TY - JOUR
T1 - Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats
AU - Stroes, E. S. G.
AU - Kastelein, J. J. P.
AU - Bénardeau, A.
AU - Kuhlmann, O.
AU - Blum, D.
AU - Campos, L. A.
AU - Clerc, R. G.
AU - Niesor, E. J.
PY - 2009
Y1 - 2009
N2 - 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
AB - 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
U2 - https://doi.org/10.1111/j.1476-5381.2009.00460.x
DO - https://doi.org/10.1111/j.1476-5381.2009.00460.x
M3 - Article
C2 - 19917065
SN - 0007-1188
VL - 158
SP - 1763
EP - 1770
JO - British journal of pharmacology
JF - British journal of pharmacology
IS - 7
ER -