title: Prevention of vascular injury by combination of an AT1 receptor blocker, olmesartan, with various calcium antagonists.
abstract: BACKGROUND
  A combination of different types of antihypertensive drugs is widely used for the treatment of hypertension. We examined the inhibitory effects of a combination of an AT(1) receptor blocker (ARB), olmesartan, with various calcium channel blockers (CCBs) on inflammatory vascular remodeling.
  
  
  METHODS
  Inflammatory vascular remodeling was induced by polyethylene-cuff placement around the femoral artery of C57BL/6J mice at 10 weeks of age. Olmesartan (0.5 mg/kg/day) was administered intraperitoneally using an osmotic minipump. CCBs (nifedipine 1.0 mg/kg/day, amlodipine 0.1 mg/kg/day, azelnidipine 0.1 mg/kg/day), and hydrochlorothiazide (HCTZ 0.5 mg/kg/day) were administered orally.
  
  
  RESULTS
  In the injured artery, superoxide anion production and expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47(phox) and Rac-1 were markedly increased, together with expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-alpha. Administration of a single drug alone at each concentration did not significantly inhibit these changes in the injured artery. However, a combination of olmesartan with various CCBs inhibited neointimal formation as well as oxidative stress and inflammatory markers in the injured artery. Moreover, among these CCBs, inhibition of these markers by olmesartan with azelnidipine was stronger than that caused by a combination with other CCBs. On the other hand, a combination of subeffective doses of olmesartan and HCTZ did not significantly affect vascular changes after cuff placement.
  
  
  CONCLUSIONS
  These results suggest that the combination of ARB with CCB synergistically inhibits vascular remodeling and that the inhibitory actions of ARB on vascular remodeling may vary depending on the combined CCB.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Inaba
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Izumi
authors.initials: I
authors.lastname: Senba
authors.forename: Megumi
authors.initials: M
authors.lastname: Furuno
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.forename: Hideki
authors.initials: H
authors.lastname: Okayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004095:Dihydropyridines / Q000494:pharmacology; D004357:Drug Synergism; D005263:Femoral Artery / Q000187:drug effects* / Q000293:injuries; D007093:Imidazoles / Q000494:pharmacology*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000096:biosynthesis; D009479:Neuropeptides / Q000096:biosynthesis; D009543:Nifedipine / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D017539:Tunica Intima / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis; D020830:rac1 GTP-Binding Protein
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004095:Dihydropyridines; D007093:Imidazoles; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D017311:Amlodipine; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D009543:Nifedipine; C061679:azelnidipine