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(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

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