Natural Products Chemistry & Research

ISSN - 2329-6836

Editorial - (2014) Volume 2, Issue 5

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 Email:


Adenosineis an important endogenous purine nucleosideand 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 beneficial effects on the cardiovascular system [5] which include negative chronotropic and dromotropic effect 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, inflammation and painful stress, there is an increased demand for energy which is met by the increased catabolismof ATP to AMP and subsequently adenosine resulting in elevated levels of adenosine in both extracellular and intracellular space [8,9]. The increased adenosine concentration ensures protection against further tissue damage or organ dysfunction [10]. There have been many studies both in animal models and humans to explore the cardiovascular effects of adenosine in the past few decades. These 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]. This can cause an increase in adenosine production in the myocytes, vascular endothelium, smooth muscle cells [16] and in the RBC [17]. The 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 different subtypes: A1, A2a, A2b and A3 [21-23]. Cross-talks between the receptors are known to occur which self regulates and provokes a specific cardiovascular response. For example activation of A1 receptor induces vasoconstriction which counteracts the A2 mediated dilating effect on vascular tone [24]. Similarly, stimulation of the A2 receptor increases cardiac contractility which is attenuated by the response mediated via the A1 subtype [25]. On the other hand, it was suggested that cardioprotection from adenosine against myocardial infarction may be mediated via stimulation of the A1 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 flow 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 endotheliumby nucleoside transporters, pharmacological effects 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 offer cardioprotection in a rabbit model of ischemiaand 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 finding a suitable adenosine receptor agonist with optimum safety and efficacy profile for a specific cardiovascular disease condition remains a therapeutic challenge [2]. A further therapeutic strategy is to inhibit adenosine uptake by the transporter to exploit the beneficial 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]. These approaches may have important therapeutic implications and warrant further investigation.

Nucleoside Transport Inhibitors (NTI) for Cardioprotection

It has been shown that nucleoside transport inhibitors (NTI) such as R75231 improves the functional recovery from an isolated rabbit heart model of ischemia followed by reperfusion [38]. Similarly, dipyridamole and other NTI such as dilazep have been shown to be protective in various animal models of myocardial ischemia, which may be mediated via adenosine A(1) receptor [39,40]. Further, anti-platelet agents including dipyridamole have been shown to reduce myocardial necrosis induced by epinephrine [41] and that lidoflazine was beneficial for coronary artery surgery [42]. It was suggested that the order of potency inhibiting adenosine uptake by RBC is draflazine ≥ dilazep >R75231>NBMPR>mioflazine=dipyridamole>lidoflazine [43]. Using mammalian cardiac myocytes, it was shown that adenosine attenuated the stimulatory effects of isoproterenol via blockade of calcium influx [44], which may explain at least partly the cardiovascular protective effect of calcium channel blockers [45-48], although these agents may also have a direct effect inhibiting the adenosine transporters [49].

Natural Health Products for Cardioprotection

Of the commonly used natural health products consumed regularly, omega-3 fatty acid, coenzyme Q10, ginseng products, resveratrol and other polyphenols appear to have most notable cardiovascular protective properties [50-57]. These products may act either directly or indirectly to enhance the protective effect of adenosine and ATP by moderating their uptake and/or metabolism. They may also enhance the cardiovascular protective effect of typical nucleoside transport inhibitors and adenosine receptor agonists via pharmacokinetic and/or pharmacodynamic interactions. Further studies identifying the natural products acting via this mechanism of action may help to identify and develop these products for cardiovascular protection and prevention.

