EFFECTS OF THE MITOGEN-ACTIVATED PROTEIN (MAP) KINASE KINASE INHIBITOR 2-(2'-AMINO-3'-METHOXYPHENYL)-OXANAPHTHALEN-4-ONE (PD98059) ON HUMANPLATELET ACTIVATION

The role of mitogen-activated protein (MAP) kinase cascades in platele t 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 rol e of the MAP kinase cascade in platelet function. An inhibitor of the mitogen activated protein kinase kinase MEK1, 2-(2'-amino-3'-methoxyph enyl)-oxanaphthalen-4-one (PD98059), was used, at concentrations consi stent with those reported to inhibit MEK1, to examine the role that th is enzyme plays in platelet function. PD98059 inhibited aggregation in response to low dose collagen and arachidonic acid, but not that in r esponse to high-dose collagen, thrombin, thrombin receptor-activating peptide (TRAP), 9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglan din F-2 alpha, (U46619), or phorbol ester. Thrombin, thrombin receptor -activating peptide, U46619, collagen, and arachidonic acid each cause d the release of [H-3]serotonin from dense granules, but only that eli cited by low-dose collagen and arachidonic acid was inhibited by PD980 59. The release of [H-3]arachidonic acid in response to thrombin or co llagen was unaffected by PD98059 pretreatment. In contrast, collagen-a nd arachidonic acid-induced thromboxane formation was inhibited by PD9 8059. These data suggest that MEK1 is not involved in the platelet res ponse to thrombin or U46619. Furthermore, the inhibitory effects of PD 98059 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 Scienc e Inc.