Abstract
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.
Footnotes
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This work was supported by Deutsche Forschungsgemeinschaft Grants Ba 1870/3 (to S.B.) and Ru 1472/1-1 (to T.R.), Deutsche Herzstiftung (to S.B. and V.R.), and National Institutes of Health Grants HL58115 and HL 64937 (to B.F.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.142414.
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ABBREVIATIONS: MPO, myeloperoxidase; BAEC, bovine aortic endothelial cells; ESI-LC-MS, electrospray ionization liquid chromatography mass spectrometry; FMD, flow-mediated dilation; ANOVA, analysis of variant; IR, interquartile range; NO, nitric oxide, TMB, tetramethylbenzidine.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received June 16, 2008.
- Accepted August 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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