Non-competitive inhibition of myo-inositol transport in cultured bovine retinal capillary pericytes by glucose and reversal by Sorbinil.
myo-Inositol transport by retinal capillary pericytes in culture was characterized. The major myo-inositol transport process was sodium-dependent, ouabain-sensitive, and saturable at 40 mM, indicating a carrier-mediated process. The sodium ion concentration required to produce one-half the maximal rate of myo-inositol uptake ([Na+]0.5) did not show dependence on the external myo-inositol concentration (22.3 mM sodium for 0.005 mM myo-inositol; 18.2 mM sodium for 0.05 mM myo-inositol). myo-Inositol transport was an energy-dependent, active process functioning against a myo-inositol concentration gradient. The kinetics of the sodium-dependent system fitted a 'velocity type' co-transport model where binding of sodium ion to the carrier increased the velocity (Vmax 28 to 313 pmol myo-inositol/micrograms DNA per 20 min when [Na+] varied from 9 to 150 mM) but not the affinity for myo-inositol (Km 0.92 to 0.83 mM when [Na+] varied from 9 to 150 mM). Metabolizable hexoses (D-glucose or D-galactose; greater than 5 mM) inhibited myo-inositol uptake. Dixon-plot analysis indicated that the inhibition was non-competitive with a Ki of 22.7 mM for D-glucose and 72.6 mM for D-galactose. The inhibition was significantly reversed by Sorbinil (0.1 mM), an aldose reductase inhibitor. In contrast, high concentrations of non-metabolizable hexoses (L-glucose, 3-O-methyl-D-glucose), or partially metabolizable 2-deoxy-D-glucose, did not significantly inhibit myo-inositol uptake. The inhibitory effect of D-glucose or D-galactose on myo-inositol transport appeared to be related to glucose or galactose metabolism via the polyol pathway.
D019325:3-O-Methylglucose; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002196:Capillaries / Q000166:cytology* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000494:pharmacology; D005690:Galactose / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006601:Hexoses / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism*; D007700:Kinetics; D008345:Manganese / Q000494:pharmacology; D008757:Methylglucosides / Q000494:pharmacology; D012160:Retina / Q000098:blood supply*
D006601:Hexoses; D007093:Imidazoles; D048289:Imidazolidines; D008757:Methylglucosides; D019325:3-O-Methylglucose; D008345:Manganese; D007294:Inositol; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000449:Aldehyde Reductase; C026411:sorbinil; D005947:Glucose; D002118:Calcium; D005690:Galactose