Inhibition of human placental Na+-H+ exchanger by cimetidine.

The Na+-H+ exchanger of human placental brush-border membrane was strongly inhibited by cimetidine, a histamine type II receptor antagonist. The inhibition was freely reversible and the apparent inhibition constant for the process was 38 microM. The nature of inhibition was found to be competitive with respect to Na+. Cimetidine inhibition was specific as other related compounds had no inhibitory effect. Treatment of the membrane vesicles with diethylpyrocarbonate inactivated the exchanger, but the presence of cimetidine during the treatment provided complete protection from this inhibition. These results show that histidine residues are located at the external Na+-binding site of the exchanger and cimetidine interacts with this site. The Na+-H+ exchanger of rabbit renal brush-border membrane was also susceptible to inhibition by the drug. However, transport of proline and glucose in placental brush-border membrane vesicles was not affected by cimetidine. The placental Na+-H+ exchanger was also inhibited by amiloride and the inhibition was freely reversible and competitive with respect to Na+. These results show that the characteristics of the inhibition of Na+-H+ exchanger by cimetidine and amiloride are very similar.