Dual Effect of Propranolol on the Human Platelet Activation by Thrombin: Potentiation of Free Intracellular Ca²⁺ Mobilization and Inhibition of Phospholipase D Activity

Abstract

Propranolol has been employed for a long time in clinical practice as non selective β-adrenoreceptor antagonist. Only the S(−) optical isomer has β-blocking activity, whereas R(+) form is totally ineffective. Early clinical observations (1978–1979) showed that treatment with propranolol improved blood platelet function in patients with cardiovascular diseases. In vitro studies indicated that this compound inhibited human PRP aggregation following exposure to ADP, collagen, epinephrine and Ca²⁺ ionophore A23187, and diminished aggregation of washed human platelets induced by a low concentration (0.025 U/ml) of thrombin (1). Both S(−) and R (+) isomers as well as (±) racemic form were active. Further studies evaluated the inhibitory effect of propranolol on phosphatidic acid (PA) phosphohydrolase, which converts PA to diacylglycerol in various type of cells (2). It was found that inhibition of PA phosphohydrolase by propranolol led to potentiation of 0₂ production in neutrophils stimulated with putative receptor agonist fMLP, suggesting a role for PA as a second messenger and for PA phosphohydrolase as a key regulatory enzyme in the interaction between PLC and PLD in the signal transduction (3,4). Sozzani et al., showed recently (5), that both S(−) and R(+) form inhibited protein kinase C (PKC) from human neutrophils and reduced [³H]PDBu binding by neutrophils in the concentration range of 100–200 μM.