Published Online
on September 27, 2004

A more recent version of this article appeared on October 5, 2004

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Submitted on April 22, 2004
Revised on June 16, 2004
Accepted on July 7, 2004

Selective Inhibition of Cyclooxygenase-2 Enhances Platelet Adhesion in Hamster Arterioles In Vivo

Martin A. Buerkle MD, Selim Lehrer MS, Hae-Young Sohn MD, Peter Conzen MD, Ulrich Pohl MD, and Florian Krötz MD^*

From the Institute of Physiology (M.A.B., S.L., U.P., F.K.), the Clinic of Anaesthesiology (M.A.B., P.C.), and the Department of Cardiology (H.-Y.S., F.K.), Medizinische Poliklinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany.

^* To whom correspondence should be addressed. E-mail: fkroetz{at}lmu.de.

Background--Selective inhibitors of cyclooxygenase-2 (Cox-2) are reported to cause cardiovascular side effects in patients at risk. However, direct proof of prothrombotic effects of these drugs is lacking. We investigated in the microcirculation in vivo whether selective inhibition of Cox-2 induces platelet activation.

Methods and Results--The behavior of fluorescence-labeled human platelets was studied in hamster arterioles (dorsal skinfold chamber) by intravital microscopy. Transient platelet-vessel wall interactions (PVWIs), firm platelet adhesion to the vessel wall, and vessel occlusion after FeCl₃-induced wall injury were analyzed as platelet activation parameters. In vitro experiments in human umbilical vein endothelial cells (HUVECs) were performed to assess specific effects of Cox-2 inhibition on platelet adhesion under shear stress (16 dyn/cm²) and on endothelial release of 6-ketoprostaglandin (PG) F₁. Selective inhibition of Cox-2 (NS-398, 0.5 mg/kg) increased platelet adhesion to the vessel wall in vivo (11.9±3.9 platelets/mm²; controls, 1.4±1.4 platelets/mm², P<0.05) and platelet adhesion after ADP stimulation in vitro. PVWIs were significantly enhanced in NS-398-treated animals, which were reduced by platelet pretreatment with aspirin (5 mg/kg) or iloprost (1 nmol/L). Inhibition of Cox-2 reduced levels of 6-keto-PGF₁ in vivo and in HUVEC supernatants. Time to occlusion after vessel wall injury was significantly shortened by NS-398 (125.4±13.6 seconds in NS-398-treated animals versus 270.8±46 seconds in controls; P<0.01).

Conclusions--Selective inhibition of Cox-2 reduces 6-keto-PGF₁ endothelial release, increases PVWIs, and increases firm platelet adhesion in hamster arterioles. Moreover, it leads to faster occlusion of damaged microvessels. Thus, selective inhibition of Cox-2 may trigger thrombotic events by diminishing the antiplatelet properties of the endothelium.

Key words: aspirin • prostaglandins • platelets • thrombosis • endothelium

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