Comparison of the effects of Zopolrestat and Sorbinil on lens myo-inositol influx.

Abstract

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 normal (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 mumol/l) were determined on normal lens MI influx. At all concentrations, Sorbinil had no effect on normal MI influx; therefore, there was no direct effect on the MI transporter. Acute exposure (4-hour incubation) in either high D- or L-glucose 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 lenses. Thus, concomitant administration of Sorbinil (10, 20 and 40 mumol/l) had no significant effect on MI influx in this short-term experiment. Sorbinil had no effect in the presence of L-glucose because L-glucose was not metabolized; thus the polyol content remained normal. To investigate the effects of large accumulations of polyol, lenses were preincubated for 8, 12 and 16 h in 30 mmol/l galactose medium. Large amounts of polyol (galactitol) rapidly accumulated because galactitol was not metabolized. Galactose served as substrate for aldose reductase, and lens polyol (galactitol) content increased markedly. Inhibition of MI influx directly correlated with the increased lens polyol content. Lens polyol accumulation resulted in noncompetitive inhibition of MI influx. Coadministration of 40 mumol/l Sorbinil inhibited 80% of polyol formation and protected 80% of MI influx. Furthermore, in the presence of Sorbinil, lens galactose increased rapidly and equilibrated with galactose in the medium further indicating that Sorbinil inhibited aldose reductase. The effects of 40 mumol/l Sorbinil were compared to 40 mumol/l Zopolrestat. Zopolrestat was as effective as Sorbinil; both aldose reductase inhibitors maintained MI influx at approximately 80% of control values after 12- and 16-hour incubations in high galactose medium. In conclusion, Sorbinil did not exert a direct effect on the sodium-dependent, MI cotransport system or prevent the direct competitive inhibition of either D- or L-glucose. Sorbinil and Zopolrestat inhibited lens polyol formation, thereby eliminating noncompetitive inhibition of MI influx.