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+ exchan ger (NHE) and the Na+ channel to the rise in cytosolic Na+ concentration ([ Na+]) that is seen in anoxic guinea pig ventricular myocytes. [Na+] was mea sured 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-6 42, selective inhibitors of the Na+ channel and NHE1, respectively. [Na+] d id not significantly rise when both drugs were present, suggesting that oth er routes of Na+ entry were insignificant. However, the relative contributi ons 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 th e dominant Na+ source during acidic anoxia. However, the NHE was the domina nt Na+ source during both hyperkalemic anoxia and simulated ischemia (hyper kalemia, 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 a nd that inhibition of Naf influx could contribute strongly to the cardiopro tective effects of NHE inhibitors.