| Cardiovascular effects of torcetrapib in conscious and pentobarbital-anesthetized dogs. | |
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MedLine Citation:
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PMID: 19770671 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Torcetrapib is a cholesteryl ester transfer protein inhibitor with an undesired response of increasing arterial pressure in humans. Pressor responses to torcetrapib have been demonstrated in multiple preclinical species. However, these studies have not related plasma concentrations to observed effects. Our purpose was to 1) characterize the cardiovascular responses of torcetrapib in conscious and anesthetized dogs with measured plasma concentrations; and 2) characterize the hemodynamic effects contributing to hypertension using comprehensively instrumented anesthetized dogs. Torcetrapib was dosed orally (3, 30 mg/kg) and intravenously (0.01, 0.33, 0.1 mg/kg) in conscious and anesthetized dogs, respectively. Mean arterial pressure and heart rate were monitored in both models; additional parameters were measured in anesthetized dogs. Plasma drug concentrations were assessed in both models. In conscious and anesthetized dogs, torcetrapib increased mean arterial pressure 25 and 18 mm Hg and heart rate 35 and 21 beats/min, at 2.94 and 3.99 microg/mL, respectively. In anesthetized dogs, torcetrapib increased pulmonary arterial pressure, both systemic and pulmonary hypertension driven by increases in vascular resistance. The compound increased rate pressure product and myocardial contractility while decreasing time to systolic pressure recovery and ejection time. Thus, torcetrapib-induced pressor responses are mediated by systemic and pulmonary vasoconstriction and are associated with increased myocardial oxygen consumption and positive inotropy. |
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Authors:
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James S Polakowski; Andrew J King; Thomas J Campbell; Richard A Nelson; Lee C Preusser; Anita J Kempf-Grote; Kennan C Marsh; Gary A Gintant; Bryan F Cox; Scott W Mittelstadt |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 54 ISSN: 1533-4023 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-22 Completed Date: 2010-04-26 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 543-51 Citation Subset: IM |
Affiliation:
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Department of Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6119, USA. jim.polakowski@abbott.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anesthesia* Animals Blood Pressure / drug effects, physiology Cardiac Output / drug effects, physiology Cardiovascular System / drug effects* Cholesterol Ester Transfer Proteins / antagonists & inhibitors Dogs Electrocardiography Heart Rate / drug effects, physiology Hemodynamics / drug effects*, physiology Male Myocardial Contraction / drug effects, physiology Pentobarbital / administration & dosage* Quinolines / administration & dosage, blood, pharmacokinetics, pharmacology* Telemetry Vascular Resistance / drug effects, physiology Ventricular Function, Left / drug effects, physiology |
| Chemical | |
Reg. No./Substance:
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0/Cholesterol Ester Transfer Proteins; 0/Quinolines; 262352-17-0/torcetrapib; 76-74-4/Pentobarbital |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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