title: Na+-K+-ATPase pumping activity is not directly linked to myo-inositol levels after sorbinil treatment in lenses of diabetic rats.
abstract: Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular metabolite and enzyme-activity levels in the streptozocin-induced diabetic rat was examined to determine what, if any, relationship exists between these changes. Two weeks of untreated diabetes did not change ouabain-inhibitable ATPase enzyme activity assayed in lens homogenates but did result in a decrease in the Na+-K+-ATPase transport activity as measured by 86Rb uptake in the intact lens. This was accompanied by a 100-fold increase in the levels of sorbitol and significant decreases in the levels of myo-inositol, ATP, and glutathione in the lens. Whereas all of these changes could be reversed by sorbinil treatment, the dose required for restoration of the depleted myo-inositol level (ED50 greater than 20 mg.kg-1.day-1) was much higher than the dose required to reverse the other changes (ED50 range 2-5 mg.kg-1.day-1). These results suggest that the restoration of lenticular Na+ -K+ -ATPase activity is not secondary to a normalization of myo-inositol levels and may provide evidence that the two parameters are not strictly associated in diabetic tissues.
authors.affiliation: Department of Metabolic Diseases, Central Research Division, Pfizer Inc., Groton, CT 06340.
authors.forename: L A
authors.initials: LA
authors.lastname: Yeh
authors.forename: C E
authors.initials: CE
authors.lastname: Rafford
authors.forename: K J
authors.initials: KJ
authors.lastname: Goddu
authors.forename: M A
authors.initials: MA
authors.lastname: Ashton
authors.forename: T A
authors.initials: TA
authors.lastname: Beyer
authors.forename: N J
authors.initials: NJ
authors.lastname: Hutson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007294:Inositol / Q000378:metabolism*; D007700:Kinetics; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D048289:Imidazolidines; D007294:Inositol; D013012:Sorbitol; D010042:Ouabain; D000255:Adenosine Triphosphate; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil; D005978:Glutathione; D012413:Rubidium