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Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve

Roger G Clerc1, Andrea Stauffer, Franziska Weibel

  • 1F Hoffmann-La Roche Ltd, Basel, Switzerland.

Journal of Hypertension
|May 26, 2010
PubMed
Abstract

Insights

Cholesteryl ester transfer protein inhibitor torcetrapib increases aldosterone and blood pressure through L-type calcium channels. Unlike other CETP inhibitors, torcetrapib uniquely affects aldosterone production and causes hypertension.

Area of Science:

  • Endocrinology
  • Cardiovascular Pharmacology
  • Molecular Biology

Background:

  • Cholesteryl ester transfer protein (CETP) inhibitors have shown increased mortality.
  • Torcetrapib, a CETP inhibitor, is associated with increased aldosterone production and blood pressure.
  • The mechanisms behind torcetrapib's side effects require investigation.

Purpose of the Study:

  • To investigate the mechanisms underlying torcetrapib-induced aldosterone production and hypertension.
  • To compare the effects of torcetrapib with angiotensin II and a structurally different CETP inhibitor, dalcetrapib.

Main Methods:

  • Aldosterone synthase (CYP11B2) mRNA profiling in H295R cells.
  • Aldosterone production, cytosolic calcium, and ERK phosphorylation assays.
  • RNA interference and genome-wide gene expression screening.
  • Telemetry in spontaneously hypertensive rats.

Main Results:

  • Torcetrapib and angiotensin II increased CYP11B2 mRNA and aldosterone production in H295R cells.
  • Torcetrapib induced a sustained increase in CYP11B2 mRNA, unlike angiotensin II.
  • Torcetrapib's steroidogenic effects were blocked by L-type calcium channel antagonists, unlike angiotensin II.
  • Torcetrapib upregulated L-type calcium channel alpha 1C subunit mRNA and caused hypertension in rats.

Conclusions:

  • Torcetrapib's unique steroidogenic and hypertensive effects are linked to voltage-gated L-type calcium channels.
  • These side effects are not shared by structurally unrelated CETP inhibitors like dalcetrapib.

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