INCREASED PHOSPHATIDIC-ACID AND DECREASED LYSOPHOSPHATIDIC ACID IN RESPONSE TO THROMBIN IS ASSOCIATED WITH INHIBITION OF PLATELET-AGGREGATION

Thromboxane A(2,) produced from the arachidonic acid released from pla telet phospholipids by phospholipase A(2,) stimulates platelet aggrega tion. It remains unresolved whether additional products of platelet ph ospholipase A(2) might promote aggregation. To address this question, we have used aspirin-treated platelets to block thromboxane A(2) forma tion and studied the influence of the phospholipase A(2) inhibitor U10 029A on platelet aggregation and secretion in response to thrombin. U1 0029A at 100 mu M markedly inhibited platelet aggregation, but had no effect on platelet secretion. Since this concentration of U10029A effe ctively blocked lysophosphatidic acid (LPA) formation, LPA was added a nd found to substantially reverse the inhibitory effect of U10029A in these platelets. Furthermore, the action of U10029A was not due to inh ibition of phosphatidate phosphohydrolase because U10029A, unlike prop ranolol, did not inhibit this enzyme. Although it is not possible to c onclusively rule out an effect of U10029A in addition to its inhibitio n of phospholipase A(2,) our results reveal that a product of phosphol ipase A(2) other than thromboxane A(2) is important for platelet aggre gation, but not for secretion in response to thrombin. Our data sugges t that this product is LPA. Since the amount of phosphatidic acid (PA) increased dramatically concurrent with inhibition of platelet aggrega tion, it is safe to conclude that PA has no direct role to promote pla telet aggregation in response to thrombin.