title: Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. e.s.stroes@amc.uva.nl
authors.forename: E S G
authors.initials: ES
authors.lastname: Stroes
authors.forename: J J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: A
authors.initials: A
authors.lastname: Bénardeau
authors.forename: O
authors.initials: O
authors.lastname: Kuhlmann
authors.forename: D
authors.initials: D
authors.lastname: Blum
authors.forename: L A
authors.initials: LA
authors.lastname: Campos
authors.forename: R G
authors.initials: RG
authors.lastname: Clerc
authors.forename: E J
authors.initials: EJ
authors.lastname: Niesor
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000633:toxicity; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004952:Esters; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D016133:Polymerase Chain Reaction; D011804:Quinolines / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D011804:Quinolines; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib