A Model of Na+/H+ Exchanger and Its Central Role in Regulation of pH and Na+ in Cardiac Myocytes

A new kinetic model of the Na+/H+ exchanger (NHE) was developed by fitting a variety of major experimental findings, such as ion-dependencies, forward/reverse mode, and the turnover rate. The role of NHE in ion homeostasis was examined by implementing the NHE model in a minimum cell model including intracellular pH buffer, Na+/K+ pump, background H+, and Na+ fluxes. This minimum cell model was validated by reconstructing recovery of pHi from acidification, accompanying transient increase in [Na+]i due to NHE activity. Based on this cell model, steady-state relationships among pHi, [Na+]I, and [Ca2+]i were quantitatively determined, and thereby the critical level of acidosis for cell survival was predicted. The acidification reported during partial blockade of the Na+/K+ pump was not attributed to a dissipation of the Na+ gradient across the membrane, but to an increase in indirect H+ production. This NHE model, though not adapted to the dimeric behavioral aspects of NHE, can provide a strong clue to quantitative prediction of degree of acidification and accompanying disturbance of ion homeostasis under various pathophysiological conditions.