Key result
Torcetrapib impairs endothelium-dependent relaxation and markedly down-regulates eNOS expression in hypertensive rats.
Why the study?
The mechanisms underlying the increased all-cause mortality associated with the CETP inhibitor torcetrapib remain elusive, necessitating investigation of its potential off-target effects.
Does torcetrapib impair endothelial function in spontaneously hypertensive rats?
Population
Spontaneously hypertensive rats and Wistar-Kyoto rats
Comparison
Torcetrapib 100 mg/kg/day vs placebo for 3 weeks
Design
Preclinical experimental study
Follow-up
3 weeks
Authors
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Torcetrapib impairs endothelial function via eNOS downregulation in hypertensive rats; hypothesis-generating for off-target mechanisms in CETP inhibition.
Does torcetrapib impair endothelial function in spontaneously hypertensive rats?
p-value: p=<0.0001
Torcetrapib causes off-target impairment of endothelial function and increases reactive oxygen species and endothelin production in hypertensive rats, potentially explaining the increased mortality seen in clinical trials.
Simic et al. (2011) studied Hypertension. Torcetrapib vs. Placebo was evaluated on Endothelium-dependent relaxations and eNOS mRNA/protein expression (p=<0.0001). Torcetrapib treatment for 3 weeks in spontaneously hypertensive rats markedly impaired endothelium-dependent relaxations and down-regulated eNOS mRNA and protein (P<0.0001 vs placebo).