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1 Department of Pharmacology and Therapeutics, and 2 Endocrinology Section, Department of Internal Medicine, University of Manitoba, Winnipeg R3E OW3, Canada
We sought to determine the mechanisms for hyperactivity and abnormal platelet Ca2+ homeostasis in diabetes. The glycosylated Hb (HbA1c) level was used as an index of glycemic control. Human platelets were loaded with Ca- green-fura red, and cytosolic Ca2+ ([Ca2+]i) and aggregation were simultaneously measured. In the first series of experiments, the platelets from diabetic and normal subjects were compared for the ability to release Ca2+ or to promote Ca2+ influx. A potent and relatively specific inhibitor of Na+/Ca2+ exchange, 5-(4-chlorobenzyl)-2',4'-dimethylbenzamil (CB-DMB), increased the second phase of thrombin-induced Ca2+ response, suggesting that the Na+/Ca2+ exchanger works in the forward mode to mediate Ca2+ efflux. In contrast, in the platelets from diabetics, CB-DMB decreased the Ca2+ response, indicating that the Na+/Ca2+ exchanger works in the reverse mode to mediate Ca2+ influx. In the second series of experiments we evaluated the direct effect of hyperglycemia on platelets in vitro. We found that thrombin- and collagen-induced increases in [Ca2+]i and aggregation were not acutely affected by high glucose concentrations of 45 mM. However, when the platelet-rich plasma was incubated with a high glucose concentration at 37°C for 24 h, the second phase after thrombin activation was inhibited by CB-DMB. In addition, collagen-stimulated [Ca2+]i response and aggregation were also increased. Thus in diabetes the direction and activity of the Na+/Ca2+ exchanger is changed, which may be one of the mechanisms for the increased platelet [Ca2+]i and hyperactivity. Prolonged hyperglycemia in vitro can induce similar changes, suggesting hyperglycemia per se may be the factor responsible for the platelet hyperactivity in diabetes.
diabetic complications; Na+/Ca2+ exchanger; 5-(4-chlorobenzyl)-2',4'-dimethylbenzamil; hyperglycemia
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