Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer.

Abstract

AIMS:

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.

METHODS AND 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.

CONCLUSION:

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: Andreas Schäfer, Daniela Fraccarollo, Julian Widder, Martin Eigenthaler, Georg Ertl, Johann Bauersachs
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 11 Issue 4 Pg. 336-41 (Apr 2009) ISSN: 1388-9842 [Print] England
• PMID: 19193626 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-fluoro-N-indan-2-yl-benzamide
• Benzamides
• Blood Proteins
• Cell Adhesion Molecules
• Microfilament Proteins
• Phosphoproteins
• vasodilator-stimulated phosphoprotein
• Nitric Oxide

Topics

• Animals
• Benzamides (administration & dosage, therapeutic use)
• Blood Platelets (drug effects, metabolism)
• Blood Proteins
• Cell Adhesion Molecules (drug effects, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Heart Failure (blood, drug therapy, physiopathology)
• Male
• Microfilament Proteins (drug effects, metabolism)
• Nitric Oxide (metabolism)
• Phosphoproteins (drug effects, metabolism)
• Phosphorylation (drug effects)
• Platelet Activation (drug effects)
• Rats
• Rats, Wistar
• Severity of Illness Index
• Treatment Outcome
• Vasoconstriction (drug effects)