title: Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer.
abstract: OBJECTIVE
  Increased risk of thrombo-embolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and reduced bioavailability of nitric oxide (NO) as well as platelet activation. We investigated whether treatment with a novel endothelial NO synthase (eNOS)-transcription enhancer positively modulates systemic NO bioavailability and reduces platelet activation in rats with CHF.
  
  
  RESULTS
  After experimental myocardial infarction, male Wistar rats were treated with either placebo or the eNOS-transcription enhancer, AVE9488 (25 ppm/day) for 10 weeks. In rats with severe CHF (left ventricular end-diastolic pressure >15 mmHg), platelet vasodilator-stimulated phosphoprotein (VASP)-phosphorylation reflecting the integrity of the NO/cGMP pathway was significantly reduced (mean immunofluorescence at Ser(157): Sham, 61.4 +/- 9.1; CHF-Placebo, 37.4 +/- 4.9; P < 0.05; Ser(239): Sham, 18.1 +/- 2.5; CHF-Placebo, 13.2 +/- 0.6; P < 0.05). Platelet surface expression of P-selectin and glycoprotein 53 were increased in CHF rats compared with sham-operated animals. Chronic treatment with AVE9488 significantly enhanced platelet VASP-phosphorylation in CHF rats (Ser(157): 70.4 +/- 16.2; Ser(239): 19.3 +/- 1.8). In parallel, platelet surface expression of P-selectin and glycoprotein 53 was reduced in the treatment group.
  
  
  CONCLUSIONS
  Platelet activation was evident in CHF rats. Therapy with the eNOS-transcription enhancer, AVE9488, reduced platelet activation in parallel to normalization of platelet NO bioavailability.
authors.affiliation: Medizinische Klinik und Poliklinik I, Julius-Maximilians-Universität Würzburg, Josef Schneider Strasse 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Julian
authors.initials: J
authors.lastname: Widder
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C528454:4-fluoro-N-indan-2-yl-benzamide; D001549:Benzamides; D001798:Blood Proteins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide