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Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events

Jane A. Mitchell^*, Ruth Lucas^*, Ivana Vojnovic, Kamrul Hasan^*, John R. Pepper^* and Timothy D. Warner^,1

^* Cardiothoracic Pharmacology, Unit of Critical Care Medicine, Royal Brompton Hospital, Imperial College School of Medicine, London, UK; and

The William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, London, UK

¹Correspondence: The William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail: t.d.warner{at}qmul.ac.uk or j.a.mitchell{at}imperial.ac.uk

Recent data have suggested that regular consumption of nonsteroid anti-inflammatory drugs (NSAIDs), particularly selective inhibitors of cyclo-oxygenase-2 (COX-2), is associated with an increased risk of thrombotic events. It has been suggested that this is due to NSAIDs reducing the release from the endothelium of the antithrombotic mediator prostaglandin I₂ as a result of inhibition of endothelial COX-2. Here, however, we show that despite normal human vessels and endothelial cells containing cyclo-oxygenase-1 (COX-1) without any detectable COX-2, COX-1 in vessels or endothelial cells is more readily inhibited by NSAIDs and COX-2-selective drugs than COX-1 in platelets (e.g., log IC₅₀±SEM values for endothelial cells vs. platelets: naproxen –5.59±0.07 vs. –4.81±0.04; rofecoxib –4.93±0.04 vs. –3.75±0.03; n=7). In broken cell preparations, the selectivities of the tested drugs toward endothelial cell over platelet COX-1 were lost. These observations suggest that variations in cellular conditions, such as endogenous peroxide tone and substrate supply, and not the isoform of cyclo-oxygenase present, dictate the effects of NSAIDs on endothelial cells vs. platelets. This may well be because the platelet is not a good representative of COX-1 activity within the body as it produces prostanoids in an explosive burst that does not reflect tonic release from other cells. The results reported here can offer an explanation for the apparent ability of NSAIDs and COX-2-selective inhibitors to increase the risk of myocardial infarction and stroke.—Mitchell, J. A., Lucas, R., Vojnovic, I., Hasan, K., Pepper, J. R., Warner, T. D. Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events.

Key Words: prostacyclin • thromboxane A2 • thrombosis • cyclooxygenase-2

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