BJPOpen RESEARCH PAPER British Journal of Pharmacology (2008) 154, 1465–1473 & 2008 Nature Publishing Group All rights reserved 0007–1188/08 $30.00 www.brjpharmacol.org Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone MJ Forrest1, D Bloomfield1, RJ Briscoe 2 , PN Brown 1 , A-M Cumiskey 1 , J Ehrhart2, JC Hershey 3 , WJ Keller2, X Ma 1 , HE McPherson 2 , E Messina 4 , LB Peterson 1 , W Sharif-Rodriguez1, PKS Siegl2, PJ Sinclair5, CP Sparrow1, AS Stevenson1, S-Y Sun1, C Tsai1, H Vargas2,6, M Walker III4, SH West1, V White1 and RF Woltmann2 1Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ, USA; 2Safety and Exploratory Pharmacology, Merck Research Laboratories, West Point, PA, USA; 3Molecular Endocrinology, West Point, PA, USA; 4Imaging, Merck Research Laboratories, Rahway, NJ, USA and 5Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ, USA Background and purpose: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib. Experimental approach: Cardiovascular effects of the CETP inhibitors torcetrapib and anacetrapib were evaluated in animal models. Key results: Torcetrapib evoked an acute increase in blood pressure in all species evaluated whereas no increase was observed with anacetrapib. The pressor effect of torcetrapib was not diminished in the presence of adrenoceptor, angiotensin II or endothelin receptor antagonists. Torcetrapib did not have a contractile effect on vascular smooth muscle suggesting its effects in vivo are via the release of a secondary mediator. Treatment with torcetrapib was associated with an increase in plasma levels of aldosterone and corticosterone and, in vitro, was shown to release aldosterone from adrenocortical cells. Increased adrenal steroid levels were not observed with anacetrapib. Inhibition of adrenal steroid synthesis did not inhibit the pressor response to torcetrapib whereas adrenalectomy prevented the ability of torcetrapib to increase blood pressure in rats. Conclusions and implications: Torcetrapib evoked an acute increase in blood pressure and an acute increase in plasma adrenal steroids. The acute pressor response to torcetrapib was not mediated by adrenal steroids but was dependent on intact adrenal glands. British Journal of Pharmacology (2008) 154, 1465 – 1473; doi:10.1038/bjp.2008.229; published online 9 June 2008 Keywords: cholesteryl ester transfer protein inhibitor; aldosterone; preclinical animal models Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein Introduction The use of statins for lowering low-density lipoprotein (LDL) in humans has unequivocally been demonstrated to reduce the incidence of cardiovascular disease and increase long- evity (Scandinavian Simvastatin Survival Study Group, 1994; Sacks et al., 1996; Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, 1998; Sever et al., Correspondence: Dr MJ Forrest, Department of Cardiovascular Diseases (RY80Y-135), Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. E-mail: mike_forrest@merck.com 6Current address: Amgen Inc., Thousand Oaks, CA, USA Received 11 February 2008; revised 22 April 2008; accepted 26 April 2008; published online 9 June 2008 2003). However, it is equally evident that greater clinical benefit can be achieved given that, at best, statins reduce the risk of major coronary events by only 30% (LaRosa et al., 1999; Maron et al., 2000). An alternative therapeutic strategy being pursued by many pharmaceutical companies is to increase circulating levels of high-density lipoprotein (HDL). This strategy is predicated on the strong epidemiologic data that document an inverse correlation between HDL levels and coronary heart disease (Gordon et al., 1989; Assmann and Schulte, 1992). A novel pharmacological approach for elevation of HDL levels is the use of inhibitors of cholesteryl ester transfer protein (CETP). Inhibitors of CETP prevent the transfer of