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Ann Thorac Surg 1999;68:1942-1948
© 1999 The Society of Thoracic Surgeons

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I. Pathophysiology of Ischemic Reperfusion Injury

Broad-spectrum cardioprotection with adenosine

^a Section of Cardiothoracic Surgery, Department of Surgery, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Emory University, Atlanta, Georgia, USA

Address reprint requests to Dr Vinten-Johansen, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center of Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30365
e-mail: jvinten{at}emory.edu

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sept 21–24, 1997.

Abstract

Ischemia-reperfusion results in contractile dysfunction, necrosis, and vascular injury. This postischemic injury is mediated in part by superoxide radical production, neutrophils, dysfunction to ionic pumps, and edema formation. Adenosine is an autacoid released tonically by myocytes, endothelium, and neutrophils; the release of adenosine from the myocyte compartment into the interstitium is increased during ischemia. The major effects of adenosine are mediated by specific receptors identified as A₁, A_2a, A_2b, and A₃. Each receptor subtype contributes to physiological responses that influence ischemia-reperfusion injury. Adenosine has potent cardioprotective properties exerted during three major windows of opportunity: pretreatment, ischemia, and reperfusion. The cardioprotective effects exerted during pretreatment and ischemia may involve metabolic changes and hyperpolarization via K_ATP-channel activation, mediated through A₁ receptor mechanisms. The cardioprotective mechanisms exerted during reperfusion involve inhibition of neutrophils directly (superoxide anion generation, expression of adhesion molecules), and by inhibiting activation of the endothelium through A₂ receptor-mediated mechanisms, thereby preventing neutrophil-endothelial cell interactions, which initiate the inflammatory-like component of reperfusion injury. Activation of the newly identified A₃ receptor has been shown to be cardioprotective partially by inhibition of neutrophil adherence to endothelium and by neutrophil-independent mechanisms. These mechanisms of cardioprotection have been suggested to play major roles in the reduction of infarction and apoptosis after myocardial ischemia, cardioplegic arrest, and subsequent reperfusion. Adenosine has been used as an adjunct to both crystalloid and blood cardioplegia, but its potential as a cardioprotective agent has not been fully explored.

Adenosine has long been recognized for its vasodilator effects; this vasodilation is a key component of autoregulation of coronary and organ blood flow [1]. In the last decade, reports of adenosine’s cardioprotective effects exerted during both ischemia [2] and reperfusion [3, 4] have emerged. Since the key observations of Olafsson and associates [4], there has been a virtual explosion of research focused on unraveling the mechanisms by which adenosine protects the heart from both reversible and irreversible injury after ischemia and reperfusion. In contrast to many purported cardioprotective agents, adenosine has the potential to exert cardioprotection during all three windows of cardioprotection: pretreatment (or preconditioning), ischemia (ie, either warm ischemia or intermittent cardioplegia), and reperfusion. Therefore, adenosine has been shown to have broad-spectrum cardioprotective effects that exert protection endogenously as well as exogenously, and by acting through multiple mechanisms, on multiple cell types (myocytes, neutrophils, endothelium), and during multiple windows of opportunity. The ability of adenosine to attenuate apoptosis in addition to necrosis and contractile dysfunction adds yet another dimension to its repertoire of physiological effects.

Pharmacology of adenosine and adenosine receptors

Adenosine produces a majority of its physiological effects by interacting with specific purinergic receptors. There are at least four types of adenosine receptors: A₁, A_2a, A_2b, and the newly identified A₃ receptor. A₁ receptors have been located on neutrophils and myocytes. Stimulation of A₁ receptors activates ATP sensitive potassium (K_ATP) channels via inhibitory G-protein-mediated transduction (reduction of adenyl cyclase activity), with resultant stimulation of potassium outward conductance. K_ATP channel activation induces hyperpolarization and inhibits calcium conductance. Physiological effects of A₁ receptor stimulation include negative chronotropy and dromotropy, antiadrenergic effects, stimulation of glycolysis, and stimulation of neutrophil adherence. Adenosine A_2a receptors are localized on neutrophils, endothelial cells, vascular smooth muscle, and platelets. Receptor-ligand interaction stimulates adenylate cyclase through a stimulatory G protein (G_s) transduction mechanism, resulting in vasodilation, renin release, and inhibition of neutrophil superoxide generation and adherence to endothelium. Adenosine A₃ receptors have been localized in heart tissue, and may be on endothelium and myocytes, although firm data are not available. The A₃ receptor is similar to the A₁ receptor in that it inhibits adenylate cyclase and stimulates protein kinase C translocation.

