Inhibition of prostaglandin E1-responsive platelet adenylate cyclase by heparin: a study of the mechanism of inhibition and its relevance to platelet aggregation.

1 Heparin can produce platelet aggregation in vitro and in vivo; it has been proposed that this may be due to the reported inhibition of the prostaglandin E(1) (PGE(1))-stimulated adenylate cyclase of the platelet by heparin.2 The effect of heparin on the cyclic adenosine 3',5'-monophosphate (cyclic AMP) response to PGE(1) was measured in intact and broken platelets both in vitro and in platelets obtained from normal subjects during intravenous infusion with herapin.3 In platelet lysates, heparin produced a dose-related inhibition of PGE(1)-stimulated adenylate cyclase. The maximum response to PGE(1) was reduced, with half-maximal inhibition occurring at 3 mug/ml heparin. This inhibition could be prevented by protamine sulphate.4 Heparin did not affect PGE(1)-stimulated cyclic AMP production in intact platelets either in vitro or in platelets taken during the infusion of 5,000iu heparin over 2h to 2 normal volunteers. Similarly, preincubation of platelets with heparin for up to 3h at 37 degrees C did not affect platelet adenylate cyclase.5 The effects of heparin were very similar to those of fluoride on the platelet adenylate cyclase: heparin and fluoride increased basal enzyme activity slightly (3-4 fold) but their effects were not additive; both inhibited the response to PGE(1) by approximately 50% when added directly to the assay and the inhibitory effects of the two were not additive; preincubation of membranes with either heparin or fluoride produced an irreversible state of inhibition.6 As heparin inhibits PGE(1)-stimulated adenylate cyclase activity only in broken platelets, we suggest that the aggregatory effects of heparin are probably independent of any action on cyclic AMP production.