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(Circulation Research. 2005;96:189.)
© 2005 American Heart Association, Inc.

Cellular Biology

ADP Acting on P2Y₁₃ Receptors Is a Negative Feedback Pathway for ATP Release From Human Red Blood Cells

Lingwei Wang, Göran Olivecrona, Matthias Götberg, Martin L. Olsson, Maria Sörhede Winzell, David Erlinge

From the Department of Cardiology (L.W., G.O., M.G., D.E.), Transfusion Medicine (M.L.O.), and Cell and Molecular Biology (M.D.W.), Lund University Hospital, Lund, Sweden.

Correspondence to Dr David Erlinge, Department of Cardiology, Lund University Hospital, S-221 85 Lund, Sweden. E-mail david.erlinge{at}kard.lu.se

Red blood cells may regulate tissue circulation and O₂ delivery by releasing the vasodilator ATP in response to hypoxia. When released extracellularly, ATP is rapidly degraded to ADP in the circulation by ectonucleotidases. In this study, we show that ADP acting on P2Y₁₃ receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release. mRNA of the ADP receptor P2Y₁₃ was highly expressed in human red blood cells and reticulocytes. The stable ADP analogue 2-MeSADP decreased ATP release from red blood cells by inhibition of cAMP. The P2Y₁₂ and P2Y₁₃ receptor antagonist AR-C67085 (30 µmol/L), but not the P2Y₁ blocker MRS2179, inhibited the effects of 2-MeSADP. At doses where AR-C67085 only blocks P2Y₁₂ (100 nmol/L), it had no effect. AR-C67085 and the nucleotidase apyrase increased cAMP per se, indicating a constant cAMP inhibitory effect of endogenous extracellular ADP. 2-MeSADP reduced plasma ATP concentrations in an in vivo pig model. Our results indicate that the ATP degradation product ADP inhibits ATP release by acting on the red blood cell P2Y₁₃ receptor. This negative feedback system could be important in the control of plasma ATP levels and tissue circulation.

Key Words: ATP release • cAMP • P2 receptors • microdialysis • red blood cells

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