Inhibition of neutrophils, endothelium, and neutrophil-endothelial cell interactions

Adenosine has been shown to be a potent inhibitor of neutrophils (PMNs) [5], platelets [6], and mononuclear leukocytes [7]. Neutrophils are important participants in ischemic-reperfusion injury, and activation of neutrophils may lead to endothelial dysfunction [8], production of free radicals [9], capillary plugging, and direct injury to myocytes. The adherence of neutrophils to the endothelium is reported to be one of the initiating factors leading in the cascade of inflammatory events that occur during myocardial reperfusion [10]. Cronstein and associates [5] reported that superoxide radical generation by neutrophils in vitro was inhibited by adenosine, involving principally A₂ receptor-mediated mechanisms. Adenosine was also found to inhibit adherence of PMNs to endothelium as well as subsequent neutrophil-mediated damage [11]. Adenosine directly inhibits the expression of CD11/CD18 on PMNs stimulated by formyl-methionyl-liveyl-phenylalanine (FMLP), and this inhibitory effect is blocked by an adenosine receptor antagonist.

Studies by Zhao and associates [12] in canine coronary arteries confirm that adenosine directly inhibits superoxide radical production and adherence-activated (platelet activating factor [PAF]) canine neutrophils (Fig 1). The attenuated superoxide production was reversed by 8-p-sulfophenyl theophylline (8-p-SPT), an adenosine receptor antagonist indicating receptor-mediated mechanisms. In addition to superoxide radical generation by neutrophils, adenosine inhibited adherence of PMNs to the endothelium (Fig 1), purportedly the first step in the neutrophil component of the ischemic-reperfusion injury. Adenosine-induced inhibition of PMN adherence was not attenuated by A₁ antagonism, but adherence was inhibited by the A_2a-receptor agonist CGS-21680. Therefore, adenosine inhibits neutrophil superoxide radical generation, adherence of neutrophils to the endothelium, and further inhibits the damage to the endothelium mediated by neutrophil-endothelial cell interaction, primarily through A_2a receptor mechanisms [12].

View larger version (29K): [in this window] [in a new window]   Fig 1. Superoxide radical production (cytochrome C reduction) from platelet-activating factor (PAF)-stimulated neutrophils (PMN) (top), and PMN adherence to coronary artery endothelium (bottom). Adenosine (ADO) significantly inhibited superoxide radical generation by PAF-stimulated PMNs, and reduced adherence, which was reversed with the ADO antagonist 8-p-SPT. ADO plus the A1-antagonist KW-3902 did not alter ADO’s inhibition of adherence; the ADO A2 receptor analog mimicked ADO inhibition, while the A2 receptor agonist CGS 21680 mimicked the effects of adenosine. Data are mean ± standard error. *p < 0.05 vs PAF-stimulated PMN group. Data in bottom are adapted from Zhao and associates [12].

View larger version (13K): [in this window] [in a new window]   Fig 2. Adherence of unstimulated neutrophils (PMNs) to coronary artery endothelium. Thrombin (THR), which stimulates translocation of p-selectin on endothelium, significantly increased PMN adherence. Adenosine (ADO) inhibited adherence in a concentration-dependent manner (10, 50, 100, and 200 µM). Adapted from Williams and associates [14] and Fernandez and associates [15].

View larger version (14K): [in this window] [in a new window]   Fig 3. Adenosine (ADO) as an adjunct to blood cardioplegia. Standard blood cardioplegia (BCP) was supplemented with adenosine at a final concentration of 400 µM. To confirm that the effects of adenosine were receptor mediated, the antagonist 8-p-SPT (SPT) was administered before the administration of adenosine cardioplegia. The slope of the end-systolic pressure-volume relationship (ESPVR) determined by impedance catheter and instantaneous left ventricular pressure recording was used to assess baseline (open bars) vs postcardioplegia (dark bars) contractile function.

