Abstract
Orthovanadate (vanadate) inhibited the platelet aggregation induced by platelet-activating factor (PAF) in a dose-dependent manner. Propranolol, a nonspecific β-adrenergic receptor antagonist, and H-8, a selective inhibitor of cAMP-dependent protein kinase (PKA), suppressed the inhibition of the PAF-induced platelet aggregation by vanadate. Vanadate increased the cAMP content in platelets accompanied by the activation of PKA. The β-adrenergic receptors of platelets have been reported to be abundant in the β2 isoform, coupled to adenylyl cyclases (R. Kerry and M. C. Scrutton, Br. J. Pharmacol., 79, 681—691 (1983)). When the washed platelets were preincubated with vanadate, salbutamol, a selective β2-adrenergic receptor agonist, or 8-Br-cAMP, the latter two mimicked the vanadate-induced anti-platelet aggregation and prolongation of clotting time of plasma, suggesting involvement of the increased intracellular cAMP content in both actions of vanadate. Butoxamine, a selective β2-adrenergic receptor antagonist, suppressed both actions of vanadate. The vanadate-induced increase in cAMP content was inhibited in part by butoxamine or genistein. These results suggest that vanadate inhibits the PAF-induced platelet aggregation by the stimulation of a cAMP/PKA-dependent process via the β2-adrenergic receptor and receptor tyrosine kinases, and that the anti-platelet aggregation is involved in part in mechanisms of the anticoagulant action of vanadate.
