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

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