Glycoprotein IIb/IIIa inhibition enhances platelet nitric oxide release.
BACKGROUND
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.


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.


CONCLUSIONS
These observations suggest that the pharmacological effects of GPIIb/IIIa antagonists on platelet function, apart from inhibition of aggregation, may contribute to their efficacy.
Chakrabarti
Subrata
S
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, 715 Albany Street, W507, Boston, MA 02481, USA.
Clutton
Patricia
P
Varghese
Sonia
S
Cox
Dermot
D
Mascelli
Mary Ann
MA
Freedman
Jane E
JE
D000077284:Abciximab; D000409:Alanine / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000032:analysis; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; C120234:orbofiban; D000409:Alanine; D002118:Calcium; D000077284:Abciximab