Document Detail


An engineered cocaine hydrolase blunts and reverses cardiovascular responses to cocaine in rats.
MedLine Citation:
PMID:  15100387     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There is increasing evidence that human plasma butyrylcholinesterase can lower the toxicity of cocaine overdose. Recently, with structure-based protein engineering, we converted this enzyme into a more efficient cocaine hydrolase (CocE). When tested in rats, CocE shortened cocaine's plasma half-life and decreased drug accumulation in heart and brain. Here, we have investigated the potential of CocE to antagonize cardiovascular responses to cocaine. Anesthetized rats were instrumented for continuous recording of blood pressure from the femoral artery. Cocaine (7 mg/kg i.v.) caused blood pressure to rise within 30 s by 25 to 37 mmHg, but pressure returned to baseline within 60 s. These transient pressor responses were prolonged up to 5 min when vagal reflexes were blocked with atropine (1 mg/kg). Under such conditions, pretreatment with CocE (3 mg/kg i.v.) reduced cocaine's pressor effect, whereas delayed treatment with CocE rapidly restored normal mean blood pressure. CocE had no hemodynamic effects in control animals not treated with cocaine. The finding that CocE can oppose pre-established physiologic actions of cocaine suggests that similar or improved hydrolases might help rescue patients from the life-threatening toxicity of drug overdose.
Authors:
Yang Gao; Stephen Brimijoin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-04-20
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  310     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-08-23     Completed Date:  2004-11-01     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1046-52     Citation Subset:  IM    
Affiliation:
Department of Molecular Pharmacology, Mayo Clinic, 200 First Street S.W., Rochester MN 55905, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiovascular System / drug effects*,  physiopathology
Cocaine / pharmacology*
Enzyme Stability
Heart Rate / drug effects
Hydrolases / genetics,  metabolism*,  pharmacology
Male
Pressoreceptors / drug effects,  physiology
Protein Engineering
Rats
Rats, Sprague-Dawley
Recombinant Proteins / metabolism,  pharmacology
Vasoconstrictor Agents / pharmacology*
Chemical
Reg. No./Substance:
0/Recombinant Proteins; 0/Vasoconstrictor Agents; 50-36-2/Cocaine; EC 3.-/Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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