The effect of clonidine, an α2-adrenergic receptor agonist, on the Na+-H+ exchanger in human placental brush-border membrane vesicles was examined. The exchanger was inhibited by clonidine. The inhibition was freely reversible, and the apparent inhibition constant for the process was 250 μM. The nature of inhibition was found to be competitive with respect to Na+. The Dixon plot ( solI v versus clonidine concentration) was linear (r2 = 0.998), indicating the interaction of the drug with a single site on the exchanger protein. Similar kinetic analyses with amiloride, a potassium-sparing diuretic, and cimetidine, a histamine type II receptor antagonist, revealed that these drugs also inhibited the Na+-H+ exchanger by interacting with a single site on the protein. The presence of clonidine increased the intercepts without affecting the slopes of the l v versus amiloride concentration and the l v versus cimetidine concentration plots. These results demonstrate that all three drugs, amiloride, cimetidine and clonidine, interact with the human placental Na+-H+ exchanger at a single site in a mutually exclusive manner, and the site of interaction is identical with the Na+-binding site on the external surface of the exchanger protein.
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