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

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.

Adenosine 5'-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection.

The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular system, which may be used for management of hypertension and cardiometabolic diseases. In response to ischemia and cardiovascular injury, ATP is broken down to release adenosine. The effect of adenosine is very short lived because it is rapidly taken up by erythrocytes (RBCs), myocardial and endothelial cells, and also rapidly catabolized to oxypurine metabolites. Intracellular adenosine is phosphorylated back to adenine nucleotides via a salvage pathway. Extracellular and intracellular ATP is broken down rapidly to ADP and AMP, and finally to adenosine by 5′-nucleotidase. These metabolic events are known to occur in the myocardium, endothelium as well as in RBCs. Exercise has been shown to increase metabolism of ATP in RBCs, which may be an important mechanism for post-exercise hypotension and cardiovascular protection. The post-exercise effect was greater in hypertensive than in normotensive rats. The review summarizes current evidence in support of ATP metabolism in the RBC as a potential surrogate biomarker for cardiovascular protection and toxicities. It also discusses the opportunities, challenges, and obstacles of exploiting ATP metabolism in RBCs as a target for drug development and precision medicine.