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Ann Thorac Surg 2001;72:1448
© 2001 The Society of Thoracic Surgeons
a Department of Surgery (Cardiothoracic), Emory University School of Medicine, 550 Peachtree St NE, Atlanta, GA 30308-2225, USA
To the Editor
In 1993, Manuel Galiñanes and colleagues [1] issued a challenge by asking whether adenosine would continue to be ignored as a cardioprotective agent. Since this challenge was issued, we [2] and a great many other laboratories have investigated the potential mechanisms by which adenosine and its analogs might protect the heart and other organs from ischemic-reperfusion injury. Adenosine is a pluripotent nucleoside that has numerous physiological effects mediated by its interaction with specific adenosine receptors. Classic among the physiological effects of adenosine is vasodilation. However, adenosine also has potent antiinflammatory effects that may be harnessed to attenuate inflammatory responses stimulated by ischemia-reperfusion and cardiopulmonary bypass, to name but a few triggers. Adenosine inhibits superoxide radical degeneration and degranulation by neutrophils, and attenuates the neutrophil-endothelial cell interactions that lead to unfavorable down-stream consequences such as vascular endothelial dysfunction, blood flow defects, and even infarction and apoptosis. Adenosine has been shown to reduce infarction in nonsurgical applications when given at the onset of reperfusion, and to reduce postcardioplegic injury in surgical models of global and regional myocardial injury when given both as an adjunct to cardioplegia solutions, or coincident with removal of the cross-clamp [3]. Recently, the intracoronary delivery of adenosine has even been advocated as a strategy to attenuate injury during off-pump coronary artery revascularization [4].
In recent years, the role of adenosine as an inhibitor of inflammatory cell activity has been expanded to include attenuating the release of cytokines that trigger and amplify the inflammatory response. These inflammatory mediators affect not only the heart, but also many other organs, including the lungs, the brain, the gut, and skeletal muscle, ie, those organs sensitive to cardiopulmonary bypass. Hence, it is not surprising that adenosine has been shown experimentally to protect these organs from inflammatory processes including ischemia-reperfusion, sepsis, as well as cardiopulmonary bypass. Therefore, Dr Machiraju’s observations that adenosine appears to attenuate neurological complications in patients undergoing surgical procedures on cardiopulmonary bypass has a good, albeit incomplete, scientific foundation. Many questions about adenosine’s potential for cerebroprotection remain to be answered, including confirmation and quantification of such purported cerebroprotection. For example, the ability of adenosine to alter the pathology caused by cerebral embolisms during cardiopulmonary bypass would be important in reducing this all-too-common cause of morbidity and mortality. Furthermore, investigation into whether adenosine reduces the release of neurotransmitters and decreases cerebral metabolism would have important clinical application in cases of deep hypothermic circulatory arrest and procedures which involve any interruption of brain blood flow. The more basic questions of what dose (concentration) of adenosine is necessary to exert antiinflammatory effects needs to be answered in attempts to limit the vasodilator effects of adenosine treatment. At first blush, the confounding response of vasodilation and hypotension may dissuade those interested in applying its protective attributes. However, vasodilation is easily corrected when on bypass, and local delivery avoids the systemic distribution of adenosine in concentrations that cause vasodilation. Furthermore, the antiinflammatory effects of adenosine may be exerted at concentrations below those that cause vasodilation, making a vasodilator response a moot point.
It is encouraging that Dr Machiraju’s group is exploring the potential protective effects of adenosine in the brain. I encourage them and others to quantify their physiological and psychological observations so that they may be reported and evaluated by other scientists and clinicians. I also encourage other investigators to expand the application of adenosine’s potential cellular protection in other organ systems that fall victims to inflammatory responses.
References
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