title: Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats.
abstract: BACKGROUND
  Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y(12) antagonists on the reactivity of vascular smooth muscle cells.
  
  
  METHODS
  Wistar rats (n=30) were pretreated with an investigated drug or placebo. Clopidogrel (50mg/kg, n=7), prasugrel (10mg/kg, n=7), ticagrelor (10mg/kg, n=7) or placebo (n=9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y(12) receptor.
  
  
  RESULTS
  Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response.
  
  
  CONCLUSIONS
  Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.
authors.affiliation: Department of Pharmacology and Therapeutics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grzesk
authors.forename: Marek
authors.initials: M
authors.lastname: Kozinski
authors.forename: Eliano Pio
authors.initials: EP
authors.lastname: Navarese
authors.forename: Marek
authors.initials: M
authors.lastname: Krzyzanowski
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Grzesk
authors.forename: Aldona
authors.initials: A
authors.lastname: Kubica
authors.forename: Jolanta Maria
authors.initials: JM
authors.lastname: Siller-Matula
authors.forename: Fausto
authors.initials: F
authors.lastname: Castriota
authors.forename: Jacek
authors.initials: J
authors.lastname: Kubica
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000166:cytology*; D000077144:Clopidogrel; D009119:Muscle Contraction / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine