| Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. | |
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MedLine Citation:
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PMID: 18536749 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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M J Forrest; D Bloomfield; R J Briscoe; P N Brown; A-M Cumiskey; J Ehrhart; J C Hershey; W J Keller; X Ma; H E McPherson; E Messina; L B Peterson; W Sharif-Rodriguez; P K S Siegl; P J Sinclair; C P Sparrow; A S Stevenson; S-Y Sun; C Tsai; H Vargas; M Walker; S H West; V White; R F Woltmann |
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Publication Detail:
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Type: Journal Article Date: 2008-06-09 |
Journal Detail:
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Title: British journal of pharmacology Volume: 154 ISSN: 0007-1188 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-07-29 Completed Date: 2008-11-25 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1465-73 Citation Subset: IM |
Affiliation:
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Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. mike_forrest@merck.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adrenal Cortex
/
cytology,
drug effects Aldosterone / blood Animals Anticholesteremic Agents / toxicity Blood Pressure / drug effects* Cholesterol Ester Transfer Proteins / antagonists & inhibitors* Corticosterone / blood Dogs Drug Evaluation, Preclinical Female Macaca mulatta Male Mice Mice, Inbred C57BL Models, Animal Muscle, Smooth, Vascular / drug effects, metabolism Oxazolidinones / toxicity* Quinolines / toxicity* Rats Rats, Sprague-Dawley Species Specificity |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Cholesterol Ester Transfer Proteins; 0/Oxazolidinones; 0/Quinolines; 0/anacetrapib; 262352-17-0/torcetrapib; 50-22-6/Corticosterone; 52-39-1/Aldosterone |
| Comments/Corrections | |
Comment In:
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Br J Pharmacol. 2008 Aug;154(7):1379-81
[PMID:
18536741
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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