The interaction of amiloride analogues with the Na+/H+ exchanger in kidney medulla microsomes.

The effects of ten amiloride analogues on Na+-H+ exchange in rabbit kidney medulla microsomes have been examined. Most of the analogues appeared to inhibit Na+ uptake into the microsomes more effectively than did amiloride either in the presence or absence of a pH gradient. However, the analogues were also capable of stimulating Na+ efflux from the microsomes at concentrations somewhat higher than the concentrations at which they inhibited Na+ influx. The concentrations at which the analogues stimulated Na+ efflux were about 2-4-times higher than the concentrations at which they blocked influx. This suggested that the two processes were related. The analogues that stimulated efflux most effectively (the 5-N-benzyl-amino analogue of amiloride and the 5-N-butyl-N-methylamino analogue) were shown to induce completely reversible effects. These analogues did not stimulate L-[3H]glucose efflux from medulla microsomes which ruled out nonspecific vesicle destruction or reversible detergent effects. These analogues also induced Na+ efflux from microsomes in the presence of high concentrations of added buffer, which ruled out weak-base uncoupling effects. The possibility exists that these analogues are carried into the microsomes via the Na+-H+ exchange protein and that this permits them to both block Na+ influx into the microsomes and stimulate Na+ efflux as well.