Effect of propranolol on platelet signal transduction.
Propranolol inhibits platelet secondary aggregation and secretion by mechanisms unrelated to its beta-adrenergic-blocking activity. We previously reported that a major effect of the drug is perturbation of the physical microenvironment of the human platelet membrane. To explore further the molecular mechanisms underlying propranolol-mediated platelet inhibition, we studied protein kinase C activity, estimated from the phosphorylation of the substrate protein pleckstrin, in propranolol-treated human platelets. The drug inhibited activation of the enzyme in thrombin-stimulated platelets but not in platelets stimulated with phorbol 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 phosphatidic acid, in platelets stimulated with thrombin as well as the non-hydrolysable GTP analogue guanosine 5'-[beta, gamma-imido]triphosphate in a dose-dependent manner. These data suggest that propranolol inhibits signal transduction in thrombin-stimulated platelets by interacting at the level of phospholipase C and exclude interaction of the drug with the downstream effector enzyme protein kinase C.
Dash
D
D
Department of Biochemistry, Banaras Hindu University, Varanasi, India.
Rao
K
K
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006801:Humans; D010712:Phosphatidic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010750:Phosphoproteins; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D001798:Blood Proteins; D010712:Phosphatidic Acids; D010750:Phosphoproteins; C039077:platelet protein P47; D006165:Guanylyl Imidodiphosphate; D011433:Propranolol; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate