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J Thorac Cardiovasc Surg 1996;112:202-203
© 1996 Mosby, Inc.
LETTERS TO THE EDITOR |
Department of Cardiothoracic Surgerya,b
To the Editor:
We read with great interest the excellent study by Randhawa, Lasley, and Mentzer,
1 which tested the cardioprotective effect of preischemic (pretreatment) intracoronary adenosine versus postischemic (i.e., onset of reperfusion) intracoronary adenosine administration in a porcine model of contractile "stunning." This study was based on the authors' hypotheses that (1) the cardioprotective effects of adenosine were mediated principally via the A1 receptor subtype located on the myocyte and (2) adenosine-induced cardioprotection required an accumulation of the purine in the interstitial fluid compartment. Adenosine was administered by intracoronary infusion either before coronary occlusion (either 5 or 50 µg/kg per minute for 10 minutes) or immediately on the onset of reperfusion (50 µg/kg per minute for 30 minutes). The investigators found that pretreatment adenosine at both low and high doses significantly attenuated postischemic contractile stunning in the ischemic-reperfused area, although accumulation of adenosine in the interstitial fluid compartment (microdialysis) was significant only in the group receiving 50 µg/kg per minute. In contrast, adenosine administered at reperfusion had no salutary effect and failed to increase interstitial fluid adenosine. The authors concluded that (1) intracoronary adenosine is cardioprotective optimally when given before ischemia, (2) adenosine levels in the interstitial compartment must be augmented to exert this protection, and (3) the mechanism underlying this cardioprotection is likely related to an interaction of adenosine with its A1 receptor subtype on the myocyte. A mechanism related to A2 receptor activation was thought not to be involved.
The requirement for adenosine accumulation in the interstitial compartment has recently come under vigorous investigation. Van Wylen 2 has shown that the critical concentration of intravascular adenosine needed to overcome the endothelial "sink" or barrier and augment interstitial adenosine concentrations is approximately 5 to 10 µg/kg per minute, which is close to the lowest dose used in the study under discussion. The failure of the 5 µg/kg per minute dose to augment interstitial fluid adenosine above preinfusion levels may be related to the inability of adenosine to traverse this barrier. However, the enhanced recovery of contractile function in this low-dose group in the absence of augmented interstitial levels is inconsistent with a requirement for interstitial accumulation. As recently demonstrated by Lasley and colleagues, 3 cardioprotection cannot be explained by simple augmentation of interstitial adenosine concentrations.
In addition to the interstitial (myocyte) compartment, a major and alternative target for adenosine is the vascular compartment. Adenosine, via activation of A2 receptors, has potent inhibitory effects on neutrophils, resulting in attenuated production of superoxide anions, inhibition of adherence to the vascular endothelium (purportedly a major initiating step in the inflammatory cascade involved in reperfusion injury), and a reduction in neutrophil-mediated endothelial damage. The importance of the intravascular space as a site for adenosine-mediated cardioprotection, independent of interstitial actions, has recently been shown by Todd and associates. 4 They showed that macromolecular adenosine, confined to the intravascular compartment, reduced infarct size in a rabbit model of myocardial reperfusion injury. Therefore the intravascular compartment may be a significant site of action of adenosine, in addition to the myocyte interstitial compartment.
When does adenosine exert cardioprotection in the two compartments mentioned? Randhawa, Lasley, and Mentzer 1 found that a beneficial effect of adenosine was exerted in their nonlethal model only when adenosine was administered as a pretreatment, and not when infused during reperfusion alone. However, the literature is rich with studies in which adenosine (both exogenous and endogenous) exerts cardioprotection during the reperfusion phase. In addition, activation of the A2 receptor specifically, rather than the A1 receptor, was found in a number of studies to be primarily involved in protecting the heart from ischemic-reperfusion injury. Zhao and associates 5 found that endogenous adenosine released during ischemia reduced infarct size predominantly by an A2-mediated effect, that is, activation of adenosine A2 receptors. This finding has been extended to exogenous adenosine administered only during reperfusion. The cardioprotection by A2 receptor activation is likely due to inhibition of neutrophil activities involved in the pathogenesis of reperfusion injury, as discussed earlier. Therefore A2-mediated effects exerted during reperfusion, in addition to A1-mediated mechanisms active during reperfusion, are key factors in the overall cardioprotection exhibited by adenosine.
The apparent questions raised by the study of Randhawa, Lasley, and Mentzer 1 regarding the optimal timing of adenosine administration and the receptor mechanisms involved may be related to the intended target of therapy and the compartment in which that target resides. A pretreatment administration of adenosine, as used by Randhawa, Lasley, and Mentzer, 1 both reduces infarct size and enhances functional recovery by predominantly A1-mediated mechanisms, possibly by activation of adenosine triphosphate–sensitive potassium channels. On the other hand, adenosine or analogs administered exclusively at the time of reperfusion significantly reduce infarct size (lethal injury), probably by inhibiting neutrophil by A2 receptor–mediated effects through activation of A2 receptors. However, neutrophils have not been clearly implicated in the pathogenesis of postischemic contractile stunning (nonlethal injury) because stunning occurs in neutrophil-free models. Therefore targeting neutrophil activation during the reperfusion phase will likely not alter postischemic stunning, although other mechanisms of injury would be engaged. This explanation is consistent with the data presented in the study by Randhawa, Lasley, and Mentzer 1 and is consistent with other studies related to the cardioprotective mechanisms of adenosine.
The optimal timing of adenosine administration may span all three windows of protection: before treatment, during the ischemic event, and during reperfusion. In cardiac surgery, these three windows of protection are open. First, adenosine can be given as a pretreatment before the operation. Second, adenosine may be included as an adjunct to either crystalloid or blood cardioplegia, 6 in which case it is administered during surgical "protected" ischemia. Third, adenosine may be administered after aortic unclamping and reperfusion. Which "window" of administration is most optimal, what dose is optimal, which receptors and effector systems are targets of adenosine, and in which compartment(s) protective effects are exerted in the surgical setting are questions that will keep young basic scientists and physician-investigators at the bench for some time.
References
This article has been cited by other articles:
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  J. Vinten-Johansen, Z.-Q. Zhao, J. S. Corvera, C. D. Morris, J. M. Budde, V. H. Thourani, and R. A. Guyton Adenosine in myocardial protection in on-pump and off-pump cardiac surgery Ann. Thorac. Surg., February 1, 2003; 75(2): S691 - 699. [Abstract] [Full Text] [PDF]
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 V. H. Thourani, R. S. Ronson, D. G.L. Van Wylen, S. T. Shearer, S. L. Katzmark, Z.-Q. Zhao, D. C. Han, R. A. Guyton, and J. Vinten-Johansen Adenosine-Supplemented Blood Cardioplegia Attenuates Postischemic Dysfunction After Severe Regional Ischemia Circulation, November 9, 1999; 100 (2009): II-376 - II-383. [Abstract] [Full Text] [PDF]
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