Human platelet activation is inhibited upstream of the activation of phospholipase A(2) by U73343

U73122 is known as an inhibitor of phospholipase C (PLC; EC 3.1.4.11). Its close structural analogue, U73343, lacks this activity and is used as a control compound. We have found that both compounds interfere with platelet signal transduction. U73122 completely abolished aggregation evoked by thrombin, TG, and collagen. Aggregation evoked by TG and collagen was also blocked by U73343, an effect due to inhibition of TxA(2) production. U73343 was a potent inhibitor of TG-evoked arachidonic acid release, but a weak inhibitor of cytosolic phospholipase A(2) (cPLA(2); EC 3.1.1.4) activity. Cytosolic PLA(2) activation in platelets involves protein tyrosine phosphorylation. U73343 inhibited TG- and collagen-evoked protein tyrosine phosphorylation, which can thus explain its action against these agents. These data indicate that caution is needed when using U73343 along with U73122 in the study of intracellular signalling pathways. (C) 1997 Elsevier Science Inc.