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


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.
Connelly
Margery A
MA
Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. mconnell@its.jnj.com
Parry
Tom J
TJ
Giardino
Edward C
EC
Huang
Zhihong
Z
Cheung
Wai-Man
WM
Chen
Cailin
C
Cools
Frank
F
Van der Linde
Henk
H
Gallacher
David J
DJ
Kuo
Gee-Hong
GH
Sarich
Troy C
TC
Demarest
Keith T
KT
Damiano
Bruce P
BP
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D011804:Quinolines; C483909:torcetrapib