Ferrari Roberto, Cardoso J, Fonseca M C, Aguiar C, Moreira J I, Fucili A, Rapezzi C
University Cardiologic Centre, University Hospital of Ferrara, Ferrara, Italy.
Maria Cecilia Hospital, Cotignola, Italy.
Clin Res Cardiol. 2020 May;109(5):599-610. doi: 10.1007/s00392-019-01547-2. Epub 2019 Sep 17.
A new class of drugs-angiotensin receptor, neprylisin inhibitors, ARNI-has shown to be prognostic superior in HFrEF to the sole inhibition of the renin-angiotensin axes with enalapril. The ultimate mechanism of action of ARNIs is unknown.
We have considered that ARNI exerts a positive modulation of the neuroendocrine balance, with enhancement of the physiological diuresis and dilatation due to neprylisin inhibition by sacubitril. This represents a shift in HF medical therapy always directed to counteract (with inhibitors of the renin-angiotensin system, beta blockers or inhibitors of aldosterone) the so-called "bad" neuroendocrine response. Development of ARNI, on the contrary, has led to consider the neuroendocrine response to HFrEF from a different angle, which is to say that the activation is not always deleterious, but it could also be beneficial. This concept is highlighted by the enhancement of the activity of atrial natriuretic peptide, induced by sacubitril/valsartan in the PARADIGM trial, and found as proof from early studies on untreated patients with constrictive pericarditis. The possibility that sacubitril inhibition of neprylisin acts by enhancing substance P and gene-related calcitonin peptide is also considered, as well as the negative effect of neprylisin inhibition.
The beneficial effects of ARNI are related, in part at least, to a positive modulation of the neuroendocrine response to the disease, resulting in an increase of physiological diuresis and dilatation.
一类新型药物——血管紧张素受体脑啡肽酶抑制剂（ARNI）——已显示在射血分数降低的心力衰竭（HFrEF）中，其预后优于依那普利单纯抑制肾素 - 血管紧张素轴。ARNI的最终作用机制尚不清楚。
我们认为ARNI对神经内分泌平衡发挥正向调节作用，由于沙库巴曲抑制脑啡肽酶，从而增强生理性利尿和扩张作用。这代表了心力衰竭医学治疗的转变，以往总是旨在（通过肾素 - 血管紧张素系统抑制剂、β受体阻滞剂或醛固酮抑制剂）对抗所谓的“不良”神经内分泌反应。相反，ARNI的研发促使人们从不同角度考虑HFrEF的神经内分泌反应，也就是说，这种激活并非总是有害的，也可能是有益的。沙库巴曲/缬沙坦在PARADIGM试验中诱导心房利钠肽活性增强，以及在未经治疗的缩窄性心包炎患者的早期研究中发现的证据都突出了这一概念。还考虑了沙库巴曲抑制脑啡肽酶可能通过增强P物质和降钙素基因相关肽发挥作用，以及抑制脑啡肽酶的负面影响。
ARNI的有益作用至少部分与对该疾病神经内分泌反应的正向调节有关，从而导致生理性利尿和扩张增加。
