Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
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.
Lyubov
L
Chaykovska
Markus L
ML
Alter
Karoline
K
von Websky
Margarete
M
Hohmann
Oleg
O
Tsuprykov
Christoph
C
Reichetzeder
Barbara
B
Kutil
Robin
R
Kraft
Thomas
T
Klein
Berthold
B
Hocher
D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000517:prevention & control; D024042:Collagen Type I; D003251:Constriction, Pathologic / Q000150:complications; D055316:Cystatin C / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D000069476:Linagliptin; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013525:Surgical Instruments; D000077333:Telmisartan
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D024042:Collagen Type I; D055316:Cystatin C; D054873:Dipeptidyl-Peptidase IV Inhibitors; D008077:Lipoproteins, LDL; D011687:Purines; D011799:Quinazolines; C099252:oxidized low density lipoprotein; D000069476:Linagliptin; D000077333:Telmisartan