Summary

An increased risk of thrombembolic events in congestive heartfailure (CHF) has been attributed to a hypercoagulable stateincluding vascular endothelial dysfunction and platelet activation.After experimental myocardial infarction, male Wistar ratswere treated with placebo, the ACE inhibitor trandolapril, theselective aldosterone receptor antagonist eplerenone or thecombination of both, for 10 weeks. Platelet-bound fibrinogenand surface-expressed P-selectin were not modulated in ratswithout CHF compared with sham-operated animals, but weresignificantly increased in CHF rats (LVEDP>15mmHg). In CHFrats, ACE inhibition significantly reduced platelet P-selectinexpression while bound fibrinogen was not modulated.Eplerenone reduced P-selectin expression to a comparableextent, while platelet-bound fibrinogen was normalised. Combination therapy with eplerenone and trandolapril completelyabolished both the increased P-selectin expression aswell as fibrinogen binding. Phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at both Ser¹⁵⁷ andSer²³⁹,which reflects the activity of platelet inhibitors includingnitric oxide, was significantly reduced in platelets from placebotreatedCHF rats, and was completely normalised by combinationtreatment, but only marginally increased by either monotherapy.The results show that platelet activation was evident only in CHFrats. Monotherapy with ACE inhibition or eplerenone partiallyreduced this increased platelet activation, which was completelyrescued to basal levels by combination therapy. Increased nitricoxide bioavailability can only partially explain the reduced plateletactivation by eplerenone and ACE inhibition.