Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Circ Heart Fail. 2012 Sep 1;5(5):627-34. doi: 10.1161/CIRCHEARTFAILURE.112.969220. Epub 2012 Aug 13.
TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein-mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin-mediated signaling. Consequently, TRV120027 inhibits angiotensin II-mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in experimental heart failure.
Two groups of anesthetized dogs (n=6 each) with tachypacing-induced heart failure were studied. After a baseline clearance, 1 group (F+V) received furosemide (1 mg/kg per hour) plus saline for 90 minutes, whereas the other (F+T) received the same dose of furosemide plus TRV120027 (0.3 and 1.5 µg/kg per minute for 45 minutes each); 2 clearances were done during drug infusion. After a washout, a postinfusion clearance was done; P<0.05 between groups. F+V and F+T increased diuresis and natriuresis to a similar extent during drug administration, but urine flow and urinary sodium excretion* were higher in the postinfusion clearance with F+T. Glomerular filtration rate was preserved in both groups. Renal blood flow increased with F+T but this was not significant versus F+V. Compared with F+V, F+T decreased mean arterial pressure*, systemic* and pulmonary* vascular resistances, and atrial natriuretic peptide*. Pulmonary capillary wedge pressure* decreased to a larger extent with F+T than with F+V.
When added to furosemide, TRV120027, a novel β-arrestin biased angiotensin II type 1 receptor ligand, preserved furosemide-mediated natriuresis and diuresis, while reducing cardiac preload and afterload. These results provide support for TRV120027 as a promising novel therapeutic for the treatment of heart failure.
TRV120027 是一种新型的血管紧张素 II 型 1 受体的β-arrestin 偏向配体；它拮抗经典的 G 蛋白介导的偶联，而与经典的血管紧张素 II 型 1 受体拮抗剂不同，它与β-arrestin 介导的信号转导结合。因此，TRV120027 抑制血管紧张素 II 介导的血管收缩，同时通过β-arrestin 偶联增加心肌细胞的收缩力。我们假设，当与呋塞米联合使用时，TRV120027 会在实验性心力衰竭中产生有益的心肾作用。
我们研究了两组麻醉犬（每组 6 只），它们通过快节奏起搏诱导心力衰竭。在基线清除后，一组（F+V）接受呋塞米（1 毫克/公斤/小时）加生理盐水 90 分钟，而另一组（F+T）接受相同剂量的呋塞米加 TRV120027（0.3 和 1.5 微克/公斤/分钟，各 45 分钟）；在药物输注过程中进行了 2 次清除。在冲洗后，进行了输注后清除；P<0.05 组间差异有统计学意义。F+V 和 F+T 在药物治疗期间均使尿量和尿钠排泄量增加到相似的程度，但 F+T 的输注后清除时尿流量和尿钠排泄量更高。两组肾小球滤过率均保持不变。肾血流量随 F+T 增加，但与 F+V 相比无统计学意义。与 F+V 相比，F+T 降低了平均动脉压、全身和肺血管阻力以及心房利钠肽*。与 F+V 相比，F+T 使肺毛细血管楔压*降低的幅度更大。
当与呋塞米联合使用时，TRV120027 是一种新型的β-arrestin 偏向血管紧张素 II 型 1 受体配体，它保留了呋塞米介导的利尿和排钠作用，同时降低了心脏前负荷和后负荷。这些结果为 TRV120027 作为心力衰竭治疗的一种有前途的新型治疗方法提供了支持。
