L8	Endothelial reperfusion injury.
H.M.Piper
Institute of Physiology, Justus Liebig Univeristy, Gießen, DE.

The endothelial lining of blood vessels forms a selective permeability barrier between plasma and interstitial spaces. In the course of ischemia-reperfusion the endothelial barrier of the coronary microvasculature becomes disturbed leading to edema due to an enhanced extravasation of water, solutes, macromolecules and blood cells. For that reason myocardial edema is a characteristic feature of the pathophysiology of reperfusion following coronary occlusion. The resulting myocardial edema prevents functional recovery of the heart during reperfusion and may even jeopardize survival of myocardial tissue. In cultured monolayers of microvascular coronary endothelial cells the cellular events leading to endothelial barrier failure can be studied in detail. Ischemic conditions cause a rise of cytosolic Ca2+ and opening of intercellular gaps. Upon reperfusion these changes are aggravated (endothelial reperfusion injury). Opening of intercellular gaps is largely due to activation of the endothelial contractile machinery. This is controlled by the Ca2+ dependent myosin light chain (MLC) kinase pathway. To prevent contractile activation and gap formation, either this pathway must be inhibited or the MLC phosphatase pathway must be activated. The latter is possible by ATP through purin receptor signaling in endothelial cells. ATP is therefore a potent agent preventing reperfusion-induced endothelial barrier failure. To be effective, enzymatic breakdown of ATP by endothelial ectonucleotidases has to be inhibited. Endothelial cells release ATP spontaneously during ischemia-reperfusion. When ectonucleotidases are inhibited, the released endogenous ATP is sufficient to protect the endothelial barrier. Barrier protection by ATP is also demonstrated in the intact coronary system. Breakdown of ATP to adenosine provokes an effect opposite to that of ATP. This is because in coronary endothelial cells adenosine activates a signaling pathway which destabilizes cell-cell junctions and promotes thereby barrier failure. Thus, extracellular ATP either released from cells or exogenously applied, protects against acute endothelial reperfusion injury in coronary endothelial monolayers and in the intact coronary system. To exploit this effect, ATP breakdown by ectonucleotidase is to be inhibited. These findings may open new therapeutic options for protection against acute coronary reperfusion injury.

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