on May 29, 2008
Published online before print May 29, 2008, doi: 10.1161/ATVBAHA.108.169219
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Submitted on December 2, 2007
Accepted on May 17, 2008
Direct Treatment of Mouse or Human Blood With Soluble 5'-Nucleotidase Inhibits Platelet Aggregation
Melanie L. Hart ;
From the Department of Anesthesiology and Intensive Care Medicine (M.L.H., D. Köhler, H.K.E.) and the Department of Pharmacology and Toxicology (D. Köhler, D. Kloor), University of Tübingen, Germany; the Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine (M.L.H., G.L.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and Mucosal Inflammation Program, Department of Anesthesiology (T.E., H.K.E.), University of Colorado Health Science Center, Denver.
* To whom correspondence should be addressed. E-mail: holger.eltzschig{at}uchsc.edu.
Objective—Adenosine signaling is known to inhibit platelet aggregation. Extracellular adenosine mainly stems from enzymatic phosphohydrolysis of precursor nucleotides via ecto-5'-nucleotidase. Previous studies suggest that soluble 5'-nucleotidase (5'-NT) derived from Crotalus atrox venom may be clinically beneficial in vascular leakage, myocardial, renal, and intestinal ischemia, or acute lung injury. However, the effects of 5'-NT treatment on platelet aggregation remain unknown. We examined the direct effects of 5'-NT treatment on platelet aggregation in vivo and ex vivo using a whole blood aggregation method.
Methods and Results—Platelet aggregation in whole human blood was completely inhibited by 5'-NT. When 5'-[
-methylene] diphosphate (APCP), a specific 5'-ecto-nucleotidase inhibitor, was added together with 5'-NT, APCP fully restored collagen- or ADP-induced aggregation. Adenosine levels in whole blood were significantly increased after 5'-NT treatment compared to controls and inhibition of platelet aggregation by 5'-NT was completely reversed by pretreatment with the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline hydrate (8-SPT), suggesting that 5'-NT inhibits aggregation via increased adenosine signaling. Administration of 5'-NT to mice in vivo abolished ADP- and collagen-induced platelet aggregation and increased adenosine concentrations and tail bleeding time.
Conclusions—5'-NT treatment inhibits platelet aggregation via generation of increased levels of extracellular adenosine and subsequent adenosine receptor signaling.
Key words: 5'-nucleotidase • platelets • aggregation • thrombosis • adenosine
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