Animal characteristics.

Renal dysfunction in heart failure increases mortality, limits treatment options and blunts responses to therapy. Angiotensin receptor-blocker and neprilysin inhibitors (ARNI) may preserve renal function by modulating both the renin-angiotensin-aldosterone system and the natriuretic peptide system. We investigated the renal effects of the ARNI Sacubitril/valsartan (Sac/Val) in rats with systolic dysfunction secondary to myocardial infarction. Male Sprague-Dawley rats underwent surgical MI induction and were randomized to six weeks of treatment with vehicle, valsartan or Sac/Val, and compared to sham operated animals. Renal function was evaluated by creatinine clearance, mean arterial pressure (MAP) by tail-cuff measurements, and cardiac function by magnetic resonance imaging and echocardiography. Vehicle treated animals developed cardiorenal syndrome, with impaired cardiac systolic function and mild renal dysfunction. Both valsartan and Sac/Val preserved renal function compared to vehicle (creatinine clearance mL/min [median with interquartile range]; sham 5.4 [4.8–6.0], vehicle 4.5 [4.1–5.1], valsartan 5.1 [5.1–5.5], Sac/Val 5.1 [5.0–5.6]; vehicle vs valsartan p = 0.034 and vehicle vs Sac/Val p = 0.044). MAP was reduced by both treatments compared to sham and vehicle groups (MAP mmHg; sham 131 [116–138], vehicle 123 [115–132], valsartan 108 [99–112], Sac/Val 111 [99–119]; sham vs valsartan p mm; sham 4.1 [3.7–4.4], vehicle 4.6 [3.8–5.6], valsartan 4.6 [4.1–5.5], Sac/Val 3.9 [3.6–4.5]; vehicle vs Sac/Val p = 0.047, valsartan vs Sac/Val p = 0.017) despite no improvement in systolic function in either treatment group. Sac/Val initiated in the acute post-MI phase preserved renal function to the same extent as valsartan alone and uniquely reduced left atrial dilatation, suggesting additional benefits beyond renoprotection in the setting of persistent systolic dysfunction.

心力衰竭合并肾功能不全可升高患者死亡率、限制治疗选择并削弱治疗应答反应。血管紧张素受体-脑啡肽酶抑制剂（Angiotensin receptor-neprilysin inhibitor, ARNI）可通过调节肾素-血管紧张素-醛固酮系统与利钠肽系统来保护肾功能。本研究探讨了ARNI类药物沙库巴曲缬沙坦（Sacubitril/valsartan, Sac/Val）对心肌梗死（myocardial infarction, MI）继发性收缩功能障碍大鼠的肾脏效应。雄性Sprague-Dawley大鼠经手术诱导MI后，被随机分为三组，分别接受溶剂对照、缬沙坦或Sac/Val治疗，共持续6周，并以假手术组作为对照。肾功能通过肌酐清除率评估，平均动脉压（mean arterial pressure, MAP）采用尾袖法测量，心功能则通过磁共振成像与超声心动图评估。溶剂对照组大鼠出现心肾综合征，表现为心脏收缩功能受损与轻度肾功能不全。与溶剂对照组相比，缬沙坦与Sac/Val均能保护肾功能（肌酐清除率单位：mL/min，数据以中位数[四分位间距]表示；假手术组：5.4[4.8~6.0]，溶剂对照组：4.5[4.1~5.1]，缬沙坦组：5.1[5.1~5.5]，Sac/Val组：5.1[5.0~5.6]；溶剂对照组vs缬沙坦组p=0.034，溶剂对照组vs Sac/Val组p=0.044）。与假手术组及溶剂对照组相比，两种治疗方案均可降低平均动脉压（MAP，单位：mmHg；假手术组：131[116~138]，溶剂对照组：123[115~132]，缬沙坦组：108[99~112]，Sac/Val组：111[99~119]；假手术组vs缬沙坦组p mm；假手术组：4.1[3.7~4.4]，溶剂对照组：4.6[3.8~5.6]，缬沙坦组：4.6[4.1~5.5]，Sac/Val组：3.9[3.6~4.5]；溶剂对照组vs Sac/Val组p=0.047，缬沙坦组vs Sac/Val组p=0.017），尽管两组治疗均未改善心脏收缩功能。在心肌梗死急性期启动Sac/Val治疗，其肾功能保护效果与单用缬沙坦相当，且可特异性降低左心房扩张程度，提示在持续性心脏收缩功能障碍的背景下，Sac/Val具有肾脏保护之外的额外获益。