Title:Hemodynamic Assessment and In vivo Catabolism of Adenosine 5’-triphosphate in Doxorubicin or Isoproterenol-induced Cardiovascular Toxicity
Volume: 14
Issue: 1
Author(s): Pollen K. Yeung*, Sheyda Mohammadizadeh, Fatemeh Akhoundi, Kelsey Mann, Remigius U. Agu and Thomas Pulinilkunnil
Affiliation:
- Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health and Medicine, Dalhousie University, Halifax, NS, C B3H 4R2,Canada
Keywords:
ATP, adenosine, cardiotoxicity, doxorubicin, isoproterenol, catabolism, rats, toxicity.
Abstract:
Objective: 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.
