Ann Thorac Surg 1998;65:586
© 1998 The Society of Thoracic Surgeons
Current Reviews
Adenosine Prevents K-Induced Ca2 Loading: Insight Into Cardioprotection During Cardioplegia
Aleksandar Jovanovi
, MD,
Jose R. Lopez, MD,
Alexey E. Alekseev, PhD,
Win K. Shen, MD,
Andre Terzic, MD
Division of Cardiovascular Diseases, Department of Medicine, and Clinical Pharmacology Unit, Department of Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, Minnesota, USA
Dr Terzic, Mayo Clinic, G-7, Rochester, MN 55905 (e-mail: terzic.andre@mayo.edu).
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Abstract
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In clinical practice, hyperkalemic cardioplegia induces sarcolemmic depolarization, and therefore is used to arrest the heart during open heart operations. However, the elevated concentration of K+ that is present in cardioplegic solutions promotes intracellular Ca2+ loading, which could aggravate ventricular dysfunction after cardiac operations. This review highlights recent findings that have established, at the single cell level, the protective action of adenosine against hyperkalemia-induced Ca2+ loading. When it was added to hyperkalemic cardioplegic solutions, adenosine, at millimolar concentrations and through a direct action on ventricular cardiomyocytes, prevented K+-induced Ca2+ loading. This action of adenosine required the activation of protein kinase C, and it was effective only in cardiomyocytes with low diastolic Ca2+ levels. Of importance, adenosine did not diminish the magnitude of K+-induced membrane depolarization, allowing unimpeded cardiac arrest. Taken together, these findings provide direct support for the idea that adenosine is valuable when used as an adjunct to hyperkalemic cardioplegia. This idea has emerged from previous clinical studies that have shown improvement of the clinical outcome after cardiac operations when adenosine or related substances were used to supplement cardioplegic solutions. Further studies are required to define more precisely the mechanism of action of adenosine, and the conditions that may determine the efficacy of adenosine as a cytoprotective supplement to cardioplegia.
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Introduction
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Hyperkalemic cardioplegia is a widely used method to arrest the heart during open heart operations [1]. Potassium, present at high concentrations (>16 mmol/L) in cardioplegic solutions, induces depolarization of the cardiac cell membrane and, thereby, electromechanical arrest of the heart. This is necessary for the surgeon to operate on a calm operating field. However, membrane depolarization also can lead to intracellular Ca2+ loading, which has been observed in myocardial cells exposed to hyperkalemic cardioplegia [2] [3]. Such K+-induced Ca2+ loading may manifest in the form of oscillations (ie, Ca2+ waves that spread within and between cells) [3] [4]. This is undesirable because elevated levels of intracellular Ca2+ ultimately could impair contraction-relaxation of a cardiac cell, perturb proper membrane excitation, induce abnormal gene expression, and contribute to the overall myocardial dysfunction associated with cardiac operations [5].
Although the pathophysiology underlying cardioplegia-related ventricular dysfunction is complex [1] [6] [7], impaired intracellular Ca2+ homeostasis could represent a major contributing factor. Indeed, Ca2+ overload has been associated with ischemia-induced cellular damage and contractile dysfunction [8] [9]. Because protective strategies during open heart operations should reduce myocardial injury during iatrogenic global ischemia and attenuate reperfusion injury after resumption of coronary blood flow, the identification of substances that will promote protection of the myocardium under hyperkalemic cardioplegia is warranted [10]. Such cardioprotective agents should inhibit K+-induced Ca2+ loading in cardiac cells, reducing the risk of cellular damage and ventricular dysfunction. At the same time, such agents should not affect the magnitude of K+-induced membrane depolarization, allowing the unimpeded cardiac arrest required for adequate open heart operations.
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Cardioprotective Properties of Adenosine: Role in Cardioplegia
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Adenosine has been considered as an adjunct to hyperkalemic cardioplegia [11] [12] [13] [14] [15] [16]. When it is added to cardioplegic solutions, adenosine improves postischemic recovery of ventricular function and reduces reperfusion injury of the ischemic myocardium [11] [13]. Moreover, acadesine, an agent that raises tissue levels of adenosine [17], when applied by intravenous infusion and through cardioplegic solutions, decreases the incidence of both perioperative myocardial infarction and cardiac death in patients undergoing coronary artery bypass grafting [18]. This review highlights recent findings at the cellular level that may help explain possible mechanism(s) involved inthe cytoprotective action of adenosine as an adjunct to hyperkalemic cardioplegia.
