Letter by Lotz et al regarding article, "Reactive oxygen species-induced stimulation of 5' AMP-activated protein kinase mediates sevoflurane-induced cardioprotection".

BACKGROUND 5'AMP-activated protein kinase (AMPK), a well-known regulator of cellular energy status, is also implicated in ischemic preconditioning leading to cardioprotection. We hypothesized that AMPK is involved in anesthetic-induced cardioprotection and that this activation is mediated by reactive oxygen species (ROS). METHODS AND RESULTS Isolated Langendorff-perfused rat hearts were subjected to 35 minutes of global ischemia (I) followed by 120 minutes of reperfusion (I/R). Hearts were assigned to a control group (Con) or a sevoflurane (Sevo) group receiving 3 times 5-minute episodes of sevoflurane (2.5vol%) before I/R. Phosphorylation of both AMPK and endothelial nitric oxide synthase (eNOS) were determined by Western blot analysis. Cardioprotection was assessed after I/R from recovery of left ventricular pressure and from infarct size (triphenyltetrazolium chloride staining). In the control group, ischemia resulted in a 2-fold increase in phosphorylation levels of AMPK (Con 0.13+/-0.01 versus Con-I 0.28+/-0.05, P<0.05), which was sustained after 120 minutes of reperfusion (Con-I/R 0.26+/-0.02, P<0.05). Sevoflurane preconditioning had no affect on AMPK phosphorylation before ischemia (Sevo 0.12+/-0.03, P>0.05), but almost doubled the increase in AMPK phosphorylation relative to control after ischemia (Sevo-I 0.48+/-0.09, P<0.05), an effect that was sustained after reperfusion (Sevo-I/R 0.49+/-0.12, P<0.05). The AMPK-inhibitor compound C (10 micromol/L) reduced the sevoflurane-mediated increase in phosphorylation of AMPK and its target eNOS and abolished cardioprotection. The ROS-scavenger n-(2-mercaptopropionyl)-glycine (1 mmol/L) blunted the sevoflurane-mediated increase in AMPK and eNOS phosphorylation and prevented cardioprotection. CONCLUSIONS Sevoflurane-induced AMPK activation protects the heart against ischemia and reperfusion injury and relies on upstream production of ROS.