title: DPP-4 inhibitor linagliptin ameliorates cardiovascular injury in salt-sensitive hypertensive rats independently of blood glucose and blood pressure.
abstract: BACKGROUND
  It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats).
  
  
  METHODS
  High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3 mg/kg/day) once a day for 4 weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated.
  
  
  RESULTS
  Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67phox and p22 phox, and angiotensin-converting enzyme (ACE).
  
  
  CONCLUSIONS
  Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Katayama
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.forename: Ken
authors.initials: K
authors.lastname: Uekawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sueta
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kusaka
authors.forename: MingJie
authors.initials: M
authors.lastname: Ma
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Bowen
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan. mitsuyam@gpo.kumamoto-u.ac.jp.
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination / Q000379:methods; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D000069476:Linagliptin; D008297:Male; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D017673:Sodium Chloride, Dietary; D000069476:Linagliptin