Future Direction

The role of adenosine in cardiovascular protection in ischemia and reperfusion injury is well established. Pharmacologic tools such as the NTI have been used successfully in animal models and patients to increase extracellular adenosine concentrations and enhance the protective effect of endogenous adenosine. While adenosine kinase which metabolizes adenosine to adenosine monophosphate (AMP) has been advocated as a target for drug development for cardiovascular and metabolic diseases [13], adenosine transporters may also be exploited as a drug target to develop selective agents for cardiovascular prevention and protection [34,58]. The relationship between the nucleotide concentrations in the RBC and those of the myocardium, and the question whether or not ATP metabolism in the RBC may be used as a surrogate biomarker for energy balance in the body warrants further studies. Understanding these concepts and the linkages would enable us to explore further the potential of NTI and other cardiovascular agents for myocardial ischemia.

As natural products and nutraceuticals are increasingly used in our societies to enhance health and prevention of chronic diseases [59-63], there is an urgent need to understand their therapeutic potentials as well as the concerns of adverse effects and their interactions with traditional medicines. Many of these natural products may moderate ATP and energy metabolism in the body, which may be measured by the concentrations of adenosine and ATP in systemic circulation. It is possible and even probable we can exploit ATP metabolism in the RBC as a surrogate for energy metabolism in the body to identify the natural health products for cardiovascular protection and prevention, which will benefits millions of patients suffering from the chronic disease worldwide.


