The nitric oxide donor pentaerythritol tetranitrate reduces platelet activation in congestive heart failure.
BACKGROUND
Platelet activation associated with endothelial dysfunction and impaired endogenous platelet inhibition is part of the cardiovascular phenotype of congestive heart failure (CHF) and contributes to the increased risk for thromboembolic complications. Pentaerythritol tetranitrate (PETN) has been shown to release nitric oxide without development of nitrate tolerance. We investigated the effect of chronic PETN treatment on platelet activation and aggregation in an experimental CHF model.


RESULTS
Chronic ischemic heart failure was induced in male Wistar rats by coronary artery ligation. Starting 7 days thereafter, rats were randomised to placebo or PETN (80 mg/kg twice daily). After 9 weeks, activation of circulating platelets was determined measuring platelet bound fibrinogen, which requires activated glycoprotein IIb/IIIa on the platelet surface. Binding was quantified by flow-cytometry using a FITC-labelled anti-fibrinogen antibody. Platelet-bound fibrinogen was significantly increased in CHF-Placebo (mean fluorescence intensity: Sham 88±4, CHF-Placebo 104±6, p<0.05) and reduced following treatment with PETN (89±7, p<0.05 vs. CHF-Placebo). Maximal and final ADP-induced aggregation was significantly enhanced in CHF-Placebo vs. Sham-operated animals and normalized / decreased following chronic PETN treatment. Moreover, platelet adhesion was significantly reduced (number of adherent platelets: control: 85.6±5.5, PETN: 40±3.3; p<0.001) and VASP phosphorylation significantly enhanced following in vitro PETN treatment.


CONCLUSIONS
Chronic NO supplementation using PETN reduces platelet activation in CHF rats. Thus, PETN may constitute a useful approach to prevent thromboembolic complications in CHF.
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Ulrike
U
Flierl
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Daniela
D
Fraccarollo
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Julian D
JD
Widder
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Jan
J
Micka
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Jonas
J
Neuser
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Johann
J
Bauersachs
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
Andreas
A
Schäfer
D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013923:Thromboembolism / Q000097:blood / Q000517:prevention & control
D020030:Nitric Oxide Donors; D010417:Pentaerythritol Tetranitrate