Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits

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Abstract
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 μmol/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 μmol/l) and by raising medium myo-inositol from 70 to 500 μmol/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 umol/l medium myoinositol to maintain the (Na+, K+)-ATPase activity that requires medium myo-inositol. The inhibition caused by raising medium glucose was reproduced by a competitive inhibitor of active myo-inositol transport, scyllo-inositol (500 μmol/l). The effect of medium glucose in an elevated plasma level on (Na+, K+)-ATPase activity in aortic intima-media appears to result from increased polyol pathway activity that makes myoinositol uptake at a normal plasma level inadequate to maintain the normal operation of a regulatory system.

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