Adenosine actions during reperfusion

Myocardial stunning
Postischemic contractile dysfunction in the absence of myocardial necrosis has been defined as contractile "stunning." The present data support the concept that exogenous adenosine and adenosine analogs must be administered as a pretreatment before ischemia, and not solely during reperfusion, in order to inhibit postischemic contractile dysfunction in models of nonlethal injury (ie, stunning) [2, 17]. Lasley and associates [18] reported that pretreatment with adenosine or the A₁ analog R-phenylisopropyl adenosine (R-PIA) before ischemia increased end points representative of ischemic damage such as the time to onset of ischemic contracture. This effect was reversed by an adenosine receptor antagonist, BW A1433U. In contrast, the A_2a-receptor analog phenylaminoadenosine had no effect on the time to ischemic contracture. Adenosine A₁-receptor activation was also found to improve postischemic function of globally ischemic rat hearts when administered during ischemia, while an A_2a-receptor analog had no protective effect [19]. In summary, infusion of adenosine during reperfusion, in in vivo models of myocardial stunning, have largely failed to improve postischemic contractile effort in the area at risk, while infusion of adenosine before ischemia significantly improved function. The reasons underlying the failure of adenosine or A₂ agonists to improve contractile stunning when given during reperfusion is not clear, but may be related to: (1) the absence of an appropriate therapeutic target (ie, neutrophils), which contributes to the pathophysiology of stunning; and (2) the compartment in which adenosine is present relative to the location of the target. The mechanisms involved in adenosine’s inhibition of contractile dysfunction effect a reduction in the severity of ischemia by hyperpolarizing the cell, augmenting anaerobic glycolysis, and improving energy status.

Reduction of myocardial necrosis
In a key study by Olafsson and associates [4], intracoronary infusion of adenosine reduced infarct size by approximately 75% and improved regional contractile function 24 hours after the initiation of reperfusion. Histological analysis demonstrated preservation of endothelial morphology with decreased neutrophil infiltration and plugging in the necrotic zone of the area at risk with administration of adenosine at reperfusion. Similar results were subsequently found by others using intravenous administration of adenosine [20] or adenosine receptor-specific analogues. Recently, Zhao and associates [21] showed in a canine model of 1 hour of LAD occlusion and 6 hours of reperfusion that adenosine infusion via the left atrium reduced infarct size by 50% compared with a vehicle group (Table 1); this infarct reduction was confirmed by reduced plasma creatine kinase levels. Postischemic contractile function in the area at risk was significantly greater after 4 hours of reperfusion in adenosine treated animals, but after 6 hours of reperfusion, this effect was lost. Analysis of myeloperoxidase activity as a specific marker for neutrophils showed that adenosine treatment significantly reduced neutrophil accumulation in both the necrotic and nonnecrotic area at risk (Table 1), consistent with the in vitro antineutrophil effects of adenosine demonstrated previously. Finally, endothelial dysfunction (basal as well as agonist stimulated) in the ischemic-reperfused LAD of the vehicle group was reversed in the adenosine-treated group. In this regard, adenosine reduced adherence of unstimulated neutrophils to LAD endothelium (basal function) from 63 ± 3 PMN/mm² to 37 ± 4 PMN/mm² (circumflex control 32 ± 2 PMN/mm²) and improved endothelial relaxation responses to the stimulators of nitric oxide synthase, acetylcholine, and the calcium ionophore A23187. Therefore, adenosine reduced infarct size and vascular endothelial cell functional injury, in part by attenuating neutrophil-mediated actions. A subsequent study by Jordan and associates reported that the adenosine A_2a-receptor analogue CGS-21680 significantly reduced infarct size from 29.8% ± 2.3% of the area at risk in a saline vehicle group to 15.4% ± 2.9% of the area at risk, and was associated with reduced neutrophil accumulation in the area at risk. However, there was no improvement in acute postischemic wall motion. These data provide further evidence for an association between adenosine’s antineutrophil effects and its infarct-sparing effect.

Adenosine in surgical cardioprotection

Pretreatment
As described above, a pretreatment infusion of adenosine (similar to preconditioning but with a chemical agent) may protect the heart, ostensibly by attenuating ischemic events. This pretreatment window of opportunity is convenient in the surgical setting. A brief pretreatment with adenosine has been shown to reduce infarct size in both isolated-perfused [23] and in vivo [24, 25] models, improve postischemic contractile function [26], and preserve metabolic or energy status of the ischemic-reperfused myocardium [26]. These pretreatment cardioprotective effects may be mediated by activation of A₁-receptors [27], opening of ATP-sensitive potassium (K_ATP) channels, and consequent reduction of calcium overload [28]. Clinically, Lee and associates [29] reported favorable results with adenosine (250 to 350 µg/kg infused 10 minutes before cardiopulmonary bypass) in patients with poor preoperative left ventricular performance and three-vessel disease. Postsurgical cardiac index was improved over nontreated patients (by 42% of prebypass vs 10% of prebypass, respectively) immediately after discontinuation of bypass and 40 hours postoperatively, and creatine kinase levels 24 hours postoperatively were significantly lower in adenosine-treated patients. These data provide evidence that the pretreatment window is available for the beneficial administration of adenosine, without significant untoward complications such as hypotension or bradycardia.

Ischemia (adjunct to cardioplegia)
The most obvious application of adenosine is as an adjunct to cardioplegia solutions. In this regard, adenosine could be useful as a primary arresting agent (by virtue of its hyperpolarizing effects) and/or as a cardioprotective agent. In 1976, Hearse and associates [30] reported that adenosine, used either alone during ischemia or as an adjunct to cardioplegia, improved postischemic function. This report was followed by others in which adenosine, either alone [31, 32] or in combination with crystalloid potassium cardioplegia [31, 33], accelerated cardiac arrest and improved postischemic contractile function [33]. The beneficial effects of adenosine-enhanced cardioplegia have been attributed to a number of mechanisms, including improvement in the rate of anaerobic glycolysis and energy status, as well as to reduction in calcium accumulation secondary to cell hyperpolarization [34]. Therefore, the efficacy of adenosine as a high-energy phosphate precursor is not clear.

Few studies have investigated adenosine as an adjunct to blood cardioplegia. Hudspeth and associates [35] investigated adenosine as an adjunct to a standard hypothermic, hyperkalemic blood cardioplegic solution in ischemically injured hearts subjected to 30 minutes of normothermic global ischemia. Blood cardioplegia supplemented with 400 µmol/L adenosine reversed the postischemic systolic dysfunction observed with unsupplemented blood cardioplegia (Fig 3). This protection was inhibited with 8-p-SPT, confirming a receptor-mediated mechanism. Interestingly, these protective effects were independent of cardioplegia volume, which was not increased by adenosine.

Reperfusion
Adenosine has potent antineutrophil effects that reduce lethal postischemic injury when given only at the onset of reperfusion. The numerous studies in nonsurgical models in which adenosine reduced postischemic damage when administered only at reperfusion suggest that administration of adenosine at the time of aortic declamping may be beneficial. Although a beneficial effect exerted during reperfusion would be in keeping with adenosine’s antineutrophil effects listed above, this benefit might apply only to lethal injury (ie, necrosis), and not necessarily to postcardioplegia contractile dysfunction. The use of adenosine strictly as a postcardioplegia treatment has been virtually ignored in other models of surgical ischemic-reperfusion injury, and well-controlled studies of mechanisms are warranted.

Is there a role for the adenosine A₃-receptor subtype?

