title: Antiplatelet effects of a novel antianginal agent, nicorandil.
abstract: Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Department of Veterans Affairs Medical Center, Brockton/West Roxbury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02132.
authors.forename: O
authors.initials: O
authors.lastname: Jaraki
authors.forename: W E
authors.initials: WE
authors.lastname: Strauss
authors.forename: S
authors.initials: S
authors.lastname: Francis
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
authors.forename: J S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005340:Fibrinogen / Q000378:metabolism; D006162:Guanylate Cyclase / Q000097:blood; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011863:Radioimmunoassay; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D010975:Platelet Aggregation Inhibitors; D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000111:Acetylcysteine