title: Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition.
abstract: An increased risk of thrombembolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and platelet activation. After experimental myocardial infarction, male Wistar rats were treated with placebo, the ACE inhibitor trandolapril, the selective aldosterone receptor antagonist eplerenone or the combination of both, for 10 weeks. Platelet-bound fibrinogen and surface-expressed P-selectin were not modulated in rats without CHF compared with sham-operated animals, but were significantly increased in CHF rats (LVEDP>15 mmHg). In CHF rats, ACE inhibition significantly reduced platelet P-selectin expression while bound fibrinogen was not modulated. Eplerenone reduced P-selectin expression to a comparable extent, while platelet-bound fibrinogen was normalised. Combination therapy with eplerenone and trandolapril completely abolished both the increased P-selectin expression as well as fibrinogen binding. Phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at both Ser(157) and Ser(239), which reflects the activity of platelet inhibitors including nitric oxide, was significantly reduced in platelets from placebo-treated CHF rats, and was completely normalised by combination treatment, but only marginally increased by either mono-therapy. The results show that platelet activation was evident only in CHF rats. Monotherapy with ACE inhibition or eplerenone partially reduced this increased platelet activation, which was completely rescued to basal levels by combination therapy. Increased nitric oxide bioavailability can only partially explain the reduced platelet activation by eplerenone and ACE inhibition.
authors.affiliation: Medizinische Universitätsklinik, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Steven
authors.initials: S
authors.lastname: Hildemann
authors.forename: Michael
authors.initials: M
authors.lastname: Christ
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
authors.forename: Anna
authors.initials: A
authors.lastname: Kobsar
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004359:Drug Therapy, Combination; D000077545:Eplerenone; D005340:Fibrinogen / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008840:Microfilament Proteins; D000451:Mineralocorticoid Receptor Antagonists; D009569:Nitric Oxide / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015815:Cell Adhesion Molecules; D007211:Indoles; D008840:Microfilament Proteins; D000451:Mineralocorticoid Receptor Antagonists; D019007:P-Selectin; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C052035:trandolapril; D013148:Spironolactone; D009569:Nitric Oxide; D000077545:Eplerenone; D005340:Fibrinogen