While the role of adenosine has been demonstrated to be beneficial in myocardial preservation, the untoward effects resulting from stimulation of the A₁ (bradycardia, neutrophil stimulation) and A_2a receptors (vasodilation by potassium) have impeded the routine use of these agents clinically. Therefore, an adenosine analog that could provide myocardial protection without untoward systemic effects may be important. However, there is a paucity of data on the cardioprotective effects of adenosine mediated by the A₃-receptor. Initial studies investigated the role of the A₃ receptor in models of simulated ischemia-reperfusion [36], as well as its ability to mimic or induce preconditioning [37, 38]. In recent studies by Thourani and associates [39] A₃ receptor stimulation with Cl-IB-MECA, a highly specific adenosine A₃ receptor agonist, attenuated postischemic (30 minutes, 37°C, no-flow ischemia) contractile dysfunction (LV developed pressure, control: 34% ± 2% baseline vs adenosine: 54% ± 3% vs CL-IB-MECA: 50% ± 6%) and creatine kinase release in buffer perfused rat hearts. This cardioprotective effect is independent of any potential antineutrophil effect of A₃ receptor activation because the buffer-perfused heart preparation is cell free. The mechanism of this protection is currently under investigation. Furthermore, Thourani and associates [40] have investigated the potential use of the A₃-receptor analog Cl-IB-MECA in a surgical model of cardioplegic arrest and reperfusion using an ischemically injured isolated buffer perfused rat heart preparation. They found that pretreatment with the adenosine A₃ receptor agonist Cl-IB-MECA (100 nM) before hypothermic (10°C) cardioplegic (plegisol) arrest significantly increased postischemic function (42% ± 2% vs 62% ± 5% of baseline LV developed pressure) and decreased CK release 1,734 ± 50 vs 1,481 ± 41 U/L) of jeopardized myocardium. However, this protective effect was not observed when Cl-IB-MECA was administered as an adjunct to hypothermic cardioplegia. The failure to protect during cardioplegia may be related to inhibition of agonist-receptor interactions by hypothermia, or a "lost opportunity" to decrease ischemic injury because the analog was not administered until after normothermic ischemia.

Conclusions

Adenosine is an endogenous autacoid that has been shown to have a broad spectrum of physiological effects, which makes it effective as a cardioprotective agent with effectiveness in all three time points of potential injury. In addition, the effects of adenosine are pluripotent, with actions exerted in a number of anatomical compartments, and actions aimed at a number of effectors involved in ischemic and reperfusion injury (Fig 4). The duration of the physiological actions seems to extend well beyond its plasma half-life, thereby making it clinically useful, but also calling into question the dependence on a direct effect of adenosine requiring its continued presence. Adenosine has the potential for reducing ischemic injury by largely A₁-receptor-mediated mechanisms involving effectors in the myocyte or interstitial compartment, including K_ATP channel activation, improved anaerobic metabolism, improved energy status, and attenuated PMN-myocyte interactions. Such effects can be initiated by treatment before the ischemic event or before cardioplegic arrest. In addition, adenosine reduces reperfusion injury primarily by inhibiting the neutrophil and the endothelium directly, as well as their interactions by predominantly A_2a-receptor mechanisms in the intravascular space. Because adenosine’s cardioprotection is dose-dependent [41], the optimal therapeutic dose for surgical (ie, adjunct to cardioplegia) as well as nonsurgical intervention needs to be identified, taking full advantage of beneficial effects while avoiding unwanted side effects. Analogs of the adenosine A₃ receptor hold promise as an agent reducing the complications of adenosine while targeting components of both ischemic injury and reperfusion injury. Further research is needed to elucidate the role of adenosine in potentially modulating "late" reperfusion injury, and differentiating a delay in injury from permanent reduction of injury. In addition, further studies need to determine adenosine’s potential role in modulating the apoptotic component of postischemic cell death [42]. Other effects of adenosine that may attract the surgeon’s interest are termination of supraventricular tachyarrhythmias, negative chronotropy, and negative inotropic effects. The latter is effective only against adrenergically augmented inotropic state, and may have mixed blessings in the postbypass patient.

View larger version (19K): [in this window] [in a new window]   Fig 4. The multi-component and multi-effector effects of adenosine acting during ischemia and reperfusion. Adenosine (ADO) can be released from the myocytes into the interstitium, or from the endothelium (EC) into both the interstitial space (INTERST) and the vascular (VASCULAR) space. Adenosine may exert cardioprotection during ischemia when released into the interstitial space, exerting effects primarily on the myocytes directly. During reperfusion, endogenously released and parenterally administered adenosine may exert cardioprotection by inhibiting the neutrophils and endothelium (or their interaction) directly.

We are grateful for the assistance of Jill Robinson, Sara Katzmark, and L. Susan Schmarkey in performing the studies cited from the authors’ laboratory. This work was supported by grants from the National Institutes of Health (Dr Vinten-Johansen: National Heart, Lung, and Blood Institute, HL-46179), the American Heart Association-North Carolina Affiliate (Dr Zhao), and the Carlyle Fraser Heart Center of Emory University. Dr Zhao is a recipient of a Scientist Development Award from the National American Heart Association.

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