Beta-adrenoceptor antagonists and human platelets: relationship of effects to lipid solubility.

Six beta-adrenoceptor antagonists (propranolol (+ and - isomers); ICI-118,551; oxprenolol; timolol; metoprolol; and practolol (+ and - isomers), chosen to represent a spectrum of physicochemical and pharmacological properties, inhibited the response of human platelets to all aggregating agents tested. For any given aggregating agent the extent of inhibition correlated with the lipid solubility of the beta-adrenoceptor antagonist and showed no relation to other properties of these compounds. Inhibition of aggregation by the beta-adrenoceptor antagonists was manifested as a parallel shift to the right in the dose-response curve. Analysis of these data according to Arunlakshana and Schild (Br. J. Pharmac. 14, 48-58 (1969] showed a dependence of the apparent pA2 on the agonist employed and gave a slope approximating unity when ADP, 9,11-epoxymethanoprostaglandin H2 (U-46619), adrenaline, 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (PAF) or arachidonate were used as agonists. Slopes significantly greater than unity, and approaching a value of 2, were obtained when this analysis was applied to data obtained using collagen in the presence or absence of aspirin, 12-O-tetradecanoylphorbol-13-acetate (TPA), or a divalent cation ionophore (A-23187) as agonists. Inhibition by (+/-) propranolol of secretion induced by collagen was manifested as a parallel shift to the right in the dose-response curve for collagen. The Schild plot of these data has a slope of unity. (+/-)-Propranolol inhibited thromboxane B2 production induced by collagen but over a similar concentration range had little effect on conversion of arachidonate to thromboxane B2. (+/-)Propranolol had no significant effect on the level of cyclic-3',5'-AMP (cAMP) in unstimulated platelets or on the increase in the level caused by addition of forskolin, but caused partial inhibition of the increase in platelet cAMP induced by prostaglandin E1. It also completely abolished inhibition by ADP of the increase in [cyclic-3',5'-AMP] induced by prostaglandin E1. These data are interpreted on the basis of a model in which interaction of propranolol with phosphatidylserine and phosphatidylinositol causes inhibition of phospholipases C and A2, inhibition of protein kinase C and alteration of membrane receptor properties as a consequence of distortion of their microenvironment.