title: Sodium fluoride mimics effects of both agonists and antagonists on intact human platelets by simultaneous modulation of phospholipase C and adenylate cyclase activity.
abstract: Using intact human platelets, we studied the effect of sodium fluoride (NaF) on platelet aggregation and release reaction and correlated the functional changes to intracellular events specific for either agonist-induced or antagonist-induced platelet responses. At lower concentrations, with a peak activity between 30 and 40 mmol/L, NaF induced aggregation and release of adenosine 5'-triphosphate (ATP) that was associated with increased formation of inositol phosphates, a rise in cytosolic free Ca2+, and phosphorylation of 20-kd and 40-kd proteins. At NaF concentrations greater than 40 mmol/L, aggregation and ATP release decreased dose-dependently in parallel with a decrease in Ca2+ mobilization, whereas neither inositol phosphate formation nor 40-kd protein phosphorylation was reduced. At these concentrations, NaF caused a dose-dependent transient rise in platelet cyclic adenosine 3',5'-monophosphate (cAMP) levels that was sufficient to account for the observed reduction in Ca2+ mobilization, aggregation, and ATP release. Stimulated cAMP levels started declining rapidly within 30 seconds of addition of NaF, however. Similarly, prostacyclin (PGI2)-induced cAMP accumulation was temporarily enhanced but subsequently suppressed by NaF, suggesting either stimulation of a cAMP phosphodiesterase or delayed inhibition of adenylate cyclase. Evidence for the latter was provided by the finding that NaF pretreatment of platelets resulted in partial inhibition of PGI2-stimulated cAMP formation in the presence of the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX). We conclude that NaF exerts a dual (stimulatory and inhibitory) effect on adenylate cyclase in intact platelets that is accompanied by simultaneous activation of a phosphoinositide-specific phospholipase C; in addition, a cAMP phosphodiesterase may be activated.
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D012969:Sodium Fluoride / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D007295:Inositol Phosphates; D010750:Phosphoproteins; D000255:Adenosine Triphosphate; D012969:Sodium Fluoride; D000242:Cyclic AMP; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium