Dissociation between the anti-aggregatory & anti-secretory effects of platelet integrin alpha IIb beta 3 (GPIIb/IIIa) antagonists, c7E3 and DMP728.
The effects of alpha IIb beta 3 antagonists on the blockade of fibrinogen binding to platelet alpha IIb beta 3 are well documented, however, little is known about their effects on platelet secretion. We compare here the effect of two potent alpha IIb beta 3 antagonists, c7E3 and DMP728, on platelet secretion. Using human platelet-rich plasma, P-selectin expression was measured by flow cytometry and type 1 plasminogen activator inhibitor (PAI-1) secretion as well as beta-thromboglobulin (beta-TG) were determined by ELISA. At various concentrations of the antagonists that inhibited 80-95% of platelet aggregation, neither had any effect on P-selectin expression. In contrast, thrombin-stimulated PAI-1 secretion is only inhibited by c7E3, 49.6% at 3.5 mumol/L (p < 0.05), but not at any other maximally effective anti-aggregatory concentrations of c7E3 or DMP728. Furthermore, a lack of any significant effects on platelet granular secretion of beta-TG induced by either thrombin or ADP was demonstrated with DMP728, c7E3 or LM609. Two protein kinase inhibitors, staurosporine and herbimycin, blocked both ADP and thrombin-induced P-selectin expression at 10 mumol/L, but not PAI-1 secretion. Taken together this suggests that: (1) the mechanism of platelet granular secretion is independent of the integrin alpha IIb beta 3 and (2) the subcellular locations of PAI-1, beta-TG and P-selectin or the signaling mechanisms that regulate their secretion might be different. Although there is no direct effect of platelet alpha IIb beta 3 antagonists on platelet secretion of PAI-1, beta-TG and P-selectin, the present data demonstrates that reduction of platelet number by alpha IIb beta 3 antagonists, via the reduction in thrombus size, might be an alternate mechanism for reduced platelet secretion. In conclusion, a discoupling between the anti-aggregatory and the anti-secretory effects of alpha IIb beta 3 antagonists has been demonstrated.
Tsao
P W
PW
DuPont Merck Pharmaceutical Company, Cardiovascular Division, Wilmington, DE 19880, USA.
Forsythe
M S
MS
Mousa
S A
SA
D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D008698:Mesylates / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D019007:P-Selectin / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine / Q000494:pharmacology; D001620:beta-Thromboglobulin / Q000032:analysis / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D047029:Lactams, Macrocyclic; D008698:Mesylates; D009842:Oligopeptides; D019007:P-Selectin; D010456:Peptides, Cyclic; D017395:Plasminogen Activator Inhibitor 1; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011809:Quinones; D001620:beta-Thromboglobulin; C085286:DMP 728; D017828:Rifabutin; C020754:herbimycin; C047981:arginyl-glycyl-aspartic acid; D019311:Staurosporine; D000077284:Abciximab