Na⁺/H⁺ and Na⁺/Ca²⁺ exchange: Their role in the rise in cytosolic free [Ca²⁺] during ischaemia and reperfusion

A rise in Ca(i) occurs during ischaemia. During the first 30 min of ischaemia, this rise does not appear to be due to Ca²⁺ entry via Ca²⁺ channels or Ca²⁺ release from the SR. The increase in Ca(i) appears to be due to Ca²⁺ entry via Na⁺/Ca²⁺ exchange, secondary to a rise in Na(i) during ischaemia. The mechanism responsible for the rise in Na(i) is controversial. There appears to be some entry via non-inactivating voltage-gated Na⁺ channels and some entry via NHE, although the exact relative percentage may depend on the metabolic activity of the cell and the magnitude of the fall in pH(i). Inhibition of the rise in Na(i) during ischaemia (whether by inhibition of Na⁺ channels, inhibition of NHE, or a combination of both) reduces the subsequent rise in Ca(i) and is cardioprotective. There is also convincing data suggesting that NHE is stimulated at the start of reflow. Inhibition of NHE at the start of reflow slows the rate of recovery of intracellular pH, but there is no measurable change in Na(i) at the start of reflow, unless the Na⁺/K⁺ ATPase is inhibited. However, although the increased Na⁺ entry on reflow does not measurably alter bulk Na(i), it appears to enhance Na⁺/Ca²⁺ exchange and this can cause a transient increase in Ca(i) on reflow. Inhibitors of NHE are cardioprotective if administered before or during ischaemia. Addition of NHE inhibitors only at the start of reflow is less protective; this is attributed to either slow delivery of the inhibitor to the myocyte or to the need for combined inhibition of NHE during ischaemia as well as for reflow for optimal protection.