PRE-CLINICAL RESEARCH: EDITORIAL COMMENT
Adenosine at ReperfusionA Conundrum Ready to Be Resolved*
Michael V. Cohen, MD, FACC* and
James M. Downey, PhD
Departments of Physiology and Medicine, College of Medicine, University of South Alabama, Mobile, Alabama
* Reprint requests and correspondence: Dr. Michael V. Cohen, Department of Physiology, MSB 3050, University of South Alabama, College of Medicine, Mobile, Alabama 36688 (Email: mcohen{at}usouthal.edu).
Key Words: myocardial infarction • liposome • drug delivery system • adenosine
The purine nucleoside adenosine is the parent compound of the ubiquitous intracellular high-energy compound adenosine triphosphate (ATP). During aerobic metabolism the intracellular adenosine concentration is only 30 to 300 nM because adenosine is being used to synthesize ATP. However, during anaerobic metabolism cellular ATP stores are depleted and the adenosine concentration increases 100-fold to as much as 10 µM. Adenosine itself has vasodilatory and negative chronotropic effects and thus causes hypotension and bradycardia when injected into the circulation. The latter effect has been used to great advantage in the acute treatment of supraventricular arrhythmias. Its use as a cardioprotective agent in both experimental animals and humans, however, has had a checkered history.
After the initial report by Murry et al. (1) in 1986 of the phenomenon of ischemic preconditioning (IPC), several laboratories began to assess possible mechanisms. An early observation by Liu et al. (2) suggested that IPC was dependent on adenosine, presumably released by ischemic cells, which would bind to its sarcolemmal Gi protein-coupled receptor to trigger downstream intracellular signaling and eventual activation of the hypothesized cardioprotective end-effector. Although the signaling is much more complicated than these investigators first imagined, even at the level of the very initial agonist-receptor binding, adenosine retained its great appeal as a promising trigger of cardioprotection, and several investigators imagined that exogenous adenosine might have the same result, thus leading to development of an effective strategy for clinical use.
Forman's group (3–7) pioneered investigation of the potential of exogenous adenosine to salvage ischemic myocardium. In a series of reports in various experimental animal models, these researchers claimed that an intravenous infusion of adenosine could indeed reduce the extent of myocardial infarction. However, other investigative groups were unable to duplicate these results (8–10). The meticulous protocol of Vander Heide and Reimer (9), which carefully duplicated that used by Forman's group, failed to produce any benefit of intravenous adenosine on infarct size in dogs. We also tested exogenous adenosine in rabbits in a comparable ischemia/reperfusion protocol (11). None of the intravenous doses of adenosine that we infused had any salutary effect. We were limited in the amount of adenosine that could be infused because of its profound hypotensive effect, and perhaps a higher intracoronary dose would have protected the heart. Despite these contradictory pre-clinical results, 2 large clinical studies have examined the effect of adenosine infusion in patients with acute myocardial infarction (12,13). The results have been mixed.
In this issue of the Journal, Takahama et al. (14) have developed a new technique for the delivery of adenosine to ischemic hearts that circumvents the problem noted above. They encapsulated adenosine in polyethylene glycol-coated (PEGylated) liposomes. These investigators infused these liposomes into rats for 10 min starting 5 min before release of a left coronary artery occlusion. The liposomes were found to be extensively taken up by the ischemic myocardium, but curiously not by nonischemic myocardium. Remarkably PEGylated liposomal adenosine at a dose of 450 µg/kg/min had no significant effects on either mean blood pressure or heart rate, whereas the same dose of free adenosine lowered mean blood pressure by 25.4%. Thus, they concluded that it is possible to intravenously administer high doses of adenosine to the ischemic heart without affecting hemodynamics.
Takahama et al. (14) then measured infarct size in rats treated with PEGylated liposomal adenosine. An infusion of 450 µg/kg/min reduced infarct size from 53.2% of the risk zone in untreated hearts to 29.5% (p < 0.05). Although it will be important for other investigators to confirm these results, it is likely that high-dose adenosine can be cardioprotective if complicating hypotension and bradycardia can be avoided.
Although up to now the ability of authentic adenosine to be cardioprotective was controversial, there is less dispute regarding whether adenosine receptor subtypes can protect the heart at the time of reperfusion. The receptor-selective adenosine analog BAY 60-6583, a highly selective adenosine A2b agonist, reduced infarction in rabbit hearts when infused minutes before reperfusion (15). Consistent with this observation was the determination that the protective effect of ischemic post-conditioning was abrogated by a specific A2b antagonist (16). Although Kin et al. (17) reported that an A2a antagonist blocked post-conditioning's protection, the selectivity of that agent is probably not sufficient to exclude an A2b mechanism. The A2a-selective agonists have also been reported to reduce infarct size when given at reperfusion by an anti-inflammatory mechanism (18). Adenosine is quickly metabolized in the tissues, and it may be that authentic adenosine simply cannot achieve a sufficiently high concentration to populate the receptors on the cardiomyocyte when delivered by an intravenous route. The analogs are stable and pass intact through the capillary endothelium.
