Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Bayerische Julius-Maximilians-Universität Würzburg, Germany.
Pharmacol Res. 2010 Nov;62(5):432-8. doi: 10.1016/j.phrs.2010.06.008. Epub 2010 Jun 22.
Endothelial dysfunction and platelet activation due to impaired endogenous platelet inhibition by nitric oxide (NO) are part of the cardiovascular phenotype in congestive heart failure (CHF). We investigated whether chronic activation of the NO target enzyme soluble guanylyl cyclase (sGC) would beneficially modulate vascular function and platelet activation in experimental CHF.
Chronic myocardial infarction was induced by coronary ligation in male Wistar rats. Animals were either treated with placebo or the sGC activator ataciguat (10 mg/kg/twice daily by gavage). After 10 weeks, hemodynamic assessment was performed and only animals with impaired left-ventricular end-diastolic pressures of more than 15 mmHg were included in the analysis. Vasomotor function was determined in organ bath studies. NO bioavailability was assessed by in vivo platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. P-selectin was determined as a marker of platelet degranulation.
Endothelium-dependent, NO-mediated vasorelaxation as well as vascular sensitivity to exogenous NO were significantly impaired in aortic rings from CHF rats and normalised by ataciguat. In parallel, in vivo VASP phosphorylation reflecting NO bioavailability was significantly attenuated in platelets from CHF rats and normalised by ataciguat. Platelet activation, which was increased in CHF, was reduced by treatment with ataciguat.
Chronic sGC activation improved vasomotor function and reduced platelet activation in CHF rats.
由于一氧化氮（NO）对内源性血小板抑制作用受损导致的内皮功能障碍和血小板活化是充血性心力衰竭（CHF）心血管表型的一部分。我们研究了慢性激活 NO 靶酶可溶性鸟苷酸环化酶（sGC）是否会有益于调节实验性 CHF 中的血管功能和血小板活化。
雄性 Wistar 大鼠通过冠状动脉结扎诱导慢性心肌梗死。动物分别接受安慰剂或 sGC 激活剂阿托昔单抗（10 mg/kg/每日两次灌胃）治疗。10 周后，进行血流动力学评估，仅将左心室舒张末期压力超过 15 mmHg 的动物纳入分析。在器官浴研究中测定血管舒缩功能。通过体内血小板血管扩张刺激磷酸化蛋白（VASP）磷酸化来评估 NO 生物利用度。P-选择素作为血小板脱颗粒的标志物。
CHF 大鼠主动脉环中内皮依赖性、NO 介导的血管舒张以及对外源性 NO 的血管敏感性显著受损，而阿托昔单抗可使其正常化。平行地，CHF 大鼠血小板中反映 NO 生物利用度的体内 VASP 磷酸化显著减弱，而阿托昔单抗可使其正常化。CHF 中增加的血小板活化通过阿托昔单抗治疗得到减少。
慢性 sGC 激活可改善 CHF 大鼠的血管舒缩功能并减少血小板活化。