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Adenosine Prevents K+-Induced Ca2+ Loading
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The mechanisms that underlie the action of adenosine on the cardiovascular system are multiple, and have included an antiadrenergic action, reduction in the degradation of adenosine triphosphate (ATP) during global ischemia, improvement in the repletion of ATP during reperfusion, inhibition of the adherence of stimulated neutrophils to endothelial cells, inhibition of platelet aggregation, inhibition of neutrophil-induced generation of superoxide anion and hydrogen peroxide, decreased oxygen demand, stimulation of glucose metabolism and inhibition of glycolysis, and increased oxygen supply as a result of coronary vasodilation [19] [20]. Traditionally, it was thought that adenosine does not have direct effects on the electromechanical properties of ventricular cardiac cells [19] [21]. Recent findings, however, have revealed that adenosine could protect ventricular cells directly from a hyperkalemic challenge [22] [23] [24] and reduce the number of nonviable cardiomyocytes under hypoxic conditions [25].
Digital epifluorescent and laser confocal microscopy, two imaging techniques that allow precise monitoring of cytosolic Ca2+, have demonstrated that adenosine prevents intracellular Ca2+ loading of cardiac cells that are exposed to hyperkalemic cardioplegia (Fig 1) [24]. Because the preparation used was a pure myocardial preparation, free of atrial, neuronal, and vascular elements, the protective effect of adenosine against K+-induced Ca2+ loading was ascribed to a direct action of this agent on ventricular cardiomyocytes [22] [24]. This effect of adenosine was observed at millimolar concentrations [22] [24], which usually are required when adenosine is used as an adjunct in K+ cardioplegia [10] [26]. Thus, a direct action of adenosine to prevent K+-induced Ca2+ loading in ventricular cardiomyocytes may contribute to the cardioprotective effect of adenosine under hyperkalemic cardioplegia. Indeed, a direct protective effect of adenosine on myocyte contractility during cardioplegic arrest recently has been reported [23].
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Adenosine prevents K+-induced intracellular Ca2+ loading. A guinea pig ventricular cardiomyocyte, loaded with the Ca2+-sensitive fluorescent dye Fluo-3 and imaged by epifluorescent microscopy, exhibited low fluorescence (frame 1), indicating low Ca2+ levels (approximately 100 nmol/L). Exposure to adenosine did not change Ca2+ levels (frame 2). In the presence of adenosine, elevated extracellular K+ failed to induce a change in Ca2+ levels (frame 3). Yet, removal of adenosine led to a significant increase in Ca2+ levels (approximately 1,000 nmol/L; frame 4). The white horizontal bar (frame 1) indicates 20 µm. (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1997;63:153–61].)
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Adenosine Triphosphate–Sensitive K+ Channels May Not Play a Role in the Cytoprotective Action of Adenosine Under Hyperkalemic Cardioplegia
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Adenosine triphosphate–sensitive K+ (KATP) channels are present at high density in cardiac cells, where they apparently link membrane excitability with the cellular metabolic state [27]. These channels are regulated by intracellular mononucleotide and dinucleotide polyphosphates [28] [29] [30] and, in the heart, they have been implicated in the shortening of the action potential and the cellular loss of K+ that occurs during metabolic stress and hypoxia [27] [31]. Although during early ischemia, the opening of KATP channels may promote cardiac arrhythmias [32], it has been demonstrated that the opening of KATP channels is an important cardioprotective mechanism under different ischemic conditions [33] [34], including hyperkalemic cardioplegia [3] [35] [36]. Specifically, it has been shown that the application of potassium channel openers to single cardiac cells prevents the Ca2+ loading that is induced by 16-mmol/L extracellular K+, a concentration that commonly is used in hyperkalemic cardioplegia [3] [35]. In this regard, it should be pointed out that adenosine can activate, at least in membrane patches, cardiac KATP channels [37], and that adenosine-induced cardioprotection, under certain conditions, appears to be mediated through the opening of myocardial KATP channels [38] [39]. However, glyburide, a selective antagonist of KATP channels in the heart [31] [39] [40], failed to antagonize adenosine to prevent Ca2+ loading under hyperkalemic conditions [24]. Moreover, direct application of adenosine to ventricular cardiomyocytes did not produce a significant K+ outward current [22]. Therefore, KATP channel opening appears not to be involved in the cytoprotective effect of adenosine under this condition.
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Role of Protein Kinase C in the Cytoprotective Action of Adenosine Under Hyperkalemic Cardioplegia
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The activation of protein kinase C has been related to a reduction in the cytosolic concentration of Ca2+ in cardiomyocytes [41] and to a cardioprotective outcome [42] [43]. Adenosine does activate specific protein kinase C isoforms in cardiac cells [44], and inhibitors of protein kinase C do abolish the adenosine-induced limitation of myocardial infarct size [45]. Therefore, it is conceivable that the activation of protein kinase C could be involved in the adenosine-mediated inhibition of K+-induced Ca2+ loading. Indeed, inhibitors of protein kinase C, such as staurosporine and chelerythrine, were shown to prevent adenosine from protecting cardiac cells against the Ca2+ loading that is induced by hyperkalemic cardioplegia (Fig 2) [24]. Therefore, it is likely that the cytoprotective action of adenosine on K+-induced Ca2+ loading is mediated by the activation of protein kinase C. Further studies are required to define the intracellular signaling cascade that mediates the effect of adenosine in cardiomyocytes that leads to a decrease in extracellular K+-induced intracellular Ca2+ loading.
