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Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase

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Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase. / Rudolph, Volker; Rudolph, Tanja K; Schopfer, Francisco J; Bonacci, Gustavo; Lau, Denise; Szöcs, Katalin; Klinke, Anna; Meinertz, Thomas; Freeman, Bruce A; Baldus, Stephan.

In: The Journal of pharmacology and experimental therapeutics, Vol. 327, No. 2, 11.2008, p. 324-331.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rudolph, V, Rudolph, TK, Schopfer, FJ, Bonacci, G, Lau, D, Szöcs, K, Klinke, A, Meinertz, T, Freeman, BA & Baldus, S 2008, 'Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase', The Journal of pharmacology and experimental therapeutics, vol. 327, no. 2, pp. 324-331. https://doi.org/10.1124/jpet.108.142414

APA

Rudolph, V., Rudolph, T. K., Schopfer, F. J., Bonacci, G., Lau, D., Szöcs, K., Klinke, A., Meinertz, T., Freeman, B. A., & Baldus, S. (2008). Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase. The Journal of pharmacology and experimental therapeutics, 327(2), 324-331. https://doi.org/10.1124/jpet.108.142414

Vancouver

Rudolph V, Rudolph TK, Schopfer FJ, Bonacci G, Lau D, Szöcs K et al. Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase. The Journal of pharmacology and experimental therapeutics. 2008 Nov;327(2):324-331. https://doi.org/10.1124/jpet.108.142414

Bibtex

@article{f5aee3a6ed8a42419ea9971004d8f80f,
title = "Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase",
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.",
keywords = "Aged, Animals, Antithrombins/pharmacology, Biological Availability, Cattle, Female, Fluorescent Antibody Technique, Hirudins/metabolism, Humans, Male, Methylation, Middle Aged, Nitric Oxide/metabolism, Peptide Fragments/metabolism, Peroxidase/blood, Recombinant Proteins/metabolism, Spectrometry, Mass, Electrospray Ionization, Tyrosine/analogs & derivatives, Vasodilation",
author = "Volker Rudolph and Rudolph, {Tanja K} and Schopfer, {Francisco J} and Gustavo Bonacci and Denise Lau and Katalin Sz{\"o}cs and Anna Klinke and Thomas Meinertz and Freeman, {Bruce A} and Stephan Baldus",
year = "2008",
month = nov,
doi = "10.1124/jpet.108.142414",
language = "English",
volume = "327",
pages = "324--331",
journal = "J PHARMACOL EXP THER",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

RIS

TY - JOUR

T1 - Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase

AU - Rudolph, Volker

AU - Rudolph, Tanja K

AU - Schopfer, Francisco J

AU - Bonacci, Gustavo

AU - Lau, Denise

AU - Szöcs, Katalin

AU - Klinke, Anna

AU - Meinertz, Thomas

AU - Freeman, Bruce A

AU - Baldus, Stephan

PY - 2008/11

Y1 - 2008/11

N2 - 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.

AB - 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.

KW - Aged

KW - Animals

KW - Antithrombins/pharmacology

KW - Biological Availability

KW - Cattle

KW - Female

KW - Fluorescent Antibody Technique

KW - Hirudins/metabolism

KW - Humans

KW - Male

KW - Methylation

KW - Middle Aged

KW - Nitric Oxide/metabolism

KW - Peptide Fragments/metabolism

KW - Peroxidase/blood

KW - Recombinant Proteins/metabolism

KW - Spectrometry, Mass, Electrospray Ionization

KW - Tyrosine/analogs & derivatives

KW - Vasodilation

U2 - 10.1124/jpet.108.142414

DO - 10.1124/jpet.108.142414

M3 - SCORING: Journal article

C2 - 18701766

VL - 327

SP - 324

EP - 331

JO - J PHARMACOL EXP THER

JF - J PHARMACOL EXP THER

SN - 0022-3565

IS - 2

ER -