On the mechanism of the calcium paradox: the release of hydrolytic enzymes.

Sequential perfusion of the heart with Ca2+-free and Ca2+ containing solutions leads to defects in myocytal surface membranes through which excess Ca2+ enters and cytosolic constituents leave the cells. During Ca2+-free perfusion the glycocalyx of the cells is damaged. Lipoprotein lipase, bound to mucopolysaccharides on the outside of cells, is released during Ca2+-free perfusion. This enzyme, involved in lipoprotein triglyceride uptake into the cells, is an alpha-lipase, which also hydrolyzes phospholipids. In addition to this phospholipase A1 activity some phospholipase A2 activity, due to another enzyme, is partially lost during Ca2+-free perfusion. The partial loss of this enzyme might be a reflection of the known increase of motional freedom of membrane phospholipids in the absence of Ca2+. The reintroduction of Ca2+ might rearrange phospholipids and activate residual phospholipase A2 so that pores arise that allow the passage of excess amounts of Ca2+. There is no reason to believe that the membranes of the organelles beyond the plasmalemma contribute to the early phenomena of the calcium paradox, as no soluble enzymes, contained within these organelles, are initially released from the heart. However, the calcium overload may stimulate Ca2+-dependent (phospho)lipases and proteases to contribute to the irreversible loss of structure and function.