Calcium and sodium control in hypoxic-reoxygenated cardiomyocytes

Summary

When oxygen-deprived cardiomyocytes become energy depleted, they accumulate Na⁺ and Ca²⁺ in the cytosol. Influx of Ca²⁺ via the Na⁺/Ca²⁺ exchange mechanism seems to contribute to the development of Ca²⁺ overload, but Ca²⁺ overload may eventually also occur when this route is blocked. Hypoxic-reoxygenated cardiomyocytes in a state of severe overload of Na⁺ and Ca²⁺ can rapidly re-establish a normal cation control when oxidative energy production is re-initiated. The recovery of cellular Ca²⁺ control may be devided into three stages: first, sequestration of large amounts of Ca²⁺ into the sarcoplasmic reticulum; second, oscillatory movement of Ca²⁺ from and back into the sarcoplasmic reticulum and gradual extrusion across the sarcolemma; third, re-establishment of constant low cytosolic Ca²⁺ concentrations. When the Na⁺/Ca²⁺ exchanger is inhibited, extrusion of Ca²⁺ from the cells' interior is impaired and oscillatory Ca²⁺ movements between cytosol and sarcoplasmic reticulum continue for long time. Thus, the functions of the sarcoplasmic reticulum and the Na⁺/Ca²⁺ exchanger are of crucial importance for the recovery of Ca²⁺ control in reoxygenated cardiomyocytes. In re-energized cardiomyocytes, a persistent elevation of the cytosolic Ca²⁺ concentration provokes maximal force development and consecutive mechanical cell injury (“oxygen paradox”). This injury can be prevented when the contractile machinery is inhibited during the initial phase of reoxygenation as long as necessary for the re-establishment of a normal cytosolic Ca²⁺ control.