The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH.

This paper describes the properties of the amiloride-sensitive Na+/H+ antiporter in chick cardiac cells, compares them with those known in other cellular systems and analyzes the role of the Na+/H+ exchanger in the regulation of internal Na+ concentrations and internal pH. Among the different properties which have been studied one can mention: (i) The external Na+ concentration [( Na+]o) dependence: the activity increases when [Na+]o increases (KNa+ = 20 mM); (ii) The external pH (pHo) dependence: the activity of the exchanger increases when pHo increases (pHmo = 7.05 and Hill coefficient = 1); (iii) The internal pH (pHi) dependence; the activity of the exchanger increases in a cooperative way when internal pH (pHi) decreases (pHmi = 7.35 and Hill coefficient = 3); (iv) There are derivatives of amiloride which are 200 times more potent than amiloride itself (Kethylisopropylamiloride = 30 nM) and which are selective on the Na+/H+ exchange system v. other Na+ transporting system including the Na+/Ca2+ exchange system. Under physiological conditions, the Na+/H+ exchange system contributes little to the regulation of the internal pH of chick cardiac cells. The antiporter then serves as an uptake system for Na+ using the H+ gradient created by other pHi regulatory mechanisms. Treatment of cardiac cells with ouabain inhibits Na+ efflux and produced an increase in intracellular Na+ activity. Ethylisopropylamiloride was used to show that the Na+/H+ exchange system is the main pathway for Na+ entry and accumulation in digitalis action. As expected amiloride derivatives which block Na+ entry via the Na+/H+ antiporter were found to antagonize ouabain action on cardiac cells. When the internal pH of cardiac cells is lowered, the Na+/H+ exchanger becomes the major pHi regulating system. It is the essential system by which cardiac cells recover from cellular acidosis. The situation is due both to an increased activity of the exchanger at acidic pHi and to a decreased activity of other pHi regulatory systems. We propose in this paper that the Na+/H+ exchange system plays a key role in Na+ accumulation followed by Ca2+ accumulation which is observed when ischemic hearts are reperfused.