Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition.

Abstract

OBJECTIVE:

Torcetrapib, a prototype cholesteryl ester transfer protein (CETP) inhibitor with potential for decreasing atherosclerotic disease, increased cardiovascular events in clinical trials. The identified hypertensive and aldosterone-elevating actions of torcetrapib may not fully account for this elevated cardiovascular risk. Therefore, we evaluated the effects of torcetrapib on endothelial mediated vasodilation in vivo.

METHODS AND RESULTS:

In vivo endothelial mediated vasodilation was assessed using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib, in addition to producing hypertension and baseline vasoconstriction, markedly inhibited acetylcholine-induced vasodilation. A structurally distinct CETP inhibitor, JNJ-28545595, did not affect endothelial function despite producing similar degrees of CETP inhibition and high-density lipoprotein elevation. Nitroprusside normalized torcetrapib's basal vasoconstriction and elicited dose-dependent vasodilation of norepinephrine preconstricted arteries in torcetrapib-treated animals, indicating torcetrapib did not impair smooth muscle function.

CONCLUSIONS:

Torcetrapib significantly impairs endothelial function in vivo, independent of CETP inhibition and high-density lipoprotein elevation. Given the well-documented association of endothelial dysfunction with cardiovascular disease and risk, this activity of torcetrapib may have contributed to increased cardiovascular risk in clinical trials.

• Authors: Margery A Connelly, Tom J Parry, Edward C Giardino, Zhihong Huang, Wai-Man Cheung, Cailin Chen, Frank Cools, Henk Van der Linde, David J Gallacher, Gee-Hong Kuo, Troy C Sarich, Keith T Demarest, Bruce P Damiano
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 55 Issue 5 Pg. 459-68 (May 2010) ISSN: 1533-4023 [Electronic] United States
• PMID: 20051879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Cholesterol Ester Transfer Proteins
• Quinolines
• torcetrapib

Topics

• Administration, Oral
• Animals
• Anticholesteremic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Cardiovascular Diseases (chemically induced, metabolism, physiopathology)
• Cholesterol Ester Transfer Proteins (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects)
• Injections, Intravenous
• Male
• Molecular Structure
• Quinolines (administration & dosage, adverse effects, pharmacokinetics)
• Rabbits
• Vasodilation (drug effects)