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An inhibitor of protein kinase C antagonized the protective effect of adenosine on K+-induced Ca2+ loading. Epifluorescent images from an adenosine-treated guinea pig ventricular cardiomyocyte, loaded with Fluo-3 and challenged with K+ before (frame 2) and after (frames 5 and 6) treatment with chelerythrine, an inhibitor of protein kinase C. Note the failure of adenosine to prevent K+-induced Ca2+ loading after treatment with the protein kinase C inhibitor. The white horizontal bar (frame 1) indicates 20 µm. (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1997;63:153–61].)
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Adenosine Does Not Prevent K+-Induced Membrane Depolarization
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The addition of adenosine to hyperkalemic cardioplegia does not modify the magnitude of K+-induced membrane depolarization, as established by patch-clamp measurements that allow precise analysis of ion currents and membrane potential (Fig 3A) [22]. This is desirable, because the lack of action of adenosine on the magnitude of K+-induced membrane depolarization would permit an unimpeded electromechanical cardiac arrest when the heart is exposed to cardioplegia containing both elevated K+ and adenosine. However, adenosine does decrease the rate of K+-induced membrane depolarization (Fig 3B) [22]. In principle, a decrease in the rate of membrane depolarization could be the consequence of a reduction in Ca2+ or Na+ inward current or an activation of K+ outward current. Adenosine does not have a pronounced effect on either Ca2+ or Na+ inward current, and it does not directly activate K+ outward current in ventricular cardiomyocytes [19] [22]. Although at present no conclusion regarding the mechanism of adenosine’s action on the rate of K+-mediated membrane depolarization can be drawn, this action of adenosine probably contributes to the adenosine-mediated inhibition of K+-induced Ca2+ loading in cardiac cells. Indeed, in experiments in which membrane depolarization was imposed on cardiac cells, at a constant magnitude but variable rate, slowing the rate of membrane depolarization was associated with a significant decrease in net Ca2+ inward current (Fig 3C) [22]. Such an effect may play a role in the beneficial action of adenosine as an adjunct to hyperkalemic cardioplegia by preventing excessive Ca2+ influx.
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(A) Adenosine does not prevent K+-induced membrane depolarization. The membrane potential of a guinea pig ventricular cardiomyocyte recorded by current-clamp using the patch-clamp method was -63 mV before and after exposure to K+ either in the absence or the presence of adenosine and -33 mV during K+ challenge either in the absence or the presence of adenosine. (B) Adenosine slows the rate of K+-induced membrane depolarization. The time course of membrane depolarization induced by K+ (upper panel) in the absence (curve 1) and presence (curve 2) of adenosine (1 mmol/L), and corresponding derivation curves (bottom panel). Data were obtained from a guinea pig current-clamped ventricular myocyte using the patch-clamp method. (C) The rate of membrane depolarization determines the magnitude of Ca2+ inward current. In a cardiomyocyte challenged with ramp-voltage depolarization of various durations (300–2,000 ms) and the same amplitude (100 mV; protocol depicted in upper panel), Ca2+ currents were recorded using the voltage-clamp mode of the patch-clamp method, and were plotted as a function of membrane potential (bottom panel). Recorded Ca2+ current traces and related pulses are marked by the same number. Note that the faster the depolarization, the larger the Ca2+ inward current. (Modified with permission from Alekseev AE, Jovanovi A, Lopez JR, Terzic A. Adenosine slows the rate of K+-induced membrane depolarization in ventricular cardiomyocytes: possible implication in hyperkalemic cardioplegia. J Mol Cell Cardiol 1996;28:1193–202.)
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Adenosine-Induced Prevention of K+-Induced Ca2+ Loading Is Not Mediated by Adenosine Receptors
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Under ischemic conditions, the cytoprotective action of adenosine was achieved at micromolar concentrations, and it was mediated through adenosine A1 receptors [12] [39] [46]. However, in cardiomyocytes exposed to hyperkalemic cardioplegia, the ability of adenosine to prevent K+-induced Ca2+ loading was not affected by isobutyl-methylxanthine, a nonselective antagonist of adenosine receptors [24]. Although this finding may be surprising, it should be pointed out that receptor-independent cardioprotective effects of adenosine have been described in whole heart preparations [47]. Further, a lack of adenosine receptor involvement may explain the fact that millimolar concentrations of adenosine are required to achieve protection under hyperkalemic cardioplegia, both in whole heart preparations [11] and at the single cell level [22] [24].
