In Reply:—

We thank Dr. Gozal for his comments. He stresses an important point: the dual role that the release of free radicals has been shown to play in myocardial preconditioning and in reperfusion injury.

The relationship between free radicals and ischemic preconditioning was shown by Tanaka et al. , 1who tested the ability of various oxygen radical scavengers to prevent the development of preconditioning. They reported that the administration of the radical scavenger mercaptopropionyl glycine, or superoxide dismutase, was able to blunt the protective effect of ischemic preconditioning on infarct size in rabbits. 1Thus, the generation of a low amount of free radicals during a short ischemic episode is not sufficient to cause cell necrosis but enough to modify cellular activity and induce preconditioning effects. This result has been confirmed in numerous studies, not only in animals but also in humans. By measuring the free radical content in coronary sinus blood during coronary artery bypass surgery, Wu et al.  2demonstrated that ischemic preconditioning generates a small amount of free radicals after ischemic preconditioning compared with the larger amount seen after declamping. It has been shown in several subsequent studies that the opening of mitochondrial KATPchannels is a key step in triggering the signal transduction cascade of both ischemic and pharmacologic preconditioning (e.g. , by opioids or volatile anesthetics). 3,4The opening of these channels causes the release of free radicals (superoxide and hydroxyl radicals, hydrogen peroxide 3), which, in turn, activate different kinases (e.g. , protein kinase C). 5 

In contrast to their beneficial effect in triggering preconditioning, a very large number of studies indicate that free radicals play a detrimental and major role in the pathogenesis of reperfusion injury. Gozal et al.  6have shown that halothane prevents the postischemic production of hydroxyl radicals. A very recent study by Kevin et al.  7demonstrated that not only ischemic preconditioning but also pharmacologic preconditioning by sevoflurane reduces free radical formation during ischemia and reperfusion. The extent of this decrease correlates with functional and structural protection. Thus, the reduction of postischemic free radical release by volatile anesthetics may contribute to their well known protective effects against reperfusion injury. 8We have shown in a previous study that, in contrast to desflurane and sevoflurane, isoflurane did not reduce myocardial reperfusion injury. 8Therefore, volatile anesthetics might differ in their effect on free radical release during reperfusion. This suggestion is supported by a recent study by Gozal et al. , 9who reported that isoflurane was not effective in reducing hydroxyl radical production during myocardial reperfusion.

Thus, the release of free radicals has been shown to play a dual role in myocardial preconditioning and reperfusion injury. Volatile anesthetics might differ in their effects on free radical signaling for preconditioning and reperfusion injury.

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