  1. Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 68: 213-237.
  2. Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets--what are the challenges? Nat Rev Drug Discov 12: 265-286.
  3. Headrick JP, Ashton KJ, Rose'meyer RB, Peart JN (2013) Cardiovascular adenosine receptors: expression, actions and interactions. PharmacolTher 140: 92-111.
  4. Schrader J (1990) Adenosine. A homeostatic metabolite in cardiac energy metabolism. Circulation 81: 389-391.
  5. Shryock JC, Belardinelli L (1997) Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol 79: 2-10.
  6. Rongen GA, Floras JS, Lenders JW, Thien T, Smits P (1997) Cardiovascular pharmacology of purines. ClinSci (Lond) 92: 13-24.
  7. Berne RM (1963) Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317-322.
  8. Cronstein BN (1995) A novel approach to the development of anti-inflammatory agents: adenosine release at inflamed sites. J Investig Med 43: 50-57.
  9. Latini S, Pedata F (2001) Adenosine in the central nervous system: release mechanisms and extracellular concentrations. J Neurochem 79: 463-484.
  10. Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50: 413-492.
  11. Deussen A (2000) Metabolic flux rates of adenosine in the heart. NaunynSchmiedebergs Arch Pharmacol 362: 351-363.
  12. Lloyd HG, Deussen A, Wuppermann H, Schrader J (1988) Thetransmethylation pathway as a source for adenosine in the isolated guinea-pig heart. Biochem J 252: 489-494.
  13. Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65: 906-943.
  14. Smolenski RT, Suitters A, Yacoub MH (1992) Adenine nucleotide catabolism and adenosine formation in isolated human cardiomyocytes. J Mol Cell Cardiol 24: 91-96.
  15. Zhang J, Duncker DJ, Xu Y, Zhang Y, Path G, et al. (1995) Transmuralbioenergetic responses of normal myocardium to high workstates. Am J Physiol 268: H1891-1905.
  16. Mullane K, Bullough D (1995) Harnessing an endogenous cardioprotective mechanism: cellular sources and sites of action of adenosine. J Mol Cell Cardiol 27: 1041-1054.
  17. Yeung P, Seeto D. (2013) A study of the effect of isoproterenol on red blood cell concentrations of adenine nucleotides in a freely moving rat model in vivo. CardiovasPharmacol 2: 102.
  18. Hori M, Kitakaze M (1991) Adenosine, the heart, and coronary circulation. Hypertension 18: 565-574.
  19. Möser GH, Schrader J, Deussen A (1989) Turnover of adenosine in plasma of human and dog blood. Am J Physiol 256: C799-806.
  20. Yang X, Cohen MV, Downey JM (2010) Mechanism of cardioprotection by early ischemic preconditioning. Cardiovasc Drugs Ther 24: 225-234.
  21. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53: 527-552.
  22. Fredholm BB (2003) Adenosine receptors as targets for drug development. Drug News Perspect 16: 283-289.
  23. Poulsen SA, Quinn RJ (1998) Adenosine receptors: new opportunities for future drugs. Bioorg Med Chem 6: 619-641.
  24. Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (2005) Role of A1 adenosine receptors in regulation of vascular tone. Am J Physiol Heart CircPhysiol 288: H1411-1416.
  25. Tikh EI, Fenton RA, Dobson JG Jr (2006) Contractile effects of adenosine A1 and A2A receptors in isolated murine hearts. Am J Physiol Heart CircPhysiol 290: H348-356.
  26. Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, et al. (1991) Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 84: 350-356.
  27. Peart JN, Gross GJ (2003) Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart CircPhysiol 285: H81-89.
  28. Kirkebøen KA, Aksnes G, Lande K, Ilebekk A (1992) Role of adenosine for reactive hyperemia in normal and stunned porcine myocardium. Am J Physiol 263: H1119-1127.
  29. Ledingham S, Katayama O, Lachno D, Patel N, Yacoub M (1990) Beneficial effect of adenosine during reperfusion following prolonged cardioplegic arrest. Cardiovasc Res 24: 247-253.
  30. Ely SW, Mentzer RM Jr, Lasley RD, Lee BK, Berne RM (1985) Functional and metabolic evidence of enhanced myocardial tolerance to ischemia and reperfusion with adenosine. J ThoracCardiovascSurg 90: 549-556.
  31. Gwirtz PA, Dodd-o JM, Brandt MA, Jones CE (1990) Augmentation of coronary flow improves myocardial function in exercise. J CardiovascPharmacol 15: 752-758.
  32. Rovetto MJ, Ford DA, Yassin A (1987) Cardiac monocyte and coronary endothelial cell adenosine transport. Topics and Perspectives in Adenosine Research 188-198.
  33. Norton ED, Jackson EK, Turner MB, Virmani R, Forman MB (1992) The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury. Am Heart J 123: 332-338.
  34. Van Belle H (1993) Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine? Cardiovasc Res 27: 68-76.
  35. Inbar S, Schrader BJ, Kaufmann E, Vestal RE, Rich S (1993) Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension. J Am CollCardiol 21: 413-418.
