title: High-dose, but not low-dose, aspirin impairs anticontractile effect of ticagrelor following ADP stimulation in rat tail artery smooth muscle cells.
abstract: OBJECTIVE
  To compare effects of low- versus high-dose aspirin coadministered with ticagrelor on the reactivity of vascular smooth muscle cells (VSMCs).
  
  
  METHODS
  Wistar rats were orally administered ticagrelor (10 mg/kg) and/or aspirin (2 or 10 mg/kg) (n = 7 per each of 4 groups) or placebo (n = 9) 12 and 2 hours before experiments. Anticontractile effects of ticagrelor were assessed in perfusion solution containing ticagrelor (1 μM/L). Changes in perfusion pressure proportional to the degree of adenosine diphosphate analogue- (2-MeS-ADP-) and phenylephrine-induced constriction of rat tail arteries were evaluated.
  
  
  RESULTS
  Pretreatment with high- but not low-dose aspirin enhanced the reactivity of VSMCs only in endothelium-lined vessels. Suppression of 2-MeS-ADP-induced VSMC contraction by ticagrelor observed in arteries with and without endothelium was maintained in endothelialized arteries pretreated only with low-dose aspirin. For endothelium-denuded vessels and low-dose aspirin we observed a significant reduction of the maximal effect of ticagrelor with no rightward shift of the concentration-response curve for phenylephrine. With high-dose aspirin pretreatment ticagrelor exerted no anticontractile effect.
  
  
  CONCLUSIONS
  High-dose, but not low-dose, aspirin impairs the anticontractile effect of ticagrelor on ADP-induced VSMC contraction in the rat model. Both the clinical significance and detailed underlying mechanism of our findings require further investigation.
authors.affiliation: Department of Pharmacology and Therapeutics, Collegium Medicum, Nicolaus Copernicus University, 9 Sklodowskiej-Curie Street, 85-094 Bydgoszcz, Poland. ggrzesk@cm.umk.pl
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grześk
authors.forename: Marek
authors.initials: M
authors.lastname: Kozinski
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
authors.forename: Michal
authors.initials: M
authors.lastname: Wicinski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Fabiszak
authors.forename: Eliano P
authors.initials: EP
authors.lastname: Navarese
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Grzesk
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Jeong
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: Jacek
authors.initials: J
authors.lastname: Kubica
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects; D001241:Aspirin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D013623:Tail / Q000166:cytology / Q000187:drug effects; D000077486:Ticagrelor; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000244:Adenosine Diphosphate; D000077486:Ticagrelor; D000241:Adenosine; D001241:Aspirin