Document Detail


Amphotericin B severely affects expression and activity of the endothelial constitutive nitric oxide synthase involving altered mRNA stability.
MedLine Citation:
PMID:  11015297     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The therapeutic use of the antifungal drug amphotericin B (AmB) is limited due to severe side effects like glomerular vasoconstriction and risk of renal failure during AmB administration. As nitric oxide (NO) has substantial functions in renal autoregulation, we have determined the effects of AmB on endothelial constitutive NO synthase (ecNOS) expression and activity in human and rat endothelial cell cultures. AmB used at concentrations of 0.6 to 1.25 microg ml(-1) led to increases in ecNOS mRNA and protein expression as well as NO production. This was the result of an increased ecNOS mRNA half-life. In contrast, incubation of cells with higher albeit subtoxic concentrations of AmB (2.5 - 5.0 microg ml(-1)) resulted in a decrease or respectively in completely abolished ecNOS mRNA and protein expression with a strongly reduced or inhibited ecNOS activity, due to a decrease of ecNOS mRNA half-life. None of the AmB concentrations affected promoter activity as found with a reporter gene construct stably transfected into ECV304 cells. Thus, our experiments show a concentration-dependent biphasic effect of AmB on expression and activity of ecNOS, an effect best explained by AmB influencing ecNOS mRNA stability. In view of the known renal accumulation of this drug the results reported here could help to elucidate its renal toxicity.
Authors:
C V Suschek; E Bonmann; H Kleinert; M Wenzel; C Mahotka; H Kolb; U Förstermann; C D Gerharz; V Kolb-Bachofen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  131     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-11-06     Completed Date:  2001-02-15     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  473-81     Citation Subset:  IM    
Affiliation:
Research Group Immunobiology, MED-Heinrich-Heine-University of Düsseldorf, P.O. Box 10 10 07, D-40001 Düsseldorf, Germany. suschek@uni-duesseldorf.de
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MeSH Terms
Descriptor/Qualifier:
Amphotericin B / pharmacology*
Animals
Anti-Bacterial Agents / pharmacology
Cells, Cultured
Cytokines / metabolism
Endothelium, Vascular / drug effects*,  metabolism
Gene Expression Regulation, Enzymologic / drug effects
Humans
Nitric Oxide Synthase / genetics*,  metabolism
Nitric Oxide Synthase Type III
Promoter Regions, Genetic / drug effects
RNA Stability / drug effects*
RNA, Messenger / drug effects,  metabolism
Rats
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Cytokines; 0/RNA, Messenger; 1397-89-3/Amphotericin B; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, rat
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