Adenosine triphosphatase activity in sciatic nerve tissue of streptozocin-induced diabetic rats with and without high dietary sucrose: effect of aldose reductase inhibitors.
The ability of aldose reductase inhibitors to prevent the decline in neural Na+,K(+)-ATPase activity in diabetic rats has not been confirmed by all laboratories. In this study, the efficacy of two structurally different aldose reductase inhibitors was evaluated under different experimental conditions. Na+,K(+)-ATPase activity was measured in sciatic nerves from streptozocin-induced diabetic rats fed normal rodent chow or a chow supplemented with 68% sucrose. Nerve homogenates from chow-fed rats were prepared with a Dounce tissue grinder, whereas homogenates from the sucrose-fed rats were prepared with an Ultra-Turrax disperser. In the chow-fed rats, 4 weeks of untreated diabetes resulted in an increase in neural sorbitol and fructose, a decrease in myoinositol, and a 54% decline in Na+,K(+)-ATPase activity. Sorbinil administration (20 mg/kg/day) completely prevented the rise in sorbitol and fructose and the depletion of myoinositol, but did not prevent the decline in Na+,K(+)-ATPase activity. In diabetic rats fed the sucrose diet for 4, 6, and 8 weeks, the neural sorbitol and fructose levels were elevated, the myoinositol concentration declined, and the Na+,K(+)-ATPase activity was 26 to 28% below the control. Prevention or intervention treatment with sorbinil (20 mg/kg/day) or tolrestat (50 mg/kg/day) for 4 to 6 weeks prevented the alterations in sorbitol, fructose, and myoinositol, and also prevented the decline in Na+,K(+)-ATPase activity. In conclusion, prevention and intervention therapy with aldose reductase inhibitors prevented the decline in Na+,K(+)-ATPase in sciatic nerves of sucrose-fed streptozocin-diabetic rats that were homogenized with an Ultra-Turrax disperser, but not in sciatic nerves from streptozocin-diabetic rats fed normal rodent chow that were homogenized with a Dounce tissue grinder. These findings indicate that the assessment of aldose reductase inhibitor efficacy is dramatically affected by the type of nerve preparation assayed and/or the diet.
Sredy
J
J
Experimental Therapeutics Department, Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Flam
B R
BR
Sawicki
D R
DR
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D005632:Fructose / Q000032:analysis; D005947:Glucose / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007294:Inositol / Q000032:analysis; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000737:chemistry / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000378:metabolism*; D013012:Sorbitol / Q000032:analysis; D013395:Sucrose / Q000008:administration & dosage*
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D007093:Imidazoles; D048289:Imidazolidines; D009281:Naphthalenes; C040550:tolrestat; D005632:Fructose; D007294:Inositol; D013012:Sorbitol; D013395:Sucrose; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil; D005947:Glucose