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J Thorac Cardiovasc Surg 1996;112:203-204
© 1996 Mosby, Inc.
LETTERS TO THE EDITOR |
Department of Surgery
University of Wisconsin School of Medicine
Room H4/383 Clinical Science Center
600 Highland Ave.
Madison, WI 53792
Reply to the Editor:
We thank Drs. Vinten-Johansen and Hammon for their interest in our work entitled "Salutary Effects of Exogenous Adenosine Administration on In Vivo Myocardial Stunning."
1 We reported that adenosine's cardioprotective effects were related to the preischemic elevation of adenosine in interstitial fluid and subsequent activation of adenosine A1 receptors located on the cardiac myocytes. We also concluded that adenosine must be administered before ischemia to attenuate stunning, because postischemic infusion of adenosine only transiently improved systolic wall thickening.
As pointed out by Vinten-Johansen and Hammon, in one protocol in this study we observed attenuation of stunning with an adenosine pretreatment dose (5 µg/kg per minute) that did not elevate preischemic dialysate adenosine concentrations. Although we acknowledged that the cardioprotective effect of this dose could have occurred independent of increased interstitial fluid adenosine, we concluded that the lack of increase in dialysate adenosine may have been due to the limitations of the dialysis technique. This technique provides only an estimate of interstitial fluid metabolites and is dependent on blood flow. In subsequent studies in the pig (unpublished data) we observed that the same intracoronary adenosine infusion (5 µg/kg per minute) increased coronary venous adenosine fivefold (from 0.31 ± 0.09 µmol/L to 1.51 ± 0.32 µmol/L). We detected a much smaller increase in dialysate adenosine—from 0.55 ± 0.05 µmol/L to 0.71 ± 0.11 µmol/L. We thus agree with Van Wylen 2 that the threshold intracoronary adenosine dose for overcoming the coronary endothelial barrier is approximately 5 µg/kg per minute.
Because both doses of adenosine undoubtedly increased plasma adenosine levels, adenosine A2 receptors were presumably activated. However, it is unlikely that the cardioprotective effects of adenosine pretreatment are related to preischemic activation of adenosine A2 receptors. This hypothesis is based on the results of numerous studies in which adenosine A1 and A2 receptor agonists and adenosine receptor antagonists were used. The preischemic activation of adenosine A1 receptors appears to be critical for the cardioprotective effects of adenosine against both reversible and irreversible injury. In our recent study in a model of irreversible injury, we 3 observed that a transient intravenous adenosine infusion (i.e., adenosine preconditioning) briefly increased preischemic levels of myocardial dialysate adenosine and reduced infarct size. The adenosine preconditioning did not, however, alter dialysate concentrations during the prolonged occlusion. These results are consistent with our working hypothesis that the cardioprotective effects of adenosine pretreatment are mediated by the preischemic activation of adenosine A1 receptors, irrespective of ischemic interstitial fluid adenosine levels.
Although the cardioprotective effects of adenosine pretreatment in models of stunning and infarction are thought to be mediated by adenosine A1 receptor activation, we agree with Drs. Vinten-Johansen and Hammon that adenosine exerts beneficial effects during reperfusion of the irreversibly injured heart. As suggested by several studies from Dr. Vinten-Johansen's laboratory, these effects appear to be mediated by activation of adenosine A2 receptors located on endothelial cells and neutrophils. In fact, there is evidence that, in contrast to the beneficial effects of A2 receptor activation, adenosine A1 receptor activation during reperfusion may exacerbate reperfusion injury by promoting neutrophil adherence to endothelium. 4
The aforementioned studies emphasize the importance of the timing of adenosine treatment. There also remains one unexplained difference between adenosine pretreatment effects on reversible and irreversible injury. A transient adenosine infusion (adenosine preconditioning) that is terminated before the onset of ischemia can reduce infarct size 3 but does not attenuate stunning. 5 Regardless of the mechanisms of adenosine-mediated cardioprotection and the optimal timing of adenosine infusion, there is evidence that adenosine pretreatment and supplementation of blood cardioplegic solution with adenosine may be beneficial in the setting of cardiac operations in human beings. 6 Finally, we also agree with Vinten-Johansen and Hammon that additional experimental and clinical studies are needed to determine the mechanism(s) and optimal timing/dose of adenosine-mediated cardioprotection.
References
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