Chaykovska Lyubov, Alter Markus L, von Websky Karoline, Hohmann Margarete, Tsuprykov Oleg, Reichetzeder Christoph, Kutil Barbara, Kraft Robin, Klein Thomas, Hocher Berthold
aCenter for Cardiovascular Research, Charité University Hospital, Berlin, Germany bClinic for Cardiovascular Surgery, University Hospital of Zürich, Zürich, Switzerland cInstitute for Nutritional Science, University of Potsdam, Nuthetal-Rehbrücke dDepartment of Nephrology, Campus Benjamin Franklin, Charité University Hospital, Berlin eCardioMetabolic Research, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany *These authors have equally contributed to this article.
J Hypertens. 2013 Nov;31(11):2290-8; discussion 2299. doi: 10.1097/HJH.0b013e3283649b4d.
To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.
Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n = 14-18 per group) receiving: telmisartan (10 mg/kg per day in drinking water), linagliptin (89 ppm in chow), combination (linagliptin 89 ppm + telmisartan 10 mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.
Renal stenosis caused an increase in mean ± SD systolic BP as compared with the sham group (157.7 ± 29.3 vs. 106.2 ± 20.5 mmHg, respectively; P < 0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 ± 24.3 mmHg and 100.4 ± 13.9 mmHg, respectively; P < 0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P = 0.03 vs. placebo) and in combination with telmisartan (P = 0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P = 0.04 vs. placebo).
Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.
研究利格列汀单独使用以及与血管紧张素II受体阻滞剂（ARB）替米沙坦联合使用对肾血管性高血压大鼠血压（BP）、肾功能、心脏形态和氧化应激的影响。
57只雄性Wistar大鼠接受单侧肾动脉手术性狭窄[双肾一夹（2k1c）法]。动物被随机分为四个治疗组（每组n = 14 - 18只），分别接受：替米沙坦（饮水中每天10 mg/kg）、利格列汀（饲料中89 ppm）、联合用药（利格列汀89 ppm + 替米沙坦每天10 mg/kg）或安慰剂。另外一组12只大鼠接受假手术。术后一周测量血压。高血压动物进入为期16周的给药期。在治疗开始后2、4、8、12和16周测量血压。在术后6、10、14和18周检测血液和尿液以评估肾功能和氧化应激。最后进行血液和尿液采样以及器官摘取。
与假手术组相比，肾狭窄导致平均±标准差收缩压升高（分别为157.7 ± 29.3 vs. 106.2 ± 20.5 mmHg；P < 0.001）。单独使用替米沙坦以及与利格列汀联合使用可使收缩压恢复正常（分别为111.1 ± 24.3 mmHg和100.4 ± 13.9 mmHg；与安慰剂相比P < 0.001）。单独使用替米沙坦以及与利格列汀联合使用可显著预防心脏肥大，通过心脏重量和心肌细胞直径衡量。通过胱抑素C测量的肾功能不受2k1c手术影响。替米沙坦显著增加血浆胱抑素C浓度。2k1c手术引发双侧肾脏纤维化。通过Col1a1蛋白表达以及间质纤维化和肾小球硬化的组织学检测，替米沙坦促进夹闭侧肾脏进一步发生纤维化改变。在未夹闭侧肾脏，替米沙坦表现出抗纤维化特性，降低Col1a1蛋白表达。与假手术动物相比，安慰剂治疗的2k1c大鼠血浆氧化型低密度脂蛋白水平更高。单独使用利格列汀（与安慰剂相比P = 0.03）以及与替米沙坦联合使用（与安慰剂相比P = 0.02）可消除这种升高。联合治疗还显著降低血浆羰基蛋白浓度（与安慰剂相比P = 0.04）。
在2k1c大鼠中，利格列汀抑制4型二肽基肽酶并不抵消ARB的降压作用。利格列汀降低2k1c大鼠的脂质和蛋白质氧化，且这种作用与血压无关。
