Published online before print May 29, 2008, doi: 10.1161/ATVBAHA.108.169219
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Direct Treatment of Mouse or Human Blood With Soluble 5'-Nucleotidase Inhibits Platelet Aggregation
From the Department of Anesthesiology and Intensive Care Medicine (M.L.H., D. Köhler, T.E., H.K.E.) and the Department of Pharmacology and Toxicology (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.
Correspondence to Dr Holger K. Eltzschig, Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Biochemistry Research Building, Room 852, 4200 E 9th Ave, Mailstop B112, Denver, CO 80262. 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'-[
β-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.
Previous studies suggest 5'-NT may be clinically beneficial. We demonstrated that 5'-NT treatment inhibits platelet aggregation via increasing adenosine through adenosine receptor signaling. 5'-NT may be an additional therapeutic for treatment of excessive aggregation or thrombosis.
Key Words: 5'-nucleotidase • platelets • aggregation • thrombosis • adenosine
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