1466 Aldosterone and pressor responses to torcetrapib MJ Forrest et al cholesteryl esters from HDL to LDL and very low-density lipoprotein and the reciprocal transfer of triglycerides from LDL and very low-density lipoprotein to HDL. Numerous preclinical and clinical studies confirm that CETP inhibitors effectively increase circulating HDL levels (Barter et al., 2003; Brousseau et al., 2004; Clark et al., 2004; Davidson et al., 2006). Furthermore, preclinical studies with CETP inhibitors demonstrated beneficial antiatherosclerotic effects in animal models (Sugano et al., 1998; Okamoto et al., 2000). The only human clinical trial to evaluate the effects of a CETP inhibitor on cardiovascular events is the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial. In this study, the effect of a CETP inhibitor, torcetrapib (Pfizer, New York, NY, USA), in combination with atorvastatin was compared to treatment with atorvastatin alone. Unfortunately, the study was terminated prematurely because of an unexpected increase in cardiovascular events and death with the combination treatment versus atorvastatin alone (Barter et al., 2007). The reason(s) for the increase in mortality is not known; however, it is known that torcetrapib adminis- tration in humans is associated with an increase in blood pressure (Davidson et al., 2006; Barter et al., 2007; Nissen et al., 2007). Furthermore, examination of serum electrolyte values from the ILLUMINATE study revealed a decrease in potassium and increases in sodium and bicarbonate at the end of 12 months in patients taking torcetrapib plus atorvastatin compared with those taking atorvastatin alone. These findings prompted a post hoc examination of aldoster- one levels, which were shown to be higher in patients who had taken torcetrapib for 3 months. The studies described herein evaluate the acute haemo- dynamic effects of torcetrapib in a variety of preclinical models and species and compare the effects of torcetrapib with another experimental CETP inhibitor, anacetrapib (MK-0859). Administration of torcetrapib was shown to acutely increase blood pressure in both rodent and non- rodent species. In addition, in rats, administration of torce- trapib was associated with the release of aldosterone and corticosterone in vivo and in vitro from primary adrenocortical cells. The other CETP inhibitor, anacetrapib, did not increase blood pressure under equivalent conditions and was not associated with adrenal steroid release either in vivo or in vitro. Methods Animals All animals were maintained in AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care)- accredited facilities at Merck Research Laboratories (Rahway, NJ, USA or West Point, PA, USA), and all experimental procedures were approved by the Institutional Animal Care and Use Committee and were in conformance with the National Research Council’s Guide for the Care and Use of Laboratory Animals. C57BL/6NTac mice (B6) were purchased from Taconic (Hudson, NY, USA); C57BL/6-Tg(CETP)1Pnu/J mice (B6-Tg(CETP)) were purchased from Jackson (Bar Harbor, ME, USA) and bred at Merck Research Laboratories. Male British Journal of Pharmacology (2008) 154 1465–1473 Sprague–Dawley rats (300–400 g body weight) with surgically implanted femoral artery and vein catheters were obtained from Charles River Laboratories (Raleigh, NC, USA). Male or female mixed breed mongrel dogs (approximately 8–12 kg) were obtained from either Covance Research Products Inc. (Cumberland, VA, USA) or Marshall BioResources (North Rose, NY, USA). Male rhesus monkeys (approximately 4–6 years old, body weight 6.5–7.5 kg) were obtained from Covance Research Products Inc. (Alice, TX, USA). Haemodynamics Heart rate and blood pressure were measured in mice, rats, dogs and rhesus monkeys under a variety of experimental conditions. For the assessment of cardiovascular function in conscious mice, animals were surgically implanted with catheters in a carotid artery and a jugular vein at least 24 h prior to study. On the day of study a Becton Dickinson (Franklin Lakes, NJ, USA) DTX pressure transducer was attached to the arterial catheter and subsequently to a Gould ACQ-7700 data acquisition system using Ponemah software. Heart rate was derived from the arterial pulse wave. Heart rate and arterial pressure were measured between 30 and 60 min to establish baseline values. Subsequently, test compound or vehicle (2% dimethyl sulphoxide:4% Cremophor EL:94% saline) was administered in a volume of 0.2 mL per mouse via a 30 min infusion. Cardiovascular data were recorded continuously and are reported as average values over 1 min intervals. Equivalent procedures were used for the measurement of haemodynamics in rats, with the exception that studies were performed in anaesthetized animals (sodium pentobarbital; 55 mg kg 1, i.p.). In some studies, rats were pithed according to the method of Gillespie et al. (1970). Test compound or vehicle (2% dimethyl sulphoxide:4% Cremophor EL:94% saline or 50% dimethylacetamide:50% polyethylene glycol 200) was administered in a volume of 1 mL per rat via an i.v. infusion of 20–30 min duration. Haemodynamic studies were performed in dogs anaesthe- tized with sodium pentobarbital (35 mg kg 1, i.v. loading dose plus 6 mg kg 1 h 1 maintenance infusion). An endo- tracheal tube was inserted into the trachea and artificial respiration with ambient room air was employed utilizing a large animal ventilator (Harvard Apparatus, Boston, MA, USA). Body temperature was maintained using an automated heating surgical table and infrared lamp. Bilateral femoral vein catheters were implanted for the i.v. administration of anaesthetics and test compounds. Arterial blood pressure was captured via a catheter inserted into a femoral artery and connected to a disposable type pressure transducer. Heart rate was derived from the pulsatile blood pressure or from the ECG signal. A CA Recorder Systems (DISS LLC) data acquisition system was used to collect and analyse input signals. Haemodynamic parameters were collected from conscious rhesus monkeys implanted with Konigsberg cardiovascular total implants. Data were transmitted via radiotelemetry and recorded by CA Recorder Systems (DISS LLC). Arterial blood pressure and heart rate were collected for X24 h prior to vehicle dosing, X2 h prior to oral dosing with test compound and X24 h postdosing. Data were collected as