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CARDIOVASCULAR ANESTHESIA

Sevoflurane Exposure Generates Superoxide but Leads to Decreased Superoxide During Ischemia and Reperfusion in Isolated Hearts

Leo G. Kevin, FCARCSI^*, Enis Novalija, MD^*,, Matthias L. Riess, MD^*,, Amadou K. S. Camara, PhD^*, Samhita S. Rhodes^*,, and David F. Stowe, MD PhD^*,,,,||

Anesthesiology Research Laboratories, Departments of *Anesthesiology and Physiology, and Cardiovascular Research Center, The Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; and ||Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin

Address correspondence and reprint requests to David F. Stowe, MD, PhD, M4280, 8701 Watertown Plank Rd., Medical College of Wisconsin, Milwaukee, WI 53226. Address e-mail to dfstowe{at}mcw.edu

Reactive oxygen species (ROS) are largely responsible for cardiac injury consequent to ischemia and reperfusion, but, paradoxically, there is evidence suggesting that anesthetics induce preconditioning (APC) by generating ROS. We hypothesized that sevoflurane generates the ROS superoxide (O₂^·-), that APC attenuates O₂^·- formation during ischemia, and that this attenuation is reversed by bracketing APC with the O₂^·- scavenger manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the putative mitochondrial adenosine triphosphate-sensitive potassium (mK_ATP) channel blocker 5-hydroxydecanoate (5-HD). O₂^·- was measured continuously in guinea pig hearts by using dihydroethidium. Sevoflurane was administered alone (APC), with MnTBAP, or with 5-HD before 30 min of ischemia and 120 min of reperfusion. Control hearts underwent no pretreatment. Sevoflurane directly increased O₂^·-; this was blocked by MnTBAP but not by 5-HD. O₂^·- increased during ischemia and during reperfusion. These increases in O₂^·- were attenuated in the APC group, but this was prevented by MnTBAP or 5-HD. We conclude that sevoflurane directly induces O₂^·- formation but that O₂^·- formation is decreased during subsequent ischemia and reperfusion. The former effect appears independent of mK_ATP channels, but not the latter. Our study indicates that APC is initiated by ROS that in turn cause mK_ATP channel opening. Although there appears to be a paradoxical role for ROS in triggering and mediating APC, a possible mechanism is offered.

IMPLICATIONS: Reactive oxygen species (ROS) are implicated in triggering anesthetic preconditioning (APC). The ROS superoxide (O₂^·-) was measured continuously in guinea pig isolated hearts. Sevoflurane directly increased O₂^·- but led to attenuated O₂^·- formation during ischemia. This demonstrates triggering of APC by ROS and clarifies the mechanism of cardioprotection during ischemia.

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