Direct Stimulation of Na⁺-K⁺-ATPase and Its Glucosylated Derivative By Aldose Reductase Inhibitor

In the presence of 10⁻⁸ M concentrations of the aldose reductase inhibitor AL 1576, there is a 20-30% increase in the rate of hydrolysis of near-saturating concentrations of ATP by bovine renal Na⁺-K⁺-ATPase. When bovine renal Na+-K+-ATPase is reacted with glucose 6-phosphate in the presence of 10⁻⁸ M concentrations of AL 1576 or 10⁻⁶ M concentrations of a second aldose reductase inhibitor, sorbinil, glucosylation occurs. Whereas sorbinil has no effect on ATP hydrolysis by the glucosylated Na⁺-K⁺-ATPase, 10⁻⁸ M AL 1576 causes a shift in the kinetics of hydrolysis of ATP from substrate inhibition to normal substrate activation. The aldose reductase inhibitors interact with the enzyme at the low-affinity ATP-binding site.