title: P2Y12 receptor blockade synergizes strongly with nitric oxide and prostacyclin to inhibit platelet activation.
abstract: OBJECTIVE
  In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs.
  
  
  METHODS
  Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NONOate) and PGI2 was studied before and following treatment.
  
  
  RESULTS
  Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, P < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, P < 0.05) inhibition when DEA/NONOate + PGI2 was present.
  
  
  CONCLUSIONS
  We have demonstrated that PGI2 and NO synergize with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to predict thrombotic outcomes better and adjust therapy to prevent adverse outcomes in individual patients.
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Melissa V
authors.initials: MV
authors.lastname: Chan
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Rebecca B M
authors.initials: RB
authors.lastname: Knowles
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Martina H
authors.initials: MH
authors.lastname: Lundberg
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Tucker
authors.affiliation: Qatar Foundation Research and Development Division, Doha, Qatar.|National Heart & Lung Institute, Imperial College London, London, UK.
authors.forename: Nura A
authors.initials: NA
authors.lastname: Mohamed
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|National Heart & Lung Institute, Imperial College London, London, UK.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Paul C J
authors.initials: PC
authors.lastname: Armstrong
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D000293:Adolescent; D000328:Adult; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D004357:Drug Synergism; D011464:Epoprostenol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D020030:Nitric Oxide Donors; D058921:Purinergic P2Y Receptor Antagonists; D009569:Nitric Oxide; D011464:Epoprostenol; D000068799:Prasugrel Hydrochloride; D001241:Aspirin
keywords: blood platelets; endothelium; epoprostenol; nitric oxide; purinergic P2Y receptor antagonists