title: Effects of telmisartan, a unique angiotensin receptor blocker with selective peroxisome proliferator-activated receptor-gamma-modulating activity, on nitric oxide bioavailability and atherosclerotic change.
abstract: OBJECTIVE
  Telmisartan is a unique angiotensin II (Ang II) receptor blocker (ARB) with selective peroxisome proliferator-activated receptor-gamma (PPAR gamma). We therefore investigated the effects of telmisartan on endothelial function and atherosclerotic change in genetically hyperlipidemic rabbits, compared with candesartan, an ARB without PPAR gamma activity.
  
  
  METHODS
  A total of 30 Watanabe heritable hyperlipidemic (WHHL) rabbits equally derived (n = 6 each) were treated with (1) vehicle (control), (2) GW9662, a PPAR gamma antagonist (0.5 mg/kg per day), (3) telmisartan (5 mg/kg per day), (4) telmisartan + GW9662, (5) candesartan (5 mg/kg per day) for 8 weeks. After treatment, acetylcholine (ACh)-induced nitric oxide production was measured as a surrogate for endothelium protective function, and vascular nitrotyrosine (a product of superoxide and nitric oxide) was measured for assessing dysfunctional endothelial nitric oxide synthase activity. Plaque area was quantified by histology.
  
  
  RESULTS
  Telmisartan increased ACh-induced nitric oxide by 5.5 nmol/l, significantly more than control. Interestingly, cotreatment with GW9662 significantly attenuated telmisartan-induced ACh-induced nitric oxide almost to the levels observed with candesartan. Vascular nitrotyrosine concentration was 1.4 pmol/mg protein in the control group and significantly higher than that in the telmisartan or candesartan group. The lowest nitrotyrosine concentration was observed in the telmisartan group, which was significantly lower than that in the candesartan or telmisartan + GW9662 group. Histology of the thoracic aorta revealed that the plaque area was more significantly decreased in the telmisartan group than in the candesartan or telmisartan + GW9662 group.
  
  
  CONCLUSIONS
  In addition to a class effect of ARBs, telmisartan may have additional effects on nitric oxide bioavailability and atherosclerotic change through its PPAR gamma-mediated effects in genetically hyperlipidemic rabbits.
authors.affiliation: Department of Cardiovascular Medicine, Wakayama Medical University Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikejima
authors.forename: Toshio
authors.initials: T
authors.lastname: Imanishi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsujioka
authors.forename: Akio
authors.initials: A
authors.lastname: Kuroi
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiomi
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Muragaki
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Masami
authors.initials: M
authors.lastname: Goto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Akasaka
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000813:Anilides; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000503:physiopathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004195:Disease Models, Animal; D006949:Hyperlipidemias; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D047495:PPAR gamma / Q000187:drug effects*; D011817:Rabbits; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D047495:PPAR gamma; D013777:Tetrazoles; D009569:Nitric Oxide; C081643:candesartan; D000077333:Telmisartan