Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits.
Hyperglycaemia decreases (Na+, K+)-ATPase activity in specific tissues by a mechanism whose effects are prevented by aldose reductase inhibitors and by raising plasma myo-inositol. This mechanism was activated and studied in vitro in normal rabbit aortic intima-media. Raising medium glucose to 10 mmol/l for 60 min inhibited a major component of (Na+, K+)-ATPase-mediated 86Rb+/K+ uptake normally operative in resting aortic intima-media in medium containing normal plasma levels of glucose (5 mmol/l) and myo-inositol (70 mumol/l); 20 or 30 mmol/l glucose had no greater effect. This effect occurred under conditions in which the aortic intima-media's normal myo-inositol content is not detectably decreased. The inhibition was prevented by sorbinil (10 mumol/l) and by raising medium myo-inositol from 70 to 500 mumol/l, which had no effect on (Na+, K+)-ATPase activity when the medium glucose remained at 5 mmol/l. Raising medium glucose selectively inhibited a component of (Na+, K+)-ATPase activity that requires medium myo-inositol, because it is maintained by a regulatory system through rapid basal phosphatidylinositol turnover in a discrete pool, which is replenished by a fraction of basal de novo phosphatidylinositol synthesis that is selectively dependent on myo-inositol uptake. Medium myo-inositol at a normal plasma level became inadequate to maintain this fraction of basal de novo phosphatidylinositol synthesis [( 1,3-14C]glycerol incorporation) when the medium glucose was raised. When sorbinil was added raising medium glucose did not alter the ability of 70 mumol/l medium myoinositol to maintain the (Na+, K+)-ATPase activity that requires medium myo-inositol.(ABSTRACT TRUNCATED AT 250 WORDS)
Simmons
D A
DA
Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia.
Winegrad
A I
AI
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D007294:Inositol; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil