Ischemic preconditioning: From adenosine receptor to K-ATP channel

Ischemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue nec rosis induced by a subsequent prolonged ischemia. It is hoped that elucidat ion of the mechanism for preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals. The combined effect of the release of these substances on G proteins and the cell's phospholipases induces the transloc ation and activation of the epsilon isozyme of protein kinase C. Protein kinase C appears to be the first element of a complex kinase cascad e that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that this cascade contains at least one tyrosin e kinase and ultimately leads to the activation of p38 mitogen-activated pr otein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-a ctivated protein kinase-activated protein kinase 2. Mitogen-activated prote in kinase-activated protein kinase 2 phosphorylates HSP27, a 27-kDa heat sh ock protein that controls actin filament polymerization, and, therefore, af fects the integrity of the cytoskeleton. Finally, mitochondrial adenosine 5 '-triphosphate-sensitive K+ channels open, and the latter may be the final mediator of protection for ischemic preconditioning. The protective pathway has many builtin redundancies, perhaps creating a safety factor. These red undancies may also explain some of the species-related differences seen in ischemic preconditioning in which one redundant pathway may predominate ove r another.