THE TRIGGER PATHWAYS ARE DIVERGENT

There are alternative explanations of how the muscarinic receptor activates PI3 kinase. Tong et al.47 propose that the coupling somehow involves receptor internalization as transgenic mutant mice in which receptor internalization was blocked could not be preconditioned. Miura s group proposes that the metalloproteinase liberates TNF rather than EGF.48 In our rabbit cardiomyocyte model, however, the evidence for EGF coupling seems very strong.49 

IPC APPEARS TO EXERT ITS PROTECTION DURING REPERFUSION BY PREVENTING MPT PORE OPENING 

The molecular structure of the MPT pore is not fully understood either. Current evidence suggests that two proteins, the voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, and the adenine nucleotide translocase (ANT-1), located in the inner mitochondrial membrane, combine to form a pore that spans both membranes. 

DRUGS THAT PROTECT AT REPERFUSION TARGET THE SAME PATHWAYS AS IPC 

The evidence that IPC exerts its protection in the reperfusion period and the fact that certain drugs that modulate the survival kinases can protect the heart when given at reperfusion has revived the concept of reperfusion injury. In 1985 Braunwald and Kloner proposed that events early in reperfusion act to kill previously ischemic heart muscle.65 Yet reperfusion is required if survival is to occur. Reperfusion injury was originally proposed to result from reperfusion-induced free radicals and/or calcium entry. The term fell out of favor because it could not be proven that a free radical scavenger could actually limit infarct size. Now attention has turned to the MPT pore. 

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