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The Cytoprotective Action of Adenosine Depends on the Diastolic Ca2+ Concentration
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In cardiac cells, the concentration of Ca2+ during diastole is 100 to 200 nmol/L. Previously, populations of cardiomyocytes with significantly different resting Ca2+ concentrations have been isolated from the same heart, and have been shown to exhibit different responses to metabolic challenge or drugs [48]. In this regard, adenosine protected cardiomyocytes against K+-induced Ca2+ loading only in cells with low levels of resting Ca2+ concentration (<300 nmol/L). This principle also may apply to single cells with different Ca2+ concentrations within different cytosolic domains [49]. Although the distribution of intracellular Ca2+ generally has been described as homogenous, heterogenous spatiotemporal patterns of intracellular Ca2+ distribution also have been observed in ventricular cardiomyocytes [4] [49]. Adenosine prevents extracellular K+ from inducing cytosolic Ca2+ loading in domains with low, but not in domains with high, basal concentrations of Ca2+ (Fig 4) [49]. Because protein kinase C apparently is involved in the protective effect of adenosine [24], a cytosolic Ca2+ domain-restricted action of adenosine may be related to differential regulation of protein kinase C, a Ca2+-sensitive enzyme [49]. Regardless of the mechanism responsible for the cytosolic Ca2+ domain-restricted action of adenosine, such dependence may lead to variable efficacy of protection within ischemic zones of the myocardium that are known to vary in their degree of intracellular Ca2+ loading. Moreover, the cytoprotective efficacy of adenosine also may depend on the nature of the pathologic condition to which the cardiomyocytes have been exposed [25].
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Domain-restricted protection by adenosine against K+-induced Ca2+ loading. (Upper panel) Epifluorescent images from a cardiomyocyte loaded with Fluo-3 and exposed to K+. (Lower panel) Corresponding values in fluorescent intensity indicative of the intracellular Ca2+ concentration. Adenosine protected domains of a cardiomyocyte with low (domain 1), but not high, Ca2+ levels (domain 2). The vertical bar in the upper panel indicates 20 µm. The open circles in the lower panel correspond to frames in the upper panel. (Reprinted from Jovanovi A, Lopez JR, Terzic A. Cytosolic Ca2+ domain-dependent protective action of adenosine in cardiomyocytes. Eur J Pharmacol 1996;298:63–9, with kind permission of Elsevier Science-NL, Sara Burgerhartstraat 25, 1055 KV Amsterdam, the Netherlands.)
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Ramifications for Cardiac Surgery
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Hyperkalemic cardioplegia is used during open heart operations to arrest the heart, but ventricular dysfunction as a result of intracellular K+-induced Ca2+ loading may be a potentially important adverse effect of this procedure [1] [5] [14]. It previously has been proposed that adenosine, as an adjunct to hyperkalemic cardioplegia, could reduce the risk of ventricular dysfunction and improve postischemic ventricular recovery [11] [13]. Recent clinical trials revealed that acadesine, an agent that raises tissue levels of adenosine, when added to cardioplegic solutions, significantly reduces the incidence of cardiovascular complications after coronary artery bypass grafting [18]. Recent findings, regrouped at the cellular level, have shown that adenosine could prevent K+-induced Ca2+ loading in ventricular cardiomyocytes without affecting the magnitude of K+-induced membrane depolarization (Fig 5). These results may provide, at least in part, an explanation for the observed ability of adenosine to protect the heart against the ventricular dysfunction that is associated with cardiac operations, without affecting the efficacy of K+ to induce cardiac arrest. Further, these findings at the single cell level [22] [24] [25] [49] [50], combined with a recent observation that adenosine protects the contractile status of a cardiac cell exposed to cardioplegia [23], provide direct support for the findings at the clinical level that adenosine or related substances are valuable as a supplement to cardioplegia [18] [51] [52].
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Adenosine prevents K+-induced Ca2+ loading in ventricular cardiomyocytes without affecting the magnitude of K+-induced membrane depolarization.
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Acknowledgments
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The work performed in our laboratory was supported through grants from the American Heart Association (Minnesota affiliate), the Miami Heart Research Institute, and the "Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery." Aleksandar Jovanovic is a recipient of the Merck Sharp & Dohme International Fellowship in Clinical Pharmacology.
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E. L. Holmuhamedov, S. Jovanovic, P. P. Dzeja, A. Jovanovic, and A. Terzic
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D. Pucar, E. Janssen, P. P. Dzeja, N. Juranic, S. Macura, B. Wieringa, and A. Terzic
Compromised Energetics in the Adenylate Kinase AK1 Gene Knockout Heart under Metabolic Stress
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Top
Abstract
Introduction
