/8, 5/11, and 0/11 for the DOX, ISO, and control groups, respectively. Systolic blood pressure was significantly lower in the DOX and ISO treated rats than in control measured at the last recorded time (76 ± 9 for DOX vs. 42 ± 8 for ISO vs. 103 ± 5 mmHg for control, p < 0.05 for all). Blood pressure fell gradually after the final injection for both DOX and control groups, but abruptly after ISO, followed by a rebound and then gradual decline till the end of the experiment. Heart rate was significantly higher after ISO, but there were no differences between the DOX and control rats (p > 0.05). RBC concentrations of ADP and AMP, and plasma concentrations of adenosine and uric acid were significantly higher in the ISO group. In contrast, hypoxanthine concentrations were significantly higher in the DOX treated group (p < 0.05). Conclusion: Acute cardiovascular toxicity induced by DOX and ISO may be measured by changes in hemodynamics and breakdown of ATP and adenosine in the systemic circulation, albeit a notable qualitative and quantitative difference was observed.