Article date: December 2009
By: ESG Stroes, JJP Kastelein, A Bénardeau, O Kuhlmann, D Blum, LA Campos, RG Clerc, EJ Niesor in Volume 158, Issue 7, pages 1763-1770
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·kg−1·day−1; dalcetrapib 100, 300 or 500 mg−1·kg·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·kg−1·day−1, dalcetrapib 500 mg·kg−1·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·kg−1·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.
DOI: 10.1111/j.1476-5381.2009.00460.x
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