Dissociation between the anti-aggregatory & anti-secretory effects of platelet integrin alpha(IIb)beta(3) (GPIIb/IIIa) antagonists, c7E3 and DMP728

被引:34
作者
Tsao, PW [1 ]
Forsythe, MS [1 ]
Mousa, SA [1 ]
机构
[1] DUPONT MERCK PHARMACEUT CO, EXPT STN, DIV CARDIOVASC, WILMINGTON, DE 19880 USA
关键词
alpha(IIb)beta(3) integrin; platelet secretion; P-selectin; type 1 plasminogen activator inhibitor; beta-thromboglobulin; alpha(v)beta(3) integrin;
D O I
10.1016/S0049-3848(97)00225-9
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu mol/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 mu mol/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. (C) 1997 Elsevier Science Ltd.
引用
收藏
页码:137 / 146
页数:10
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