Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats.
2009
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.
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