  36. Yeung P, Feng J, Fice D (2005) Pharmacodynamic interactions between diltiazem and adenosine in rabbits in vivo. Current Topics in Pharmacology 9:117-121.
  37. Schaper W (2005) Dipyridamole, an underestimated vascular protective drug. Cardiovasc Drugs Ther 19: 357-363.
  38. Masuda M, Demeulemeester A, Chen CC, Hendrikx M, Van Belle H, et al. (1991) Cardioprotective effects of nucleoside transport inhibition in rabbit hearts. Ann ThoracSurg 52: 1300-1305.
  39. Figueredo VM, Diamond I, Zhou HZ, Camacho SA (1999) Chronicdipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury. Am J Physiol 277: H2091-2097.
  40. Yamasaki K, Tanaka M, Yokota R, Fujiwara H, Sasayama S (2000) Dilazep dihydrochloride prolongs the infarct size-limiting effect of ischemic preconditioning in rabbits. Heart Vessels 15: 227-232.
  41. Haft J, Gershengorn K, Kranz PD, Oestreicher R (1972) Protection against epinephrine-induced myocardial necrosis by drugs that inhibit platelet aggregation. Am J Cardiol 30: 838-843.
  42. De Hert SG, Rodrigus IE, Haenen LR, Ten Broecke PW, Boeckxstaens CJ, et al. (1997) Effects of lidoflazine on left ventricular function in patients. J CardiothoracVascAnesth 11: 42-48.
  43. Pirovano IM, Van Belle H, Ijzerman AP (1990) Inhibition of nucleoside uptake in human erythrocytes by a new series of compounds related to lidoflazine and mioflazine. Eur J Pharmacol 189: 419-422.
  44. Isenberg G, Belardinelli L (1984) Ionic basis for the antagonism between adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res 55: 309-325.
  45. Cohn PF (1998) Treatment of chronic myocardial ischemia: rationale and treatment options. Cardiovasc Drugs Ther 12 Suppl 3: 217-223.
  46. Gross GJ, Kersten JR, Warltier DC (1999) Mechanisms of postischemic contractile dysfunction. Ann ThoracSurg 68: 1898-1904.
  47. Wang QD, Pernow J, Sjöquist PO, Rydén L (2002) Pharmacological possibilities for protection against myocardial reperfusion injury. Cardiovasc Res 55: 25-37.
  48. Yeung P, Seeto D (2012) Diltiazem attenuates cardiovascular toxicites and reduces mortality induced by isoproterenol in a freely moving rat model in vivo. Canadian Journal of Cardiology 28:S195
  49. Li RW, Yang C, Sit AS, Lin SY, Ho EY, et al. (2012) Physiological and pharmacological roles of vascular nucleoside transporters. J CardiovascPharmacol 59: 10-15.
  50. Gurusamy N, Lekli I, Mukherjee S, Ray D, Ahsan MK, et al. (2010) Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res 86: 103-112.
  51. Kim TH, Lee SM (2010) The effects of ginseng total saponin, panaxadiol and panaxatriol on ischemia/reperfusion injury in isolated rat heart. Food Chem Toxicol 48: 1516-1520.
  52. Gao L, Mao Q, Cao J, Wang Y, Zhou X, et al. (2012) Effects of coenzyme Q10 on vascular endothelial function in humans: a meta-analysis of randomized controlled trials. Atherosclerosis 221: 311-316.
  53. Littarru GP, Tiano L, Belardinelli R, Watts GF (2011) Coenzyme Q(10) , endothelial function, and cardiovascular disease. Biofactors 37: 366-373.
  54. Cheng D, Zhu C, Cao J, Jiang W (2012) The protective effects of polyphenols from jujube peel (Ziziphus Jujube Mill) on isoproterenol-induced myocardial ischemia and aluminum-induced oxidative damage in rats. Food Chem Toxicol 50: 1302-1308.
  55. Al-Numair KS, Chandramohan G, Alsaif MA (2012) Pretreatment with morin, a flavonoid, ameliorates adenosine triphosphatases and glycoproteins in isoproterenol-induced myocardial infarction in rats. J Nat Med 66: 95-101.
  56. Richard D, Oszust F2, Guillaume C3, Millart H2, Laurent-Maquin D3, et al. (2014) Infusion of docosahexaenoic acid protects against myocardial infarction. Prostaglandins LeukotEssent Fatty Acids 90: 139-143.
  57. Lorente-Cebrián S, Costa AG, Navas-Carretero S, Zabala M, Martínez JA, et al. (2013) Role of omega-3 fatty acids in obesity, metabolic syndrome, and cardiovascular diseases: a review of the evidence. J PhysiolBiochem 69: 633-651.
  58. Yeung P (2013) ATP Metabolism as Biomarker Target for Cardiovascular Protection (Editorial). CardiolPharmacol 2: e118
  59. Middleton E Jr, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52: 673-751.
  60. Mozaffarian D, Rimm EB (2006) Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 296: 1885-1899.
  61. Calder PC, Yaqoob P (2009) Omega-3 polyunsaturated fatty acids and human health outcomes. Biofactors 35: 266-272.
  62. Zuchi C, Ambrosio G, Lüscher TF, Landmesser U (2010) Nutraceuticals in cardiovascular prevention: lessons from studies on endothelial function. CardiovascTher 28: 187-201.
  63. Shukla SK, Gupta S, Ojha SK, Sharma SB (2010) Cardiovascular friendly natural products: a promising approach in the management of CVD. Nat Prod Res 24: 873-898.
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.

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.