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Ann Thorac Surg 1997;64:588-589
© 1997 The Society of Thoracic Surgeons
Division of Cardiology, Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Ave, Nw Washington, Dc 20037
To the Editor:
I read with interest the article on adenosine-mediated cardioprotection by Jovanovi
and associates [1]. In view of the promising result of adenosine-regulatory agents (acadesine) for mitigating ischemia reported in animals treated under bypass conditions [2] and in clinical trials [3], I wonder if acadesine may not be a better agent than adenosine as a cytoprotective agent. Acadesine is also a target-specific arterial dilator, via its adenosine mechanism, to increase the delivery of cardioplegic solutions beyond coronary stenoses.
The goal of protective strategies in open heart surgery is to reduce myocardial injury during the period of obligate "protected" ischemia and attenuate the consequent reperfusion injury attending resumption of coronary blood flow [2]. Adenosine is a myoprotective autacoid that is released from the ischemic myocardium during the catabolism of the adenine nucleotide pool [4]. This inherent myoprotective capability may be used to greater advantage if the tissue levels of endogenous adenosine were pharmacologically augmented. Acadesine (AICA riboside, 5-aminoimidazole-4-carboxamide riboside) is a purine nucleoside analogue that increases adenosine levels specifically in ischemic myocardium [4].
Incidentally, Jovanovi and associates [1] cited in their reference 7 the work of Vinten-Johansen and colleagues [2] to support the use of adenosine as a beneficial supplement to conventional hyperkalemic cardioplegic solution in reducing the risk of contractile dysfunction after cardiac operations. But it was acadesine, not adenosine, that Vinten-Johansen and colleagues [2] used in their study, as was evident in the title of their article.
References
A, Alekseev AE, Lopez JR, Shen WK, Terzic A. Adenosine prevents hyperkalemia-induced calcium loading in cardiac cells: relevance for cardioplegia. Ann Thorac Surg 1997;63:153–61., MD, PhDDivision of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Guggenheim 7, Rochester Mn 55905
Reply To the Editor:
Over the last decade, adenosine has been found to possess cardioprotective properties and has therefore been advocated as a possible component of cardioplegic solutions [1]. Indeed, in more recent studies cardioprotective actions of adenosine have been confirmed [2, 3], and its beneficial effect as a supplement to hyperkalemic cardioplegia has been established [4, 5]. As expected, agents that raise tissue levels of adenosine, eg, acadesine and pentostatin, mimicked such effects of adenosine [6, 7], supporting the notion that adenosine possesses cardioprotective properties of benefit in open heart operations.
However, the mechanism underlying the effect of adenosine as an adjunct to hyperkalemic cardioplegia remained unknown. The majority of previous studies were performed on a whole heart preparation, which, although valuable in assessing the outcome of adenosine's action, provided only limited information in terms of mechanism of action. Consequently, it remained unresolved whether the protective effect of adenosine was due to an action on cardiomyocytes or to actions on neuronal or vascular cells also present in whole heart preparations. Moreover, as adenosine is known to have a variety of potentially protective effects including antiadrenergic action, reduction of adenosine triphosphate degradation, inhibition of platelet aggregation, decrease in oxygen demand, and increase in oxygen supply, it was warranted to define the mechanism of action of adenosine.
Therefore, to determine more precisely the cardioprotective action of adenosine under hyperkalemic conditions, we studied isolated single ventricular cardiomyocytes, a pure myocardial preparation with no neurogenic, hormonal, or other noncardiac influences. This approach uncovered that adenosine protects single cardiomyocytes against K+-induced Ca2+ loading [8], a major cause of ventricular dysfunction associated with hyperkalemic cardioplegia. Furthermore, our results suggest that the cytoprotective action of adenosine on cardiac cells is mediated through a protein kinase C-dependent mechanism and an associated decrease in the rate of K+-induced sarcolemmal depolarization [8, 9]. These findings may provide a framework for future development of targeted cardioprotective agents. It is conceivable, for example, that agents aimed at cardiac isoforms of protein kinase C, and also capable of decreasing net Ca2+ influx, may have improved cardioprotective properties under hyperkalemic conditions. State-of-the-art techniques of digital intracellular imaging and laser confocal microscopy further revealed that the cytoprotective action of adenosine, under high external K+ concentration, is dependent upon the cytosolic Ca2+ concentration of cardiac cells [10]. Although the underlying mechanism of the cytosolic Ca2+-dependent action of adenosine is at present unknown, it may provide the basis for selective protection within ischemic zones of the myocardium known to vary in the degree of intracellular Ca2+ loading.
In our studies, we did not compare the effect of adenosine with that of adenosine analogues or other agents that can indirectly act via an adenosine-mediated mechanism. Rather, the aim of our studies was to establish whether adenosine protects single ventricular cells against high extracellular K+. We concur that as an alternative to adenosine proper, use of adenosine-regulatory agents may also be effective, and therefore a comparison of adenosine with agents, such as acadesine, that act through adenosine-dependent mechanisms would be in order. Yet, a search for cardioprotective agents that can activate protein kinase C and decrease net Ca2+ influx may be more direct way to improve cardiac protection during open heart operations.
References
A, Alekseev AE, Lopez JR, Shen WK, Terzic A. Adenosine prevents hyperkalemia-induced calcium loading in cardiac cells: relevance for cardioplegia. Ann Thorac Surg 1997;63:153–61. A, Lopez JR, Terzic A. Cytosolic Ca2+ domain-dependent protective action of adenosine in a cardiomyocytes. Eur J Pharmacol 1996;298:63–9.[Medline]This article has been cited by other articles:
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  S. Jovanovic, A. Jovanovic, W. K. Shen, and A. Terzic Protective action of 17{beta}-estradiol in cardiac cells: implications for hyperkalemic cardioplegia Ann. Thorac. Surg., November 1, 1998; 66(5): 1658 - 1661. [Abstract] [Full Text] [PDF]
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A. Jovanovic, J. R. Lopez, A. E. Alekseev, W. K. Shen, and A. Terzic Adenosine Prevents K-Induced Ca2 Loading: Insight Into Cardioprotection During Cardioplegia Ann. Thorac. Surg., February 1, 1998; 65(2): 586 - 586. [Abstract] [Full Text] [PDF]
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