This Article Full Text Full Text (PDF) All Versions of this Article: 26/7/1648    most recent 01.ATV.0000225288.74170.dcv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heitzer, T. Articles by Baldus, S. Search for Related Content PubMed PubMed Citation Articles by Heitzer, T. Articles by Baldus, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID NITRIC OXIDE Medline Plus Health Information Antioxidants Coronary Artery Disease

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1648.)
© 2006 American Heart Association, Inc.

Thrombosis

Clopidogrel Improves Systemic Endothelial Nitric Oxide Bioavailability in Patients With Coronary Artery Disease

Evidence for Antioxidant and Antiinflammatory Effects

Thomas Heitzer; Volker Rudolph; Edzard Schwedhelm; Manuela Karstens; Karsten Sydow; Michelle Ortak; Peter Tschentscher; Thomas Meinertz; Rainer Böger; Stephan Baldus

From the Universitäres Herzzentrum Hamburg (T.H., V.R., M.K., K.S., M.O., T.M., S.B.), Institut für Experimentelle und Klinische Pharmakologie (E.S., R.B.), Institut für Klinische Chemie (P.T.), Universitätsklinikum Hamburg-Eppendorf, Germany.

Correspondence to Thomas Heitzer, Universitäres Herzzentrum Hamburg, Medizinische Klinik III, Abteilung Kardiologie und Angiologie, Martinistrasse 5220246 Hamburg, Germany. E-mail heitzer{at}uke.uni-hamburg.de

Background— Platelet stimulation and activation are known not only as prerequisite of clot formation but are increasingly recognized as important contributors to inflammation and vascular injury. The present study in patients with symptomatic coronary disease investigated whether platelet adenosine diphosphate receptor blockade by clopidogrel exerts beneficial effects on endothelial nitric oxide bioavailability, oxidative stress, and/or inflammatory status.

Methods and Results— One hundred three consecutive patients with symptomatic coronary disease and long-term aspirin therapy were studied. Endothelium-dependent and -independent vasodilation was determined measuring forearm blood flow (FBF)-responses to acetylcholine with and without N^G-monomethyl-L-arginin (L-NMMA) and sodium nitroprusside, by using venous occlusion plethysmography. Patients were randomized to receive additional treatment with clopidogrel or placebo. Vascular function tests were repeated after 5 weeks and showed significant improvement of acetylcholine-induced vasodilatation and L-NMMA responses in the clopidogrel-added group (max. FBF from 9.8±0.3 to 14.7±0.4; L-NMMA-response from 3.7±0.1 to 6.8±0.3 mL/100 mL/min). In contrast, no significant changes were observed in the placebo group. Sodium nitroprusside–induced vasodilation was not changed in either group. Urinary excretion of 8-iso-prostaglandin F2 and plasma levels of hsCRP, sCD40L, and RANTES were reduced in patients on additional treatment with clopidogrel, but not in patients on placebo.

Conclusions— Clopidogrel improves endothelial nitric oxide bioavailability and diminishes biomarkers of oxidant stress and inflammation in patients with symptomatic coronary artery disease, suggesting that beyond inhibition of platelet aggregation, adenosine phosphate receptor blockade may also have promising vasoprotective effects.

Platelet adenosine phosphate receptor blockade by clopidogrel improved endothelium-dependent vasodilation to acetylcholine and vascular bioavailability of nitric oxide in the human forearm of patients with symptomatic coronary artery disease. In addition, inflammatory parameters, ie, hsCRP, sCD40L, and RANTES and oxidative parameters, ie, 8-iso-PG F₂ were reduced. These findings support the concept that activated platelets contribute to endothelial dysfunction and impaired nitric oxide bioavailability.

Key Words: clopidogrel • endothelial function • nitric oxide • platelets • coronary artery disease

This article has been cited by other articles:

				K. Y. Stokes, L. Calahan, C. M. Hamric, J. M. Russell, and D. N. Granger CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H689 - H697. [Abstract] [Full Text] [PDF]

				V. Rudolph, T. K. Rudolph, F. J. Schopfer, G. Bonacci, D. Lau, K. Szocs, A. Klinke, T. Meinertz, B. A. Freeman, and S. Baldus Bivalirudin Decreases NO Bioavailability by Vascular Immobilization of Myeloperoxidase J. Pharmacol. Exp. Ther., November 1, 2008; 327(2): 324 - 331. [Abstract] [Full Text] [PDF]

				M. O'Donoghue, D. A. Morrow, C. P. Cannon, W. Guo, S. A. Murphy, C. M. Gibson, and M. S. Sabatine Association between baseline neutrophil count, clopidogrel therapy, and clinical and angiographic outcomes in patients with ST-elevation myocardial infarction receiving fibrinolytic therapy Eur. Heart J., April 2, 2008; 29(8): 984 - 991. [Abstract] [Full Text] [PDF]

				M. I. Worthley, R. S. Kanani, Y.-H. Sun, Y. Sun, D. M. Goodhart, M. J. Curtis, and T. J. Anderson Effects of tetrahydrobiopterin on coronary vascular reactivity in atherosclerotic human coronary arteries Cardiovasc Res, December 1, 2007; 76(3): 539 - 546. [Abstract] [Full Text] [PDF]

				B. Hocher, L. Liefeldt, T. Quaschning, P. Kalk, R. Ziebig, M. Godes, K. Relle, G. Asmus, and J.-P. Stasch Soluble CD154 Is a Unique Predictor of Nonfatal and Fatal Atherothrombotic Events in Patients Who Have End-Stage Renal Disease and Are on Hemodialysis J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1323 - 1330. [Abstract] [Full Text] [PDF]