Document Detail

Domoic acid impairment of cardiac energetics.
MedLine Citation:
PMID:  18596025     Owner:  NLM     Status:  MEDLINE    
Excitatory mediated neuronal injury has been shown to involve a complex cascade of events. However, the associated cardiac damage reported in humans and marine animals following exposure to excitotoxins has not been well characterized. We hypothesized that the excitotoxin domoic acid can traverse cardiac cell membranes and elicit a deleterious effect on cardiac mitochondrial energetics. Domoic acid (0.05-0.25 microM; 10 min) treatment of isolated rat cardiac mitochondria produced a marked decrease of both mitochondrial flavin adenine dinucleotide (FAD)- and nicotinamide adenine linked respiratory control indices (p < 0.001). Enzymatic assays of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial matrix marker enzyme citrate synthase, showed marked concentration-dependent impairment in activity and integrity following exposure to domoic acid (p < 0.01). Similar mitochondrial effects were seen following exposure to the glutamic acid analog, kainic acid (0.5-2 microM). Domoic acid (0.05-10 microM; 40 min) was shown by competitive enzyme-linked immunosorbent assay to traverse the cellular membrane of H9c2 rat cardiac myoblasts. Exposure of intact H9c2 cells to domoic acid (10 microM; 24 h) impaired complex II-III activity but did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid (0.05-5 microM). This is the first study to demonstrate a direct effect of domoic acid on cardiac mitochondrial energetics. However, the absence of substantial damage to intact cardiomyocytes raises questions regarding direct toxicological effects on cardiac energetics or viability under conditions of natural domoic acid exposure.
Alexandra Vranyac-Tramoundanas; Joanne C Harrison; Andrew N Clarkson; Mohit Kapoor; Ian C Winburn; D Steven Kerr; Ivan A Sammut
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-01
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  105     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-03     Completed Date:  2008-10-14     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  395-407     Citation Subset:  IM    
Department of Pharmacology and Toxicology, University of Otago Faculty of Medicine, Dunedin, New Zealand.
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MeSH Terms
Cell Line
Cell Membrane / drug effects,  metabolism
Cell Membrane Permeability
Cell Respiration / drug effects
Cell Survival / drug effects
Citrate (si)-Synthase / metabolism
Citric Acid Cycle / drug effects
Dose-Response Relationship, Drug
Electron Transport Complex I / metabolism
Electron Transport Complex II / metabolism
Electron Transport Complex III / metabolism
Electron Transport Complex IV / metabolism
Energy Metabolism / drug effects*
Excitatory Amino Acid Agonists / metabolism,  toxicity*
Kainic Acid / analogs & derivatives*,  metabolism,  toxicity
Mitochondria, Heart / drug effects*,  enzymology
Mitochondrial Membranes / drug effects,  metabolism
Myocytes, Cardiac / drug effects*,  enzymology
Rats, Sprague-Dawley
Reactive Oxygen Species / metabolism
Risk Assessment
Time Factors
Reg. No./Substance:
0/Excitatory Amino Acid Agonists; 0/Reactive Oxygen Species; 14277-97-5/domoic acid; 487-79-6/Kainic Acid; EC Transport Complex III; EC Transport Complex II; EC Transport Complex I; EC Transport Complex IV; EC (si)-Synthase

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

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