COMPARISON OF THE EFFECTS OF ZOPOLRESTAT AND SORBINIL ON LENS MYOINOSITOL INFLUX

The effects of two structurally dissimilar aldose reductase inhibitors , Zopolrestat and Sorbinil, were investigated on the sodium-dependent, myo-inositol (MI) cotransporter in rat lenses maintained in either no rmal (5.5 mmol/l) or high sugar medium (35.5 mmol/l glucose or 30 mmol /l galactose). MI influx was compared to the lens polyol content. The effects of Sorbinil (10, 20 and 40 mu mol/l) were determined on normal lens MI influx. At all concentrations, Sorbinil had no effect on norm al MI influx; therefore, there was no direct effect on the MI transpor ter. Acute exposure (4-hour incubation) in either high D- or Lglucose media significantly inhibited lens MI influx, which was attributed to competitive inhibition by either D- or L-glucose with MI cotransporter . Due to the short incubation period and rapid metabolism of D-glucose to fructose, there was a low level of polyol (sorbitol) in these lens es. Thus, concomitant administration of Sorbinil (10, 20 and 40 mu mol /l) had no significant effect on MI influx in this short-term experime nt. Sorbinil had no effect in the presence of L-glucose because L-gluc ose was not metabolized; thus the polyol content remained normal. To i nvestigate the effects of large accumulations of polyol, lenses were p reincubated for 8, 12 and 16 h in 30 mmol/l galactose medium. Large am ounts of polyol (galaclitol) rapidly accumulated because galactitol wa s not metabolized. Galactose served as substrate for aldose reductase, and lens polyol (galactitol) content increased markedly. Inhibition o f MI influx directly correlated with the increased lens polyol content . Lens polyol accumulation resulted in noncompetitive inhibition of MI influx. Coadministration of 40 mu mol/l Sorbinil inhibited 80% of pol yol formation and protected 80% of MI influx. Furthermore, in the pres ence of Sorbinil, lens galactose increased rapidly and equilibrated wi th galactose in the medium further indicating that Sorbinil inhibited aldose reductase. The effects of 40 mu mol/l Sorbinil were compared to 40 mu mol/l Zopolrestat. Zopolrestat was as effective as Sorbinil; bo th aldose reductase inhibitors maintained MI influx at approximately 8 0% of control values after 12- and 16-hour incubations in high galacto se medium. In conclusion, Sorbinil did not exert a direct effect on th e sodium-dependent, MI cotransport system or prevent the direct compet itive inhibition of either D- or L-glucose. Sorbinil and Zopolrestat i nhibited lens polyol formation, thereby eliminating noncompetitive inh ibition of MI influx.