Sodium regulation during ischemia versus reperfusion and its role in injury.

There are considerable data to support the general hypothesis that accumulation of [Na]i during ischemia and early reperfusion leads, via Na/Ca exchange, to elevated [Ca]i, resulting in myocardial damage.1–10 Despite the strong support for the general aspects of this hypothesis, there is controversy regarding some details that have important implications for the design of therapeutic interventions. The relative importance of the increase in [Na]i during ischemia versus the increase in [Na]i during reperfusion in contributing to the rise in [Ca]i and resultant injury is debated. These issues are important because it has been suggested that inhibition of the Na/H exchanger (NHE) during reperfusion alone would be beneficial. This would allow clinical intervention after an ischemic episode. It is also important to understand why an increase in [Na]i is detrimental. It is commonly assumed that [Na]i is detrimental because it leads to increased [Ca]i during reperfusion, either due to diminished Ca efflux via Na/Ca exchange or due to increased Ca influx due to reverse Na/Ca exchange. Recent data presented by Cross et al9 suggest that reverse Na/Ca exchange is involved in postischemic contractile dysfunction. However, an increase in [Na]i could also be detrimental because of effects on K loss11 or energetics. An understanding of the mechanism responsible for the detrimental effects of Na accumulation is important for the design of therapeutic interventions. A study12 published in this issue of Circulation Research adds new insight into these important issues.