Published online before print February 7, 2002, doi: 10.1161/01.RES.0000012582.11979.8B
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Submitted on July 27, 2001
Revised on January 29, 2002
Accepted on January 29, 2002
Inhibition of Nitrobenzylthioinosine-Sensitive Adenosine Transport by Elevated D-Glucose Involves Activation of P2Y2 Purinoceptors in Human Umbilical Vein Endothelial Cells
Jorge Parodi ;
From the Cellular and Molecular Physiology Laboratory, Department of Physiology (J.P., C.F., C.A., M.I.R., P.C., L.S.), the Department of Pharmacology (M.I.R.), Faculty of Biological Sciences, and the Department of Obstetrics and Gynecology (P.C.), Faculty of Medicine, University of Concepción, Concepción, Chile.
* To whom correspondence should be addressed. E-mail: lsobrev{at}udec.cl.
Chronic incubation with elevated D-glucose reduces adenosine transport in endothelial cells. In this study, exposure of human umbilical vein endothelial cells to 25 mmol/L D-glucose or 100 µmol/L ATP, ATP-
-S, or UTP, but not ADP or 
,ß-methylene ATP, reduced adenosine transport with no change in transport affinity. Inhibition of transport by D-glucose, ATP, and ATP--S was associated with reduced maximal binding, with no changes in the apparent dissociation constant for nitrobenzylthioinosine (NBMPR). A significant reduction (
60±10%, P<0.05; n=6) in the number of human equilibrative NBMPR-sensitive nucleoside transporters (hENT1s) per cell (1.8±0.1x106 in 5 mmol/L D-glucose) and in hENT1 mRNA levels was observed in cells exposed to D-glucose or ATP--S. Incubation with elevated D-glucose, but not with D-mannitol, increased the ATP release by 3±0.2-fold . The effects of D-glucose and nucleotides on the number and activity of hENT1 and hENT1 mRNA were blocked by reactive blue 2 (nonspecific P2Y purinoceptor antagonist), suramin (Gs protein inhibitor), or hexokinase but not by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (nonselective P2 purinoceptor antagonist). Our findings demonstrate that inhibition of adenosine transport via hENT1 in endothelial cells cultured in 25 mmol/L D-glucose could be due to stimulation of P2Y2 purinoceptors by ATP, which is released from these cells in response to D-glucose. This could be a mechanism to explain in part the vasodilatation observed in the early stages of diabetes mellitus or in response to D-glucose infusion.
Key words: endothelium • adenosine • nitric oxide • glucose • purinoceptors
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