PLATELET AGGREGATION Enhancement of the antiaggregatory activity of prostacyclin by propranolol in human platelets

The f3-adrenergic antagonist propranolol has been found to inhibit platelet aggregation. We investigated the possibility that propranolol exerts this action by stimulating the synthesis or enhancing the antiaggregatory activity of prostaglandin (PG) 12. The media from cultures of human endothelial cells inhibited thrombin-induced platelet aggregation, an effect attributed to PGI2 production by the cells. When endothelial cells were incubated with dlor d-propranolol, the media had two to three times the inhibitory activity of control media. However, this increased activity was not due to increased synthesis of PGI2 because control and propranolol-treated cultures synthesized similar amounts of the PGI2 metabolite, 6-keto-PGFM,. Instead, propranolol enhanced the antiaggregatory activity of PGI2. Propranolol (1 ,M) and PGI2 (0.05 nM), when tested separately, inhibited aggregation by 19% and 13%, respectively, whereas the combination inhibited aggregation by 51%. PGI2 inhibited platelet aggregation and thromboxane (Tx) B2 production but stimulated cyclic AMP formation. The adenyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA) had no effect of its own on these parameters, but blocked the actions of PGI2. Propranolol inhibited aggregation and TxB2 synthesis without changing cyclic AMP levels. Unlike PGI2, propranolol's effects were not altered by DDA. While the combination of propranolol and PGI2 inhibited aggregation to a greater extent than either agent alone, this enhanced effect with the combination did not extend to TxB2 or cyclic AMP production. Propranolol, PGI2, and the combination inhibited TxB2 synthesis to a similar extent, and PGI2 produced a similar increase in cyclic AMP in the presence and absence of propranolol. These findings indicate that propranolol and PGI2 inhibit platelet aggregation through cyclic AMP-independent and dependent mechanisms, respectively. While propranolol does not alter the synthesis of PGI2, it enhances the inhibition of aggregation by PGI2, and this may contribute to its antiplatelet effect. Circulation 71, No. 6, 1237-1246, 1985. PROPRANOLOL is widely used in the treatment of hypertension and coronary artery disease. Various studies have indicated that propranolol inhibits platelet activation both in vitro'-3 and in vivo.i' We have found that propranolol inhibits platelet aggregation and decreases thromboxane (Tx) A2 synthesis in platelet-rich plasma (PRP) obtained from normal subjects as well as in PRP prepared from hypertensive patients treated with this agent.6 7 Similar results have been From the Department of Pharmacology, the University of Texas Health Sciences Center at Dallas. Supported by grants from the National Heart, Lung, and Blood Institute (HL-25471 and HL-18826). Address for correspondence: William B. Campbell, Ph.D., Department of Pharmacology, the University of Texas Health Sciences Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235. Received Feb. 7, 1985; revision accepted March 15, 1985. Dr. Callahan was a National Institute of Health predoctorial trainee (ST32 GM-07062-06). Dr. Campbell is the recipient of a Research Career Development Award from the National Institutes of Health (K04-HL-00801). reported with the 4-hydroxy metabolite of propranolol.' Prostacyclin (prostaglandin [PG] 12) is a potent vasodilator and inhibitor of platelet aggregation.9 The vessel wall appears to be a primary site of PGI2 synthesis, with the intimal surface generating greater amounts than that formed by cells closer to the adventitia.'0 Numerous investigators have demonstrated that the vascular endothelium synthesizes PGI2. 11-6 Since the vascular endothelium is in direct contact with platelets circulating in the blood, the stimulation of PGL2 synthesis from this tissue by pharmacologic agents could produce an antiplatelet effect. The intent of the current investigation was to determine whether propranolol exerts a portion of its antiplatelet activity by increasing the synthesis or affecting the activity of PGI2. Consequently, the effect of propranolol on PGI2 synthesis was studied in cultured human endothelial cells. Additionally, the effects of propranolol on platelet aggregation, platelet cyclic AMP production, and Vol. 17, No. 6, June 1985 1237 by gest on Sptem er 5, 2017 http://ciajournals.org/ D ow nladed from