Takahama et al. (14) administered liposomal adenosine to hearts and also infused either the nonselective adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (8-SPT) or 1 of the selective adenosine A1, A2a, A2b, or A3 receptor subtype antagonists. Not surprisingly, 8-SPT blocked protection confirming involvement of an adenosine receptor. What is puzzling is that an antagonist to each of the 4 adenosine receptor subtypes also attenuated protection from liposomal adenosine. It seems unlikely that all 4 subtypes would be involved in protection. This implausible result could even reflect false-positive observations related to the very wide range of infarct sizes in some groups (3% to 48% and 16% to 65% infarction of the ischemic zone in the liposomal adenosine and liposomal adenosine plus MRS1754 groups, respectively). Such wide ranges make statistical significance difficult to determine, especially when the numbers of experiments are small and a normal distribution has not been achieved. Hence, the identity of the specific adenosine receptor subtype or subtypes involved in these studies has not yet been fully determined and additional experimental studies are probably warranted.
Thus, a novel delivery vehicle for adenosine has been described that minimizes adverse hemodynamic effects and permits delivery of large amounts of the drug to ischemic tissue. Although the exact pathways involved in the protection remain obscure, the clinical implications are obvious. The intravenous route of administration simplifies use of this adenosine preparation, and adenosine is clearly not toxic. This liposomal adenosine can be added to a growing list of drugs that seem to limit infarct size in animal models when administered at the time of reperfusion (19).
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium Circulation 1986;74:1124-1136.[Abstract/Free Full Text]2. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart Circulation 1991;84:350-356.[Abstract/Free Full Text] 3. Olafsson B, Forman MB, Puett DW, et al. Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon Circulation 1987;76:1135-1145.[Abstract/Free Full Text] 4. Norton ED, Jackson EK, Virmani R, Forman MB. Effect of intravenous adenosine on myocardial reperfusion injury in a model with low myocardial collateral blood flow Am Heart J 1991;122:1283-1291.[CrossRef][Web of Science][Medline] 5. Velasco CE, Turner M, Cobb MA, Virmani R, Forman MB. Myocardial reperfusion injury in the canine model after 40 minutes of ischemia: effect of intracoronary adenosine Am Heart J 1991;122:1561-1570.[CrossRef][Web of Science][Medline] 6. Pitarys II CJ, Virmani R, Vildibill Jr. HD, Jackson EK, Forman MB. Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period Circulation 1991;83:237-247.[Abstract/Free Full Text] 7. Norton ED, Jackson EK, Turner MB, Virmani R, Forman MB. The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury Am Heart J 1992;123:332-338.[CrossRef][Web of Science][Medline] 8. Goto M, Miura T, Iliodoromitis EK, et al. Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species Cardiovasc Res 1991;25:943-949.[Abstract/Free Full Text] 9. Vander Heide RS, Reimer KA. Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs Cardiovasc Res 1996;31:711-718.[Abstract/Free Full Text] 10. Budde JM, Velez DA, Zhao Z-Q, et al. Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion Cardiovasc Res 2000;47:294-305.[Abstract/Free Full Text] 11. Xu Z, Downey JM, Cohen MV. AMP 579 reduces contracture and limits infarction in rabbit heart by activating adenosine A2 receptors J Cardiovasc Pharmacol 2001;38:474-481.[CrossRef][Web of Science][Medline] 12. Mahaffey KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction. Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol 1999;34:1711-1720.[Abstract/Free Full Text] 13. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II) J Am Coll Cardiol 2005;45:1775-1780.[Abstract/Free Full Text] 14. Takahama H, Minamino T, Asanuma H, et al. Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine augments cardioprotection in rats J Am Coll Cardiol 2009;53:709-717.[Abstract/Free Full Text] 15. Kuno A, Critz SD, Cui L, et al. Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion J Mol Cell Cardiol 2007;43:262-271.[CrossRef][Web of Science][Medline] 16. Philipp S, Yang X-M, Cui L, Davis AM, Downey JM, Cohen MV. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade Cardiovasc Res 2006;70:308-314.[Abstract/Free Full Text] 17. Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine Cardiovasc Res 2005;67:124-133.[Abstract/Free Full Text] 18. Glover DK, Riou LM, Ruiz M, et al. Reduction of infarct size and postischemic inflammation from ATL-146e, a highly selective adenosine A2A receptor agonist, in reperfused canine myocardium Am J Physiol 2005;288:H1851-H1858.[Web of Science] 19. Tissier R, Cohen MV, Downey JM. Protecting the acutely ischemic myocardium beyond reperfusion therapies: are we any closer to realizing the dream of infarct size elimination? Arch Mal Coeur Vaiss 2007;100:794-802.[Web of Science][Medline]
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