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

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.