%0 Journal Article %A JACK Y. VANDERHOEK %A MAURICE B. FEINSTEIN %T Local Anesthetics, Chlorpromazine and Propranolol Inhibit Stimulus-Activation of Phospholipase A2 in Human Platelets %D 1979 %J Molecular Pharmacology %P 171-180 %V 16 %N 1 %X Stimulation of platelets by various agents such as thrombin, collagen and A23187 leads to a rapid Ca2+ - dependent, phospholipase A2-mediated mobilization of arachidonic acid from certain phospholipids and the biotransformation of this fatty acid to prostaglandin endoperoxides, thromboxanes A2 and B2, prostaglandins, hydroxyacids and malonyldialdehyde (MDA). Local anesthetics (dibucaine, tetracaine, benzocaine, and QX572), chlorpromazine and propranolol are very effective inhibitors of MDA formation induced by thrombin, collagen and A23187, but they do not block conversion of exogenous arachidonate to MDA. This result indicates that these drugs do not affect the enzyme prostaglandin synthetase responsible for the initial steps in arachidonate conversion to PG endoperoxides and thromboxanes. Utilizing platelets whose phospholipids were prelabeled with 14C-arachidonate and then stimulated with thrombin or A23187 we have found that local anesthetics, chlorpromazine and propranolol block: (a) formation of 14C-thromboxane B2, 14C-prostaglandins and 14C-hydroxyacids (12-L-hydroxy-5,8,10,14-eicosatetraenoic acid and 12-L-hydroxy-5,8,10-heptadecatrienoic acid) from endogenous (phospholipid) 14C-archidonate; and (b) block the fall in the 14C-arachidonate content of platelet phospholipids, especially phosphatidyl choline. Local anesthetics, chlorpromazine and propranolol did not inhibit the conversion of 14C-arachidonate to l4C-l2-L-hydroxy-5,8,10,14-eicosatetraenoic acid by a soluble fraction from platelets containing lipoxygenase activity. These results conclusively demonstrate that local anesthetics, chlorpromazine and propranolol inhibit the activation of PLA2 by stimuli, which is the initial and rate-limiting step in arachidonate metabolism. To some extent the ability of local anesthetics, chlorpromazine and propranolol to inhibit platelet aggregation and the release reaction (secretion of ADP, serotonin, etc.) can undoubtedly be attributed to their effect on PLA2 activation which prevents formation of the aggregating agents PG endoperoxides and thromboxane A2. However, other actions of these drugs, notably their ability to block aggregation induced by thromboxane A2 and by other aggregating agents, under conditions which are independent of PG endoperoxide and thromboxane A2 production, indicates additional mechanisms of action which can prevent cellular adhesion and exocytosis. These other actions may be related to non-arachidonate mediated effects on Ca2+-dependent phospholipases, antagonism of Ca2+-dependent phenomena necessary for membrane adhesion and fusion, or interference with the process of intracellular Ca2+ release by stimuli. ACKNOWLEDGMENT We gratefully acknowledge the technical assistance of Mrs. Carol Fraser. %U https://molpharm.aspetjournals.org/content/molpharm/16/1/171.full.pdf