Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

E. S. G. Stroes, J. J. P. Kastelein, A. Bénardeau, O. Kuhlmann, D. Blum, L. A. Campos, R. G. Clerc, E. J. Niesor

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Abstract

Background and purpose: The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model. Experimental approach: Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg center dot kg-1 center dot day-1; dalcetrapib 100, 300 or 500 mg-1 center dot kg center dot day-1; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days' treatment with torcetrapib 40 mg center dot kg-1 center dot day-1, dalcetrapib 500 mg center dot kg-1 center dot day-1 or vehicle was measured by quantitative polymerase chain reaction. Key results: Torcetrapib transiently increased mean AP in normotensive rats (+3.7 +/- 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 +/- 0.6 mmHg with 40 mg center dot kg-1 center dot day-1 at day 1 (P <0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas. Conclusions and implications: In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein
Original languageEnglish
Pages (from-to)1763-1770
JournalBritish journal of pharmacology
Volume158
Issue number7
DOIs
Publication statusPublished - 2009

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