Contribution of the Na⁺ channel and Na⁺/H⁺ exchanger to the anoxic rise of [Na⁺] in ventricular myocytes

The aim of this study was to quantify the contribution of the Na⁺/H⁺ exchanger (NHE) and the Na⁺ channel to the rise in cytosolic Na⁺ concentration ([Na⁺]) that is seen in anoxic guinea pig ventricular myocytes. [Na⁺] was measured with the use of microfluorometry and was found to rise to 44 mM after prolonged anoxia. This rise was partially sensitive to either TTX or HOE-642, selective inhibitors of the Na⁺ channel and NHE1, respectively. [Na⁺] did not significantly rise when both drugs were present, suggesting that other routes of Na⁺ entry were insignificant. However, the relative contributions of the NHE and the Na⁺ channel were found to be remarkably sensitive to ionic conditions expected to occur during ischemia. The Na⁺ channel was the dominant Na⁺ source during acidic anoxia. However, the NHE was the dominant Na⁺ source during both hyperkalemic anoxia and simulated ischemia (hyperkalemia, low pH, and anoxia). The data suggest that the NHE may prove to be the best pharmacological target to reduce Na⁺ entry during true ischemia and that inhibition of Na⁺ influx could contribute strongly to the cardioprotective effects of NHE inhibitors.