| Na+ currents in cardioprotection: better to be late. | |
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MedLine Citation:
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PMID: 19514733 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We report the discovery of a selective, potent inhibitor of the late current mediated by the cardiac isoform of the sodium channel (Na(V)1.5). The compound, 3,4-dihydro-N-[(2S)-3-[(2-hydroxy-3-methylphenyl)thio]-2-methylpropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (2d) (F 15741), blocks the late component of the Na(+) currents and greatly reduces veratridine- or ischemia-induced contracture in isolated tissue and whole heart. The cardioprotective action of 2d was further established in a model of myocardial infarction in the pig in which 2d prevents ischemia-reperfusion damage after 60 min of coronary occlusion and 48 h reperfusion. Under these experimental conditions, only 2d and cariporide reduce infarct size. Remarkably, myocardial protection afforded by 2d occurs in the absence of hemodynamic effects. These data expand the therapeutic potential of late I(Na) blockers and suggest that 2d could be useful in pathologies for which pharmacological treatments are not yet available. |
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Authors:
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Bruno Le Grand; Christophe Pignier; Robert Létienne; Francis Colpaert; Florence Cuisiat; Françoise Rolland; Agnes Mas; Maud Borras; Bernard Vacher |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 52 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-16 Completed Date: 2009-08-25 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4149-60 Citation Subset: IM |
Affiliation:
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Pierre Fabre Research Center, 81106 Castres Cedex, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzothiepins / chemical synthesis, chemistry, pharmacology*, therapeutic use Benzoxazoles / chemical synthesis, chemistry, pharmacology*, therapeutic use Cardiotonic Agents / chemical synthesis, chemistry, pharmacology*, therapeutic use Cell Line Electric Conductivity* Female Guinea Pigs Humans Male Myocardial Infarction / drug therapy, metabolism, pathology, physiopathology Rats Sodium Channel Blockers / chemical synthesis, chemistry, pharmacology*, therapeutic use Sodium Channels / metabolism* Structure-Activity Relationship Swine Time Factors |
| Chemical | |
Reg. No./Substance:
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0/3,4-dihydro-N-(3-((2-hydroxy-3-methylphenyl)thio)-2-methylpropyl)-2H-1,5-benzoxathiepin-3-amine; 0/Benzothiepins; 0/Benzoxazoles; 0/Cardiotonic Agents; 0/Sodium Channel Blockers; 0/Sodium Channels |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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