Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer.
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.
Schäfer
Andreas
A
Medizinische Klinik und Poliklinik I, Julius-Maximilians-Universität Würzburg, Josef Schneider Strasse 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Fraccarollo
Daniela
D
Widder
Julian
J
Eigenthaler
Martin
M
Ertl
Georg
G
Bauersachs
Johann
J
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
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