title: Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC.
abstract: OBJECTIVE
  The soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient's oxidative burden. We here describe two platelet-based assays that allow determining the extent of oxidised sGC and thus provide a basis for an individualised pharmacotherapy.
  
  
  RESULTS
  Platelets obtained from patients with (n=12) and without (n=12) coronary artery disease (CAD) were examined by flow cytometry (P-selectin expression), and Western blots (vasodilator associated phosphoprotein, VASP-phosphorylation). Results were compared to maximal oxidation of sGC achieved by the oxidising agent ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). Treatment of platelets with Cinaciguat resulted in differential activation of oxidised sGC. Platelet P-selectin expression and VASP-phosphorylation revealed significant differences (p=0.012, p=0.039, respectively) between CAD and non-CAD patients.
  
  
  CONCLUSIONS
  We describe platelet-based assays that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.
authors.affiliation: Atherothrombosis & Vascular Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Australia. ingo.ahrens@uniklinik-freiburg.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Ahrens
authors.forename: Jonathon
authors.initials: J
authors.lastname: Habersberger
authors.forename: Nadège
authors.initials: N
authors.lastname: Baumlin
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Belinda K
authors.initials: BK
authors.lastname: Smith
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Peter
mesh_terms: D000368:Aged; D001565:Benzoates / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003324:Coronary Artery Disease / Q000097:blood / Q000378:metabolism*; D005260:Female; D006162:Guanylate Cyclase / Q000097:blood*; D006418:Heme / Q000737:chemistry*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry*; D019007:P-Selectin / Q000097:blood; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D001565:Benzoates; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D019007:P-Selectin; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C480588:BAY 58-2667; D006418:Heme; D006162:Guanylate Cyclase; D010100:Oxygen