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Torcetrapib impairs endothelial function in hypertension

Simic, Branko ; Hermann, Matthias ; Shaw, Sidney G. ; Bigler, Laurent ; Stalder, Urs ; Dörries, Carola ; Besler, Christian ; Lüscher, Thomas F. ; Ruschitzka, Frank

In: European Heart Journal, 2012, vol. 33, no. 13, p. 1615-1624

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    Titre
    • Torcetrapib impairs endothelial function in hypertension
    Auteur
    • Simic, Branko. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    • Hermann, Matthias. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    • Shaw, Sidney G.. Department of Clinical Research, Medical Faculty of the University of Bern, Bern, Switzerland
    • Bigler, Laurent. Department of Organic Chemistry, University of Zurich, Zurich, Switzerland
    • Stalder, Urs. Department of Organic Chemistry, University of Zurich, Zurich, Switzerland
    • Dörries, Carola. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    • Besler, Christian. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    • Lüscher, Thomas F.. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    • Ruschitzka, Frank. Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • European Heart Journal, 2012, vol. 33, no. 13, p. 1615-1624. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:291252
    Summary
    Aims 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. Methods and 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 (ETA/B) antagonist bosentan normalized endothelial function in SHR-T (P < 0.05). Conclusion 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 ETA/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