Drug Metabolism Letters Send Orders for Reprints to reprints@benthamscience.ae Drug Metabolism Letters, 2016, 10, 219-226 219 RESEARCH ARTICLE Effect of Cardiovascular Injury on Catabolism of Adenosine and Adeno- sine 5-‘Triphosphate in Systemic Blood in a Freely Moving Rat Model In Vivo Pollen K. Yeung *,1 , Shyam S. Kolathuru 1 and Remigius U. Agu 2 1 Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Canada; 2 College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS, Canada A R T I C L E H I S T O R Y Received: February 04, 2016 Revised: May 25, 2016 Accepted: June 01, 2016 DOI: 10.2174/18723128106661606070138 59 Abstract: Background: Previous studies have shown that catabolism of adenosine 5’-triphosphate (ATP) in red blood cell (RBC) may be a key factor for cardiovascu- lar protection and maintaining cardiovascular homeostasis. Objective: To investigate the effect of cardiovascular injury on adenosine and ATP catabolism in systemic blood using a freely moving rat model in vivo. Method: After acclimatized to the experimental environment, Sprague Dawley (SD) rats were each given either isoproterenol (30 mg/kg) or saline (1 mL/kg) by subcu- taneous (sc) injection. Blood samples were collected sequentially for up to 6 hours for measurement of red blood cell (RBC) concentrations of adenine nucleotides and plasma concentrations of adenosine and its oxypurine metabolites. Results: We have found isoproterenol induced 50% mortality under the experimental condition. Plasma concentrations of adenosine (ADO) and uric acid (UA) and red blood cell (RBC) concentrations of adenosine 5’-diphosphate (ADP) and adenosine 5’-monophosphate (AMP) in RBC were significantly higher in the isoproterenol treated rats (p < 0.05 for all the comparison). On the other hand, plasma con- centrations of hypoxanthine (HYP) were higher in the control group (p < 0.05), but there was no statis- tically significant changes in ATP concentrations in the RBC (p > 0.05). Conclusion: 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. Keywords: Adenosine, ATP, cardiovascular injury, catabolism, energetic, metabolites, rats. INTRODUCTION The importance of adenosine and adenosine 5’- triphosphate (ATP) in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular system [1-10]. It is known that adenosine and ATP are key factors in regulation of coronary blood flow [5, 11-13], inhibiting platelet aggregation [14], protection of myocardium [10, 15-17], neuromodulation [18-25], attenuat- ing tissue necrosis [7, 26], ischemic preconditioning [27-32], immunomodulation [33], energy metabolism [9, 34-36], and perhaps other functions as well (e.g. pain mediation) which maintain the homeostasis of the cardiovascular system. Adenosine (ADO) is available commercially for intravenous (iv) injection as an anti-arrhythmic drug primarily for return- ing paroxysmal supraventricular tachycardia (PSVT) to *Address correspondence to this author at the Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Canada; Tel: 902-494-3845; Fax: 902-494-1396; E-mail: Pollen.Yeung@Dal.Ca normal rhythms [37]. On the other hand, dipyridamole is an inhibitor of ADO uptake into platelets, endothelial cells and red blood cells (RBC) and used clinically as a coronary vasodilator and an anti-platelet agent [37]. Under normal physiological conditions the main source of ADO is 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]. Another source of ADO is from hydrolysis of S- adenosylhomocysteine which is derived from the transmeth- ylation pathway utilizing S-adenosylmethionine [39]. Intra- cellular ADO can undergo rephosphorylation to form AMP and other adenine nucleotides by adenosine kinase [40] or metabolized to inosine (INO) and subsequently to hypoxan- thine (HYP), xanthine (XAN) and eventually to uric acid (UA) [1, 11, 41-43], which maintains low basal concentra- tions of ADO under normal physiologic condition [38]. However, during ischemia/hypoxia or in extremely heavy workloads, there is an increased demand of energy which triggers a breakdown of ATP and release of ADO locally and 187 - 8/16 $58.00+.00 © 2016 Bentham Science Publishers