EFFECT OF PROPRANOLOL ON PLATELET SIGNAL-TRANSDUCTION

Propranolol inhibits platelet secondary aggregation and secretion by m echanisms unrelated to its beta-adrenergic-blocking activity. We previ ously reported that a major effect of the drug is perturbation of the physical microenvironment of the human platelet membrane. To explore f urther the molecular mechanisms underlying propranolol-mediated platel et inhibition, we studied protein kinase C activity, estimated from th e phosphorylation of the substrate protein pleckstrin, in propranolol- treated human platelets. The drug inhibited activation of the enzyme i n thrombin-stimulated platelets but not in platelets stimulated with p horbol esters, indicating that its site of action might be upstream of protein kinase C. It also inhibited the activity of phospholipase C, determined from the extent of generation of inositol phosphates and ph osphatidic acid, in platelets stimulated with thrombin as well as the non-hydrolysable GTP analogue guanosine 5'-[beta,gamma-imido]triphosph ate in a dose-dependent manner. These data suggest that propranolol in hibits signal transduction in thrombin-stimulated platelets by interac ting at the level of phospholipase C and exclude interaction of the dr ug with the downstream effector enzyme protein kinase C.