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Thrombosis Research
Volume 113, Issues 3-4 , 2004, Pages 225-233


Glycoprotein IIb/IIIa inhibition enhances platelet nitric oxide release

Subrata Chakrabartia, Patricia Cluttona, Sonia Varghesea, Dermot Coxb, Mary Ann Mascellic and Jane E. FreedmanCorresponding Author Contact Information, a, Corresponding Author Contact Information, E-mail The Corresponding Author

a Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 715 Albany Street, W507, Boston, MA 02481, USA
b Royal College of Surgeons, Dublin, Ireland
c Centocor Inc., Malvern, PA, USA

Received 20 August 2003; Revised 24 February 2004; accepted 24 February 2004. Available online 12 April 2004.


Abstract

Introduction: Platelet aggregates form by fibrinogen binding to the membrane receptor glycoprotein IIb/IIIa (GPIIb/IIIa). While GPIIb/IIIa inhibitors block fibrinogen-platelet binding, stimulation of other functionally important platelet receptors may still occur. Blocking the GPIIb/IIIa receptor prevents platelet aggregation but not activation and the subsequent effect on other platelet pathways is largely unknown. Materials and methods: As activated platelets release reactive oxygen species that may influence thrombosis or vascular function, the effect of GPIIb/IIIa inhibitors on the platelet release of nitric oxide (NO) and superoxide was determined using an electrochemical detector and luminescence, respectively. Location of relevant platelet proteins and the interaction between platelets and leukocytes in the presence or absence of GPIIb/IIIa inhibition was determined. Results: Although incubation with GPIIb/IIIa inhibitors completely abolished platelet aggregation, stimulation dependent NO release was significantly enhanced. Superoxide is known to alter the bioavailability of NO, and its contribution to the GPIIb/IIIa dependent increase in NO release was determined. In the presence of GPIIb/IIIa inhibitors, platelet superoxide release was significantly decreased. Preincubation with GPIIb/IIIa inhibitors also modified aggregation induced membrane translocation of the platelet proteins, endothelial NO synthase (eNOS) and NADPH oxidase (p67phox and p47phox), known to contribute to the generation of NO and superoxide, respectively. In the presence of leukocytes, abciximab incubation led to enhanced NO release and attenuated superoxide generation. Conclusion: These observations suggest that the pharmacological effects of GPIIb/IIIa antagonists on platelet function, apart from inhibition of aggregation, may contribute to their efficacy.

Author Keywords: Platelets; Glycoprotein IIb/IIIa inhibitors; NO; Superoxide; Abciximab

Corresponding Author Contact InformationCorresponding author. Tel.: +1-617-638-4022; fax: +1-617-638-4066.

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