Flierl Ulrike, Fraccarollo Daniela, Widder Julian D, Micka Jan, Neuser Jonas, Bauersachs Johann, Schäfer Andreas
Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Germany.
PLoS One. 2015 Apr 30;10(4):e0123621. doi: 10.1371/journal.pone.0123621. eCollection 2015.
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.
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.
Chronic NO supplementation using PETN reduces platelet activation in CHF rats. Thus, PETN may constitute a useful approach to prevent thromboembolic complications in CHF.
与内皮功能障碍及内源性血小板抑制受损相关的血小板激活是充血性心力衰竭（CHF）心血管表型的一部分，并导致血栓栓塞并发症风险增加。已证明季戊四醇四硝酸酯（PETN）可释放一氧化氮且不会产生硝酸盐耐受性。我们在实验性CHF模型中研究了慢性PETN治疗对血小板激活和聚集的影响。
通过冠状动脉结扎在雄性Wistar大鼠中诱导慢性缺血性心力衰竭。此后7天开始，将大鼠随机分为安慰剂组或PETN组（80 mg/kg，每日两次）。9周后，通过测量血小板结合的纤维蛋白原确定循环血小板的激活情况，这需要血小板表面的活化糖蛋白IIb/IIIa。使用异硫氰酸荧光素（FITC）标记的抗纤维蛋白原抗体通过流式细胞术对结合进行定量。CHF-安慰剂组中血小板结合的纤维蛋白原显著增加（平均荧光强度：假手术组88±4，CHF-安慰剂组104±6，p<0.05），而PETN治疗后降低（89±7，与CHF-安慰剂组相比p<0.05）。与假手术动物相比，CHF-安慰剂组中最大和最终ADP诱导的聚集显著增强，慢性PETN治疗后恢复正常/降低。此外，体外PETN治疗后血小板黏附显著减少（黏附血小板数量：对照组：85.6±5.5，PETN组：40±3.3；p<0.001）且血管平滑肌肌动蛋白（VASP）磷酸化显著增强。
使用PETN进行慢性一氧化氮补充可降低CHF大鼠的血小板激活。因此，PETN可能是预防CHF血栓栓塞并发症的一种有用方法。
