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Assessing Endothelial Vasodilator Function with the Endo-PAT 2000
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Torcetrapib impairs endothelial function in hypertension.

Branko Simic1, Matthias Hermann, Sidney G Shaw

  • 1Department of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland.

European Heart Journal
|September 17, 2011
PubMed
Summary
This summary is machine-generated.

Cholesterol ester transfer protein (CETP) inhibitor torcetrapib impaired endothelial function and increased mortality. Torcetrapib reduced nitric oxide and increased oxidative stress, effects reversed by endothelin-1 receptor blockade.

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Area of Science:

  • Pharmacology
  • Cardiovascular Research
  • Endothelial Biology

Background:

  • Cholesterol ester transfer protein (CETP) inhibitor torcetrapib increased HDL but also all-cause mortality in the ILLUMINATE trial.
  • Underlying mechanisms for torcetrapib's adverse effects remain unclear, necessitating investigation into potential off-target actions.

Purpose of the Study:

  • To investigate the potential off-target effects of torcetrapib on endothelial function.
  • To elucidate the mechanisms contributing to torcetrapib-associated mortality.

Main Methods:

  • Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib or placebo for 3 weeks.
  • Vascular reactivity, nitric oxide (NO) release, reactive oxygen species (ROS) generation, and endothelin-1 (ET-1) levels were assessed.
  • Effects of ET-1 receptor blockade with bosentan were evaluated.

Main Results:

  • Torcetrapib impaired endothelium-dependent relaxations and reduced endothelial nitric oxide synthase (eNOS) mRNA and protein in SHRs.
  • Torcetrapib decreased NO release, increased ROS generation, and elevated vascular ET-1 levels.
  • Bosentan treatment normalized endothelial function in torcetrapib-treated SHRs.

Conclusions:

  • Torcetrapib induces sustained endothelial dysfunction, reduced NO bioavailability, and increased oxidative stress and ET-1 production.
  • These detrimental effects are preventable with ET(A/B)-receptor blockade.
  • Novel CETP inhibitors require thorough evaluation for similar off-target effects before clinical use in high-risk populations.