Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone.

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.

Cross-generalization of an EtOH "hangover" cue to endogenously and exogenously induced stimuli.

Twenty male Sprague-Dawley rats were trained in a two-choice food-reinforced drug discrimination task (10 min sessions) using the state-dependent interoceptive stimulus attributes of ethanol's (EtOH) delayed or rebound effects (EDE) versus "normal" basal homeostasis. Cross-generalization tests were conducted with 0.18 mg/kg naloxone injected after three days of three injections per day of either SAL or 10 mg/kg morphine. Naloxone failed to generalize to the EDE-state after chronic saline; however, the precipitated morphine withdrawal state produced complete generalization to the EDE training cue. Daily tests were conducted after 8 h photoperiod phase-shifts. An 8 h phase-advance, equivalent to a west-to-east intercontinental night-time flight in humans, produced a biphasic, graded, increase in EDE-appropriate responding, which peaked on the second day after the phase-advance and recovered by the fourth day. The 8 h phase-delays failed to engender significant EDE-appropriate responding. These data provide evidence for the subjective similarity between EtOH hangover, opiate withdrawal states, and the physiological disruption induced by circadian phase-advances.

Cumulative vs. acute dose-response procedures produce differential BAC and behavioral functions for ethanol.

The discriminative stimulus attributes of ethanol (ETOH) were characterized in rats trained to discriminate between 1.25 g/kg ETOH and saline. The ETOH generalization functions were assessed using both acute and cumulative dosing procedures. The cumulative procedures differed in the individual incremented doses used to generate the functions. Acute dosing procedures produced discriminative functions that were significantly different from cumulative dose-response curves (DRCs). Similar cumulative DRC's were generated within each cumulative dosing procedure, whereas significant differences were produced between the two dosing incremented procedures. When blood alcohol concentrations (BACs) were quantified, a cumulative testing procedure produced significantly lower BACs than acute testing procedures at every dose above the initial or starting dose. Interestingly, response rate functions did not differ within or between cumulative and acute procedures. These data may suggest that differential ETOH dosing procedures may differentially influence the behavioral choice and BAC functions in rats, and cautions against the use of cumulative procedures to assess shifts in DRCs during chronic treatments without a concomitant assessment of BACs.

Influence of thiamine on the behavioral sensitivity to ethanol.

Changes in sensitivity to ethanol's rate-decreasing effects on operant performance were examined in control rats and cohorts that received diet-induced or diet+pyrithiamine-induced thiamine deficiency. Seven groups of male Sprague-Dawley rats (12 rats/group) were trained in a 5-cycle lever-press operant task under a fixed-ratio 30 schedule of food reinforcement. Once trained to maintain consistent operant performance across all 5 cycles, each rat was tested with various doses of ethanol injected at the beginning of each time-out cycle. Each group of rats demonstrated equivalent saline baseline operant performance and ED50 for ethanol's rate-suppressing effects. Training sessions were suspended and rats received either a short- (9 days) or long-term (5-week) exposure to regular rat chow diet or thiamine-deficient diet, and received either saline or pyrithiamine injections in a 2 x 2 design. Three additional control groups were maintained on a regular rat chow diet and received supplemental injections of either thiamine+pyrithiamine injections, thiamine+saline injections, or saline+pyrithiamine injections. The controlled diet phase continued until the development of overt signs of thiamine deficiency, at which time thiamine supplements were administered for 4 days. In phase 3, all rats were retrained in the operant task and a second ethanol dose-effect function was generated. A history of thiamine deficiency and recovery failed to shift the behavioral dose-effect functions significantly for ethanol and their associated blood alcohol curves. Most interestingly, significant behavioral sensitization to ethanol's rate suppressant effects was demonstrated in the two control groups of rats receiving regular rat chow diet in combination with supplemental injections of thiamine and either saline or pyrithiamine.(ABSTRACT TRUNCATED AT 250 WORDS)