Effect of orthovanadate on platelet aggregation induced by platelet-activating factor.
Orthovanadate (vanadate) inhibited the platelet aggregation induced by platelet-activating factor (PAF) in a dose-dependent manner. Propranolol, a nonspecific beta-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 beta-adrenergic receptors of platelets have been reported to be abundant in the beta(2) 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 beta(2)-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 beta(2)-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 beta(2)-adrenergic receptor and receptor tyrosine kinases, and that the anti-platelet aggregation is involved in part in mechanisms of the anticoagulant action of vanadate.
Suenaga
Aya
A
Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
Ueki
Hiroshi
H
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D002078:Butoxamine / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology*
D058672:Adrenergic beta-2 Receptor Antagonists; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D018343:Receptors, Adrenergic, beta-2; D002078:Butoxamine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014638:Vanadates; D011433:Propranolol; D019833:Genistein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000420:Albuterol