Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Hypertens Res. 2019 Mar;42(3):319-328. doi: 10.1038/s41440-018-0169-3. Epub 2018 Dec 17.
The vasopressin type 2 receptor antagonist tolvaptan may have renoprotective effects in patients with heart failure (HF). This study aimed to reveal the renoprotective effect of tolvaptan from the viewpoint of hemodynamic combined with catheter and ultrasound examinations in a hypertensive HF model. Dahl salt-sensitive rats (n = 24) were fed an 8% high-salt diet after the age of 6 weeks and were treated with tolvaptan (n = 16) or vehicle (control group; n = 8). The tolvaptan-treated rats were divided into two groups: a low-dose group (0.01% tolvaptan diet; Low-Tol) and a high-dose group (0.05% tolvaptan diet; High-Tol). At 24 weeks, catheterizations to measure central venous pressure (CVP) and renal medullary pressure (RMP) were performed, followed by intrarenal Doppler (IRD) studies and contrast-enhanced ultrasonography (CEUS) to evaluate renal medullary perfusion. The tolvaptan diet reduced CVP (7.7 ± 1.5, 9.0 ± 1.1, and 12.2 ± 0.8 mmHg in the High-Tol, Low-Tol, and control groups, respectively; p < 0.001) and RMP (7.7 ± 0.8, 9.4 ± 1.3, and 13.7 ± 1.2 mmHg in the High-Tol, Low-Tol, and control groups, respectively; p < 0.001). Tolvaptan also reduced the venous impedance index (VII) in the IRD analysis (0.18 ± 0.03, 0.26 ± 0.04, and 0.40 ± 0.08 in the High-Tol, Low-Tol, and control groups, respectively; p < 0.001), and the time to peak intensity in CEUS (6.0 ± 0.5, 7.3 ± 1.3, 9.8 ± 1.8 s in the High-Tol, Low-Tol, and control groups, respectively; p < 0.001). Creatinine clearance (Ccr) was preserved in both the High-Tol and Low-Tol groups compared to the control group (4.80 ± 1.9, 4.24 ± 0.8, and 1.35 ± 0.3 mg/min, respectively; p = 0.001). Ccr was negatively correlated with RMP (R = -0.76, P < 0.001), the venous impedance index (R = -0.70, p < 0.001), time to peak intensity (R = -0.75, P < 0.001), and renal fibrosis (R = -0.70, p < 0.001). In contrast, Ccr had modest correlations with systolic blood pressure (R = -0.50, P = 0.02) and left ventricular ejection fraction (R = 0.48, P = 0.03). This study revealed that the renoprotective effects of tolvaptan in a hypertensive HF model depended on renal decongestion.
加压素 2 型受体拮抗剂托伐普坦可能对心力衰竭（HF）患者具有肾脏保护作用。本研究旨在通过导管和超声检查从血流动力学的角度揭示托伐普坦在高血压 HF 模型中的肾脏保护作用。24 周时，进行中心静脉压（CVP）和肾髓质压力（RMP）的导管检查，随后进行肾内多普勒（IRD）研究和对比增强超声（CEUS）以评估肾髓质灌注。托伐普坦饮食降低了 CVP（High-Tol、Low-Tol 和对照组分别为 7.7±1.5、9.0±1.1 和 12.2±0.8mmHg；p<0.001）和 RMP（7.7±0.8、9.4±1.3 和 13.7±1.2mmHg；p<0.001）。托伐普坦还降低了 IRD 分析中的静脉阻抗指数（VII）（High-Tol、Low-Tol 和对照组分别为 0.18±0.03、0.26±0.04 和 0.40±0.08；p<0.001），并且 CEUS 中的达峰时间（6.0±0.5、7.3±1.3 和 9.8±1.8s；p<0.001）。与对照组相比，High-Tol 和 Low-Tol 组的肌酐清除率（Ccr）均得到保留（4.80±1.9、4.24±0.8 和 1.35±0.3mg/min；p=0.001）。Ccr 与 RMP（R=-0.76，P<0.001）、静脉阻抗指数（R=-0.70，p<0.001）、达峰时间（R=-0.75，P<0.001）和肾纤维化（R=-0.70，p<0.001）呈负相关。相反，Ccr 与收缩压（R=-0.50，P=0.02）和左心室射血分数（R=0.48，P=0.03）呈中度相关。本研究表明，托伐普坦在高血压 HF 模型中的肾脏保护作用取决于肾脏去充血。
