title: Torcetrapib impairs endothelial function in hypertension.
abstract: OBJECTIVE
  A marked increase in HDL notwithstanding, the cholesterol ester transfer protein (CETP) inhibitor torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial. As underlying mechanisms remain elusive, the present study was designed to delineate potential off-target effects of torcetrapib.
  
  
  RESULTS
  Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib (100 mg/kg/day; SHR-T and WKY-T) or placebo (SHR-P and WKY-P) for 3 weeks. Blood pressure transiently increased during the first 3 days of torcetrapib administration in SHRs and returned to baseline thereafter despite continued drug administration. Acetylcholine-induced endothelium-dependent relaxations of aortic rings were markedly impaired, and endothelial nitric oxide synthase (eNOS) mRNA and protein were down-regulated after 3 weeks of torcetrapib treatment in SHR (P < 0.0001, <0.01, and <0.05, resp. vs. SHR-P). Torcetrapib reduced NO release in cultured aortic endothelial cells (P < 0.01 vs. vehicle-treated cells) and increased generation of reactive oxygen species in aortas of SHR-T (P < 0.05, vs. SHR-P). Vascular reactivity to endothelin-1 (ET-1) and aortic ET-1 tissue content were increased in SHR-T (P < 0.05 vs. SHR-P). Importantly, the ET-1 receptor A/B (ET(A/B)) antagonist bosentan normalized endothelial function in SHR-T (P < 0.05).
  
  
  CONCLUSIONS
  Torcetrapib induces a sustained impairment of endothelial function, decreases eNOS mRNA, protein as well as NO release, stimulates vascular ROS and ET production, an effect that is prevented by chronic ET(A/B)-receptor blockade. These unexpected off-target effects of torcetrapib need to be ruled out in the clinical development of novel CETP inhibitors, particularly before a large patient population at increased cardiovascular risk is exposed to these compounds.
authors.affiliation: Department of Cardiovascular Research, Institute of Physiology,  University of Zurich, Zurich,  Switzerland.
authors.forename: Branko
authors.initials: B
authors.lastname: Simic
authors.forename: Matthias
authors.initials: M
authors.lastname: Hermann
authors.forename: Sidney G
authors.initials: SG
authors.lastname: Shaw
authors.forename: Laurent
authors.initials: L
authors.lastname: Bigler
authors.forename: Urs
authors.initials: U
authors.lastname: Stalder
authors.forename: Carola
authors.initials: C
authors.lastname: Dörries
authors.forename: Christian
authors.initials: C
authors.lastname: Besler
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011804:Quinolines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C483909:torcetrapib; D052250:Nitric Oxide Synthase Type III; D000077300:Bosentan