Fig. 5. Preconditioning by xenon involves the activation of protein kinase C (PKC). The effect was shown by the use of the specific PKC inhibitors staurosporine and calphostin C. Tyrosine kinases (TK) may also be mediators of cardioprotection by halogenated anesthetics, but their relation to PKC is not yet defined. In addition, the mitogen-activated protein kinase (MAPK) family (p38, JNK and ERK) seems to be involved because the blockade by the specific inhibitors PD98059 (ERK-1/2) and SB203580 (p38 MAPK) completely abolished the cardioprotection elicited by xenon. Downstream of p38 MAPK, the phosphorylation of a member of the heat shock protein (HSP) family, HSP27, is up-regulated, resulting in cytoskeleton changes in the myocytes. Whether the upstream kinases of MAPK, the MAPK kinases (MKKs) and MKK kinases (MKKKs), are involved is poorly investigated. The upstream signaling of PKC is not yet clearly defined. It remains to be determined in detail whether the activation occurs via the phospholipase C (PLC)/3-phosphoinositide–dependent kinase 1 (PDK-1) pathway involving activation of G protein–linked receptors or via opening of mitochondrial KATP(mKATP) channels and release of reactive oxygen species (ROS), or in parallel. The role of mKATPhas been extensively studied by the use of 5-hydroxydecanoate (5-HD), a specific blocker of the mKATPchannels. Alternatively, it is suggested that the activation of endothelial nitric oxide (NO) synthase (eNOS)/AKT/HSP90 complex may lead to NO release and that this in turn activates KATPchannels. AKT (PKB) = protein kinase B; ERK-1/2 = extracellular signaling regulated kinase 1 and 2; JNK = c-jun NH2-terminal kinase; l-NAME = N -nitro-l-arginine methyl ester; p38 = mitogen-activated protein kinase p38; PD98059 = blocker of ERK-1/2; PDK = phosphatidylinositol trisphosphate–dependent kinase; PLC = protein lipase C; SP600125 = blocker of JNK.