EFFECTS OF TRIFLUOPERAZINE ON PLATELET ACTIVATION

Previous reports of the inhibitory effects of trifluoperazine on [human] platelet responses to different aggregating agents were conflicting and the mechanism of action remains unclear. Aggregation by minimum concentrations of collagen and arachidonic acid, and 2nd phase aggregation by minimum concentrations of ADP, thrombin, epinephrine and the calcium ionophore A23187 were inhibited by 40-60 .mu.M trifluoperazine. The 1st phase of aggregation by a minimum concentration of epinephrine was completely inhibited by 100 .mu.M trifluoperazine, and the first phase of aggregation induced by ADP, thrombin or A23187 was decreased by 300 .mu.M trifluoperazine. The platelet shape change caused by collagen, but by no other aggregating agent examined, was inhibited by 300 .mu.M trifluoperazine. Secretion of 3H-5 hydroxytryptamine by minimum concentrations of ADP, collagen, epinephrine and arachidonic acid was completely suppressed by 50 .mu.M trifluoperazine. Secretion by thrombin and A23187 was incompletely inhibited by 300 .mu.M trifluoperazine. Thromboxane B2 formation caused by all aggregating agents, except epinephrine, was incompletely suppressed by 50 .mu.M trifluoperazine, and 300 .mu.M trifluoperazine only caused complete inhibition of thromboxane B2 formation by ADP, collagen and epinephrine. The phorbol ester, TPA, (12-0-tetradecanoylphorbol-13-acetate), which mimics diacylglycerol by activating protein kinase C, caused aggregation and secretion. Aggregation, but not secretion, by low concentrations of TPA was inhibited by concentrations of trifluoperazine as low as 50 .mu.M. However, aggregation by a combination of TPA and A23187 was only inhibited by concentrations of trifluoperazine in excess of 100 .mu.M. Secretion by TPA was inhibited by concentrations of trifluoperazine in excess of 200 .mu.M. Apparently, low concentrations of trifluoperazine inhibit platelet activation by inhibiting phospholipase A2 and higher concentrations inhibit platelet responses by interfering with protein kinase C.