Effects of the mitogen-activated protein (MAP) kinase kinase inhibitor 2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one (PD98059) on human platelet activation

The role of mitogen-activated protein (MAP) kinase cascades in platelet function remains to be determined. Several studies have suggested a role in the activation of phospholipase A(2); however, other functions seem likely. The object of the present study was to determine the role of the MAP kinase cascade in platelet function. An inhibitor of the mitogen activated protein kinase kinase MEK1, 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059), was used, at concentrations consistent with those reported to inhibit MEK1, to examine the role that this enzyme plays in platelet function. PD98059 inhibited aggregation in response to low dose collagen and arachidonic acid, but not that in response to high-dose collagen, thrombin, thrombin receptor-activating peptide (TRAP), 9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F-2 alpha, (U46619), or phorbol ester. Thrombin, thrombin receptor-activating peptide, U46619, collagen, and arachidonic acid each caused the release of [H-3]serotonin from dense granules, but only that elicited by low-dose collagen and arachidonic acid was inhibited by PD98059. The release of [H-3]arachidonic acid in response to thrombin or collagen was unaffected by PD98059 pretreatment. In contrast, collagen-and arachidonic acid-induced thromboxane formation was inhibited by PD98059. These data suggest that MEK1 is not involved in the platelet response to thrombin or U46619. Furthermore, the inhibitory effects of PD98059 on collagen-and arachidonic acid-induced responses suggest that PD98059 may inhibit the conversion of arachidonic acid to thromboxane, in addition to its reported effects on MEK1. (C) 1998 Elsevier Science Inc.