Department of Anesthesiology, Pain Medicine and Critical Care, Steward St Elizabeth's Medical Center/Tufts University School of Medicine, Boston, Massachusetts.
Department of Anesthesiology, Pain Medicine and Critical Care, Steward St Elizabeth's Medical Center/Tufts University School of Medicine, Boston, Massachusetts.
J Card Fail. 2018 Nov;24(11):773-782. doi: 10.1016/j.cardfail.2018.10.006. Epub 2018 Oct 19.
Simultaneous angiotensin receptor (AT) blockade and neprilysin inhibition with the use of sacubitril/valsartan has been recently approved to treat patients with heart failure (HF). Therapeutic benefits of this therapy have been attributed to natriuretic peptide elevation and AT receptor blockade. However, that pharmacologic picture may not be complete. The aims of this study were to investigate the pharmacology of sacubitril/valsartan compared with sacubitril and valsartan alone and to examine their impact on peptides up-regulated by neprilysin inhibition, such as beta-endorphin.
An HF model was induced by pressure overload via constriction of the suprarenal abdominal aorta in rats. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or placebo was administered by daily oral gavage (starting 4 weeks after pressure overload onset and continued for 4 additional weeks; n = 8 in each group). Exercise tolerance testing was conducted using a rodent treadmill and hemodynamic assessments were conducted under anesthesia with the use of Millar left ventricular (LV) conductance technology. Pressure overload led to exercise intolerance by 4 weeks and to hypertension and LV dysfunction and remodeling by 8 weeks. Both sacubitril/valsartan and sacubitril elevated beta-endorphin levels, by 40% and 54%, respectively, and improved exercise tolerance, by 93% and 112%, whereas valsartan did not. Indices of LV dysfunction persisted with the use of sacubitril/valsartan and valsartan therapies and even deteriorated in sacubitril group.
When added to valsartan, sacubitril increases beta-endorphin concentrations and improves exercise tolerance. These data suggest beta-endorphin elevation as a potential mechanism of action leading to improvement in exercise tolerance that is seen with sacubitril/valsartan. This therapeutic benefit is potentially independent from LV function.
最近，使用沙库巴曲/缬沙坦同时抑制血管紧张素受体 (AT) 和 Neprilysin 的治疗方法已被批准用于治疗心力衰竭 (HF) 患者。这种治疗的治疗益处归因于利钠肽的升高和 AT 受体的阻断。然而，这种药理学作用可能并不完全。本研究的目的是研究沙库巴曲/缬沙坦与沙库巴曲和缬沙坦单独使用的药理学，并研究它们对 Neprilysin 抑制上调的肽，如β-内啡肽的影响。
通过在大鼠肾上腹主动脉缩窄引起压力超负荷来诱导 HF 模型。沙库巴曲/缬沙坦 (68mg/kg)、缬沙坦 (31mg/kg)、沙库巴曲 (31mg/kg) 或安慰剂通过每日口服灌胃给药（在压力超负荷开始后 4 周开始并持续 4 周；每组 8 只）。使用啮齿动物跑步机进行运动耐量测试，并使用 Millar 左心室 (LV) 电导技术在麻醉下进行血流动力学评估。压力超负荷导致 4 周时运动不耐受，8 周时高血压和 LV 功能障碍和重塑。沙库巴曲/缬沙坦和沙库巴曲分别使β-内啡肽水平升高 40%和 54%，并使运动耐量分别提高 93%和 112%，而缬沙坦则没有。沙库巴曲/缬沙坦和缬沙坦治疗仍存在 LV 功能障碍指标，沙库巴曲组甚至恶化。
当添加到缬沙坦时，沙库巴曲增加β-内啡肽浓度并提高运动耐量。这些数据表明β-内啡肽升高是导致沙库巴曲/缬沙坦改善运动耐量的潜在作用机制。这种治疗益处可能与 LV 功能无关。
