Volume 2 • Issue 5 • 1000e109 Nat Prod Chem Res ISSN: 2329-6836 NPCR, an open access journal Kolathuru and Yeung, Nat Prod Chem Res 2014, 2:5 DOI: 10.4172/2329-6836.1000e109 Editorial Open Access Natural Health Products as Modulators of Adenosine and ATP Metabolism for Cardiovascular Protection Shyam Sundar Kolathuru and Pollen K Yeung* College of Pharmacy and Department of Medicine, Dalhousie University, Halifax, NS, Canada *Corresponding author: Pollen K Yeung, Dalhousie University, Halifax, NS, Canada, Tel: 902-4943845; Fax: 902-4941396; E-mail: Pollen.Yeung@Dal.Ca Received July 18, 2014; Accepted July 20, 2014; Published July 22, 2014 Citation: Kolathuru SS, Yeung PK (2014) Natural Health Products as Modulators of Adenosine and ATP Metabolism for Cardiovascular Protection. Nat Prod Chem Res 2: e109. doi:10.4172/2329-6836.1000e109 Copyright: © 2014 Kolathuru SS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Adenosine is an important endogenous purine nucleoside and an essential component of the molecular energy generated from adenosine 5’-triphosphate (ATP). It acts as both a precursor and metabolite of adenine nucleotides. As every cell utilizes the energy generated from catabolism of ATP, adenosine is found ubiquitously in the body. It is also a signaling molecule in the cardiovascular system, and its role for cardioprotection and cardiovascular homeostasis has been studied for over 80 years [1-3]. Adenosine is also known as a “homeostatic metabolite in cardiac energy metabolism” [4] owing to its wide range of benefcial efects on the cardiovascular system [5] which include negative chronotropic and dromotropic efect in cardiac tissue, vasodilatation, inhibition of platelet aggregation, modulation of vascular smooth muscles and endothelium and induction of ischemic preconditioning [6]. Adenosine modulates these actions by interacting with adenosine receptors (AR), which are widely distributed throughout the body. It is believed that metabolic condition of the myocardium may be assessed quantitatively by the level of adenosine production which maintains a healthy balance between energy supply and demand in the cardiovascular system [7]. Under adverse conditions such as ischemia, hypoxia, trauma, seizure, infammation and painful stress, there is an increased demand for energy which is met by the increased catabolism of ATP to AMP and subsequently adenosine resulting in elevated levels of adenosine in both extracellular and intracellular space [8,9]. Te increased adenosine concentration ensures protection against further tissue damage or organ dysfunction [10]. Tere have been many studies both in animal models and humans to explore the cardiovascular efects of adenosine in the past few decades. Tese studies have laid the ground work and set the pace for future research on adenosine, adenosine agonists and adenosine re-uptake inhibitors as cardiovascular protective agents. Adenosine Production and Metabolism Under Physiological Conditions in the Cardiovascular System Under normal physiological conditions the main source of adenosine in intracellular and extracellular space is from catabolism of ATP to ADP and then to AMP, which is further catabolized by ecto and endo 5`nucleotidase to produce adenosine [11]. Another source of adenosine is from hydrolysis of S-adenosylhomocystein which is derived from the transmethylation pathway from S-adenosylmethionine [12]. Intracellular adenosine can undergo rephosphorylation to form AMP and other adenine nucleotides by adenosine kinase [13] or metabolized to inosine by adenosine deaminase respectively [14], which maintain low concentrations of adenosine under basal (normal) condition [11]. However, during ischemia/hypoxia or in extremely heavy workloads, there is an increased demand of energy such that an imbalance between energy supply and demand may occur which increases ATP breakdown to produce other high energy phosphates (e.g. ADP and AMP) [15]. Tis can cause an increase in adenosine production in the myocytes, vascular endothelium, smooth muscle cells [16] and in the RBC [17]. Te adenosine released into the circulation is taken up rapidly by endothelial cells and red blood cells via nucleoside transporters and subsequently metabolized [18,19]. Adenosine Receptors and Cardiovascular Protection Adenosine is a key mediator in ischemia preconditioning which is an important factor responsible for cardiovascular protection [20]. Adenosine modulates its actions via membrane bound adenosine receptors which are coupled to G-protein and subdivided into 4 diferent subtypes: A 1 , A 2a , A 2b and A 3 [21-23]. Cross-talks between the receptors are known to occur which self regulates and provokes a specifc cardiovascular response. For example activation of A 1 receptor induces vasoconstriction which counteracts the A 2 mediated dilating efect on vascular tone [24]. Similarly, stimulation of the A 2 receptor increases cardiac contractility which is attenuated by the response mediated via the A 1 subtype [25]. On the other hand, it was suggested that cardioprotection from adenosine against myocardial infarction may be mediated via stimulation of the A 1 receptor [26]. Further, there is evidence to suggest adenosine receptors may also interact with the opioid receptors which together protect cellular damage and cell death caused by ischemia-reperfusion injury [27]. Several lines of experimental studies have shown that adenosine plays a key role in reactive hyperemia [28] and cardioprotection by increasing coronary blood fow and attenuating the breakdown of ATP in myocardium during ischemia and facilitating its repletion when perfusion is restored during recovery [29-31]. However due to the rapid cellular uptake into RBC, myocardium and endothelium by nucleoside transporters, pharmacological efects of adenosine are extremely short lived (<1 min) [19,32]. Several therapeutic strategies have been explored to prolong the action of adenosine. Intra-coronary infusion of adenosine was shown to ofer cardioprotection in a rabbit model of ischemia and reperfusion [33], but clinical application of this approach is restricted and not practical in most clinical settings. Another approach of exploiting adenosine is use of adenosine agonists which is much more stable and longer acting, but fnding a suitable adenosine receptor agonist with optimum safety and efcacy profle for a specifc cardiovascular disease condition remains a therapeutic challenge [2]. A further therapeutic strategy is to inhibit adenosine uptake by the transporter to exploit the benefcial properties of adenosine in the cardiovascular system [34]. Administration of exogenous adenosine in the presence of an inhibitor of the transporter such as calcium channel blockers or dipyridamole has been shown to enhance the action of adenosine in vivo in animal models as well as in patients [35-37]. Tese approaches may have important therapeutic implications and warrant further investigation. N a t u r a l P r o d u c t s C h e m i s t r y & R e s e a r c h ISSN: 2329-6836 Natural Products Chemistry & Research