title: Pioglitazone enhances the blood pressure-lowering effect of losartan via synergistic attenuation of angiotensin II-induced vasoconstriction.
abstract: BACKGROUND
  This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats.
  
  
  METHODS
  An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT1), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox), level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected.
  
  
  RESULTS
  After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47(phox) and AT1, NADPH oxidase activity, and nitrotyrosine level.
  
  
  CONCLUSIONS
  Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.
authors.affiliation: Department of Endocrinology, Xinhua Hospital,Shanghai Jiaotong University School of Medicine, China Department of Pharmacology, Third-Grade Pharmacology Laboratory of State Administration of Traditional Chinese Medicine, Wannan Medical College,China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, China.
authors.forename: Ming-Zhe
authors.initials: MZ
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, Xinhua Hospital,Shanghai Jiaotong University School of Medicine, China.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Gastroenterology,Yijishan Hospital Affiliated to Wannan Medical College, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Xinhua Hospital,Shanghai Jiaotong University School of Medicine, China.
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Wannan Medical College,China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Xinhua Hospital,Shanghai Jiaotong University School of Medicine, China suqingxinhua@yahoo.com.cn yjszhangdaoyou@sina.com.
authors.forename: Qing
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Nephrology,Yijishan Hospital Affiliated to Wannan Medical College, China.
authors.forename: Dao-You
authors.initials: DY
authors.lastname: Zhang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D000077205:Pioglitazone; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D044140:Receptor, Angiotensin, Type 1; D045162:Thiazolidinediones; D000804:Angiotensin II; D009599:Nitroprusside; D010656:Phenylephrine; C002744:3-nitrotyrosine; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D019808:Losartan; D000109:Acetylcholine; D000077205:Pioglitazone
keywords: Losartan; angiotensin II; endothelial dysfunction; pioglitazone