Effect of Cardiovascular Injury on Catabolism of Adenosine and Adenosine 5-‘Triphosphate in Systemic Blood in a Freely Moving Rat Model In Vivo

Abstract

Cardiovascular injury induced by isoproterenol resulted in breakdown of ATP to ADP and AMP in the RBC and also breakdown of ADO to UA in plasma and other tissues.

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

“…Under normal physiological conditions, the main source of intracellular ADO is from hydrolysis of S -adenosylhomocysteine, and from catabolism of ATP to adenosine 5′-diphosphate (ADP) and then to adenosine 5′-monophosphate (AMP), which is further catabolized by ecto and endo 5′ nucleotidase to produce ADO [ 38 , 40 , 41 ]. Extracellular concentrations of ADO, such as those found in plasma under normal physiological conditions, are kept very low (uM range or below) because of rapid uptake by active nucleoside transporters throughout the vasculature, and also by catabolism to other oxypurine metabolites, such as hypoxanthine and uric acid [ 42 , 43 , 44 ]. However, during ischemia/hypoxia or in extremely heavy workloads, such as intense exercise, there is an increased demand of energy, which triggers a rapid breakdown of ATP and release of ADO locally and into systemic circulation [ 43 , 45 ].…”

“…Extracellular concentrations of ADO, such as those found in plasma under normal physiological conditions, are kept very low (uM range or below) because of rapid uptake by active nucleoside transporters throughout the vasculature, and also by catabolism to other oxypurine metabolites, such as hypoxanthine and uric acid [ 42 , 43 , 44 ]. However, during ischemia/hypoxia or in extremely heavy workloads, such as intense exercise, there is an increased demand of energy, which triggers a rapid breakdown of ATP and release of ADO locally and into systemic circulation [ 43 , 45 ]. After restoring the hypoxia to normal physiologic conditions, the released ADO is taken up rapidly by endothelial cells and RBC via the nucleoside transporters, and subsequently converted back to ATP by ADO and adenylate kinases [ 46 , 47 ].…”

“…Based on the definition proposed by the FDA Biomarker Definition Working Group [ 51 ], a “Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. It has been suggested ADO and ATP catabolism may be used as biomarkers to quantify myocardial and endothelial ischemia [ 1 , 52 , 53 ], cardiovascular toxicities [ 43 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. On the other hand, exercise has been shown to improve cardiovascular hemodynamic and increase RBC concentrations of ATP in both humans and animal models [ 59 , 60 ].…”

“…On the other hand, exercise has been shown to improve cardiovascular hemodynamic and increase RBC concentrations of ATP in both humans and animal models [ 59 , 60 ]. The increase of circulatory concentrations of ADO and ATP are believed to be key factors for exercise preconditioning and post-exercise hypotension, and could be a mechanism responsible for cardiovascular protection [ 27 , 43 , 61 , 62 ]. The review summarizes currently available evidence in support of ATP metabolism in the RBC as a potential systemic biomarker for cardiovascular protection and toxicities.…”

Metabolomics and Biomarkers for Drug Discovery

“…Advances in biomarker development can offer promise to all three of these challenges and a solution to determining a patient’s immune status; something that is critical in guiding effective and safe immunomodulatory therapy [ 16 ]. Finally, the feasibility of exploiting ATP metabolism in the red blood cell as a sensor for energy metabolism in the body, and as surrogate biomarker for serious cardiovascular toxicities, as well as a drug target for cardiovascular protection, is increasingly being explored [ 17 , 18 , 19 ]. Advances in this research area could lead to breakthrough treatments and prevention strategies for cardiovascular and metabolic diseases which affects millions of patients world-wide.…”