title: Analysis of platelet alpha2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy.
abstract: Combined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited. Born aggregometry was performed with adenosine diphosphate (ADP), collagen and epinephrine. To verify platelet adrenergic activity, potentiation by low-dose epinephrine and inhibition by selective alpha-2 receptor blocker atipamezole were determined. To assess the P2Y(12)-specific residual activity, cangrelor was used. Plasma norepinephrine, soluble CD40-ligand, high-sensitivity-C-reactive protein (hsCRP) - and in 24 subjects platelet P-selectin positivity were measured. Epinephrine - at very low concentration (10(-9)g/ml) - significantly potentiates (1.25 microM ADP: 26.5% vs. 43%; 5 microM ADP: 53% vs. 64.5%; collagen: 17% vs 42%, p < 0.001) while atipamezole inhibits ADP- and collagen-induced platelet aggregations (1.25 microM ADP: 26.5% vs. 23%; 5 microM ADP: 53% vs. 47%; collagen: 17% vs. 11%, p < 0.001). Patients with high adrenergic activity have significantly increased baseline ADP- and collagen-induced platelet aggregation. Based on cangrelor's efficacy, these patients have significantly more residual P2Y(12) activity as well. HsCRP and soluble CD40-ligand levels were similar. In conclusion, stable coronary heart disease patients with prominent adrenoceptor activity in vitro have significantly increased platelet aggregability and more functional P2Y(12) receptor, indicating poor inhibitory response to thienopyridines. Therefore, platelet adrenergic receptor represents a considerable, dynamic factor of high residual platelet reactivity and might contribute to cardiovascular events indicating failure of antiplatelet therapy.
authors.affiliation: State Health Center, Department of Cardiology, 1134-Budapest Róbert Károly körút 44, Hungary. beresbernat@yahoo.co.uk
authors.forename: Bernát János
authors.initials: BJ
authors.lastname: Béres
authors.forename: Emese
authors.initials: E
authors.lastname: Tóth-Zsámboki
authors.forename: Katarína
authors.initials: K
authors.lastname: Vargová
authors.forename: Adám
authors.initials: A
authors.lastname: László
authors.forename: Tamás
authors.initials: T
authors.lastname: Masszi
authors.forename: Gábor
authors.initials: G
authors.lastname: Kerecsen
authors.forename: István
authors.initials: I
authors.lastname: Préda
authors.forename: Róbert Gábor
authors.initials: RG
authors.lastname: Kiss
mesh_terms: D000244:Adenosine Diphosphate; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000368:Aged; D001241:Aspirin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000077144:Clopidogrel; D003094:Collagen; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy*; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010979:Platelet Function Tests; D018341:Receptors, Adrenergic, alpha-2 / Q000097:blood / Q000187:drug effects*; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000187:drug effects; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; C050701:atipamezole; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D003094:Collagen; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; D009638:Norepinephrine