title: Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia.
abstract: BACKGROUND
  Clopidogrel resistance is more common in patients with loss-of-function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting.
  
  
  METHODS
  Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ∆ADP, and Platelet Reactivity Index (∆PRI). Data were analysed according to CYP2C19 genotype.
  
  
  RESULTS
  In patients without loss of function mutations (n=18), ∆ADP but not ∆PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ∆ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (β=-0.609, p<0.001) and the baseline response to PGE1 (β=0.303, p=0.03).
  
  
  CONCLUSIONS
  While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance.
authors.affiliation: Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Basil Hetzel Institute, Woodville South, Australia; University of South Australia, Australia.
authors.forename: V B
authors.initials: VB
authors.lastname: Nooney
authors.affiliation: Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Basil Hetzel Institute, Woodville South, Australia; The University of Adelaide, Australia.
authors.forename: N L
authors.initials: NL
authors.lastname: Hurst
authors.affiliation: Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Basil Hetzel Institute, Woodville South, Australia; The University of Adelaide, Australia.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Chirkov
authors.affiliation: Institute of Cardiology, Center of Excellence on Aging, "G. d'Annunzio" University-Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospital, Basil Hetzel Institute, Woodville South, Australia; The University of Adelaide, Australia; University of South Australia, Australia. Electronic address: john.horowitz@adelaide.edu.au.
authors.forename: J D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000368:Aged; D000527:Alprostadil / Q000494:pharmacology; D000787:Angina Pectoris / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D009599:Nitroprusside; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000262:Adenylyl Cyclases; D000527:Alprostadil; D013988:Ticlopidine
keywords: Adenylate cyclase; Antiplatelet drugs; Clopidogrel; Cyclic AMP; Prostaglandin E(1)