Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase.
Bivalirudin, a direct thrombin inhibitor, has emerged as an important alternative to heparin in patients undergoing percutaneous coronary intervention. However, it remains elusive if potentially adverse extracoagulant properties are responsible for the fact that its favorable effects in clinical studies are mainly driven by a reduction in bleeding events. The aim of the current study was to determine the effects and mechanisms of acute treatment with bivalirudin in comparison to heparin on NO bioavailability, an important factor for the pathogenesis of ischemic events. In particular, we studied the interaction between bivalirudin and myeloperoxidase (MPO), a leukocyte-derived enzyme that consumes endothelial-derived nitric oxide (NO), modifies a variety of biological targets, and thus affects the integrity of the vessel wall. In patients undergoing elective percutaneous coronary intervention, bivalirudin, in contrast to heparin, exhibited a significant decrease in plasma MPO levels (p = 0.03) accompanied by a deterioration of flow-mediated dilation (p = 0.02), a surrogate for endothelial NO bioavailability. In vitro experiments revealed avid binding of bivalirudin to both bovine aortic endothelial cells (BAEC) and MPO. Methylation of bivalirudin carboxyl groups at the carboxyl-terminal end revealed the specific binding site of bivalirudin to MPO. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications. These results illustrate dichotomous extracoagulant properties of heparins and thrombin inhibitors and suggest that bivalirudin acutely impairs endothelial NO bioavailability, thereby underscoring the potentially critical role of MPO as a mediator of vascular function.
Rudolph
Volker
V
University Hospital Hamburg-Eppendorf, Heart Center, Department of Cardiology and Angiology, Martinistrasse 52, 20246 Hamburg, Germany. v.rudolph@uke.unihamburg.de
Rudolph
Tanja K
TK
Schopfer
Francisco J
FJ
Bonacci
Gustavo
G
Lau
Denise
D
Szöcs
Katalin
K
Klinke
Anna
A
Meinertz
Thomas
T
Freeman
Bruce A
BA
Baldus
Stephan
S
D000368:Aged; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001682:Biological Availability; D002417:Cattle; D005260:Female; D005455:Fluorescent Antibody Technique; D006629:Hirudins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D009195:Peroxidase / Q000097:blood / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014664:Vasodilation
D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; C074619:bivalirudin