Involvement of Na⁺/Ca²⁺ Exchange in Normal Cardiac Excitation-Contraction Coupling and in Ca²⁺ Overload during Ischemia and Reperfusion

Summary

The Ca²⁺ overload is known to play a major role in cellular dysfunction and death in ischemic and reperfused myocardium. The sarcolemmal Na⁺/Ca²⁺ exchange (NCX) is one of the essential regulators of Ca²⁺ homeostasis in normal excitation-contraction (E-C) coupling and can be a possible route for Ca²⁺ overload during ischemia and reperfusion. NCX is a bidirectional transport process, capable of moving Ca²⁺ in either direction across the sarcolemma, depending on the membrane potential and the transmembrane gradients of Na⁺ and Ca²⁺. In normal E-C coupling, NCX mainly operates to extrude Ca²⁺ from cytoplasm and the role of Ca²⁺ entering via NCX seems to be rather small, although there may be species difference. During ischemia, the decrease in Ca²⁺ efflux via the forward mode of NCX by high [Na⁺]_i,membrane depolarization, low pH_i, and low ATP would delay the Ca²⁺ transient decay and would increase diastolic [Ca²⁺]_i. After reperfusion, the recovery of NCX activity, with sustained cellular Na⁺ loading, can induce Ca²⁺ influx via the reverse mode of NCX, causing spontaneous Ca²⁺ release from the sarcoplasmic reticulum and triggered arrhythmias. While there are some possible therapeutic agents which may reduce ischemia/reperfusion injury, a relatively specific blocker of the reverse mode of NCX has been shown to protect myocardium from Ca²⁺ overload. These findings indicate the importance of NCX for normal E-C coupling and Ca²⁺ overload in ischemia/reperfusion injury, and the possibility of specific and clinically useful drugs targeting NCX.