Elevated extracellular glucose inhibits an adenosine-(Na+,K+)-ATPase regulatory system in rabbit aortic wall.
The mechanism by which hyperglycaemia causes decreased (Na+,K+)-ATPase activity preventable by aldose reductase inhibitors and by raising plasma myo-inositol in specific tissues can be activated in vitro in normal rabbit aortic wall; it selectively inhibits a component of resting (Na+,K+)-ATPase activity maintained by a novel regulatory system through rapid basal phosphatidylinositol turnover (hydrolysis) in a discrete pool, which is replenished by a fraction of phosphatidylinositol synthesis that selectively requires myo-inositol transport. A role for endogenously released adenosine in this regulatory system was examined. Adding adenosine deaminase or 8-phenyltheophylline, an adenosine receptor antagonist, selectively inhibited the component of (Na+,K+)-ATPase activity maintained by the regulatory system; when inhibited with adenosine deaminase this component was restored by 2-chloroadenosine, 5'-N-ethylcarbox-amidoadenosine, and 1-oleoyl-2-acetylglycerol, but not by forskolin (which also did not inhibit this component). Adenosine deaminase inhibited the rapid basal turnover of the discrete phosphatidylinositol pool, and 2-chloroadenosine then stimulated its turnover. Raising medium glucose from 5 to 10-30 mmol/l inhibits the regulatory system by making myo-inositol transport at a normal plasma level inadequate to maintain the replenishment of the discrete phosphatidylinositol pool. 2-Chloroadenosine stimulation of the "adenosine-sensitive" component of (Na+,K+)-ATPase activity was inhibited in tissue incubated with 30 mmol/l glucose and myo-inositol in a normal plasma level, but this effect was demonstrable when the medium myo-inositol was raised seven-fold. Hyperglycaemia-induced decreased (Na+,K+)-ATPase activity that is preventable by aldose reductase inhibitors and by raising plasma myo-inositol results from the inhibition of a novel adenosine-(Na+,K+)-ATPase regulatory system.
Simmons
D A
DA
Cox Institute, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia.
Winegrad
A I
AI
D015762:2-Chloroadenosine / Q000494:pharmacology*; D000241:Adenosine / Q000502:physiology*; D000243:Adenosine Deaminase / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000201:enzymology*; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D005990:Glycerol / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007294:Inositol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D012413:Rubidium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
D004075:Diglycerides; D010716:Phosphatidylinositols; D015762:2-Chloroadenosine; D005576:Colforsin; D007294:Inositol; C038237:1-oleoyl-2-acetylglycerol; D013806:Theophylline; C028322:8-phenyltheophylline; D000243:Adenosine Deaminase; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D000241:Adenosine; D012413:Rubidium; D005990:Glycerol; D011188:Potassium