Combined Angiotensin Receptor-Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure.
Combined Angiotensin Receptor-Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure.
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DOI：
10.1161/jaha.117.008268
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发表时间：
2018-03-03
影响因子：
5.4
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Trivedi RK;Polhemus DJ;Li Z;Yoo D;Koiwaya H;Scarborough A;Goodchild TT;Lefer DJ
关于萨舒比利/valsartan(也称为LCZ696)改善心力衰竭患者预后的机制，数据很少。具体地说，萨舒比利/valsartan对血管功能和NO生物利用度的影响尚未被研究。我们假设，在心力衰竭的情况下，萨舒比利/valsartan治疗可以增加循环中的NO水平，改善血管功能。雄性自发性高血压大鼠接受心肌缺血/再灌流手术造成心力衰竭，并通过连续超声心动图对其进行长达12周的跟踪观察。大鼠在再灌流后4周开始给予萨舒比利/valsartan(68 mg/kg)、valsartan(31 mg/kg)或赋形剂。在再灌流8周或12周时，对动物实施安乐死，并收集组织进行体外NO生物利用度、主动脉血管反应性、心肌和血管组织学以及心脏分子分析。与赋形剂相比，Valsartan和萨舒比利/valsartan均能改善左心结构和功能。萨舒比利/valsartan带来了更好的心血管益处，左心室射血分数和舒张末压力的持续改善证明了这一点。体外血管功能是通过对乙酰胆碱和硝普钠的主动脉松弛反应来衡量的，Valsartan和萨舒比利/valsartan显著改善了体外血管功能，萨舒比利/valsartan提供了更持久的改善。此外，在接受萨舒比利/valsartan治疗的动物中，心肌NO生物利用度显著提高。与单独使用valsartan相比，萨舒比利/valsartan在治疗心力衰竭时提供卓越的心血管保护，并在更大程度上改善血管功能。萨舒比利/valsartan介导的心脏和血管功能的改善可能与NO生物利用度的增加有关，这在一定程度上解释了血管紧张素受体阻断以外的好处。
There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end‐diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan‐mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.