Department of Anesthesiology, Pain Medicine and Critical Care, Steward St. Elizabeth's Medical Center/Tufts University School of Medicine , Boston, Massachusetts.
Department of Cardiology, Steward St. Elizabeth's Medical Center/Tufts University School of Medicine , Boston, Massachusetts.
Am J Physiol Heart Circ Physiol. 2019 Feb 1;316(2):H289-H297. doi: 10.1152/ajpheart.00579.2018. Epub 2018 Nov 21.
Simultaneous neprilysin inhibition (NEPi) and angiotensin receptor blockade (ARB) with sacubitril/valsartan improves cardiac function and exercise tolerance in patients with heart failure. However, it is not known whether these therapeutic benefits are primarily due to NEPi with sacubitril or ARB with valsartan or their combination. Therefore, the aim of the present study was to investigate the potential contribution of sacubitril and valsartan to the benefits of the combination therapy on left ventricular (LV) function and exercise tolerance. Heart failure was induced by volume overload via partial disruption of the aortic valve in rats. Therapy began 4 wk after valve disruption and lasted through 8 wk. Drugs were administered daily via oral gavage [sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), and sacubitril (31 mg/kg)]. Hemodynamic assessments were conducted using Millar technology, and an exercise tolerance test was conducted using a rodent treadmill. Therapy with sacubitril/valsartan improved load-dependent indexes of LV contractility (dP/d t) and relaxation (dP/d t), exercise tolerance, and mitigated myocardial fibrosis, whereas monotherapies with valsartan, or sacubitril did not. Both sacubitril/valsartan and valsartan similarly improved a load-independent index of contractility [slope of the end-systolic pressure-volume relationship ( E)]. Sacubitril did not improve E. First, synergy of NEPi with sacubitril and ARB with valsartan leads to the improvement of load-dependent LV contractility and relaxation, exercise tolerance, and reduction of myocardial collagen content. Second, the improvement in load-independent LV contractility with sacubitril/valsartan appears to be solely due to ARB with valsartan constituent. NEW & NOTEWORTHY Our data suggest the following explanation for the effects of sacubitril/valsartan: 1) synergy of sacubitril and valsartan leads to the improvement of load-dependent left ventricular contractility and relaxation, exercise tolerance, and reduction of myocardial fibrosis and 2) improvement in load-independent left ventricular contractility is solely due to the valsartan constituent. The findings offer a better understanding of the outcomes observed in clinical studies and might facilitate the continuing development of the next generations of angiotensin receptor neprilysin inhibitors.
沙库巴曲缬沙坦的同时抑制脑啡肽酶（NEPi）和血管紧张素受体阻断（ARB）可改善心力衰竭患者的心脏功能和运动耐量。然而，尚不清楚这些治疗益处主要是由于沙库巴曲中的 NEPi 还是缬沙坦中的 ARB 或它们的联合作用。因此，本研究旨在探讨沙库巴曲和缬沙坦对联合治疗对左心室（LV）功能和运动耐量的潜在益处的贡献。通过部分破坏主动脉瓣在大鼠中诱导心脏衰竭。在瓣膜破坏后 4 周开始治疗，并持续 8 周。药物通过口服灌胃给药[沙库巴曲缬沙坦（68mg/kg）、缬沙坦（31mg/kg）和沙库巴曲（31mg/kg）]。使用 Millar 技术进行血流动力学评估，使用啮齿动物跑步机进行运动耐量测试。沙库巴曲缬沙坦治疗可改善负荷依赖性 LV 收缩性（dP/d t）和舒张性（dP/d t）、运动耐量，并减轻心肌纤维化，而缬沙坦或沙库巴曲单药治疗则不能。沙库巴曲缬沙坦和缬沙坦均能改善收缩性的非负荷依赖性指标[收缩末期压力-容积关系（E）斜率]。沙库巴曲不能改善 E。首先，NEPi 与沙库巴曲的协同作用以及 ARB 与缬沙坦的协同作用可改善负荷依赖性 LV 收缩性和舒张性、运动耐量，并降低心肌胶原含量。其次，沙库巴曲缬沙坦改善非负荷依赖性 LV 收缩性似乎仅归因于缬沙坦成分的 ARB。新的和值得注意的是：我们的数据对沙库巴曲缬沙坦的作用提出了如下解释：1）沙库巴曲和缬沙坦的协同作用可改善负荷依赖性左心室收缩性和舒张性、运动耐量以及减少心肌纤维化；2）改善非负荷依赖性左心室收缩性仅归因于缬沙坦成分的 ARB。这些发现有助于更好地理解临床研究中观察到的结果，并可能有助于继续开发下一代血管紧张素受体脑啡肽酶抑制剂。
