| 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845) prevents ischemia-induced heart remodeling by reduction of the intracellular Na+ overload. | |
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MedLine Citation:
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PMID: 19515969 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The present study investigates whether 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845), a new, persistent sodium current blocker, can reduce the ischemic Na(+) accumulation and exert short- and long-term cardioprotection after myocardial infarction. First, F 15845 concentration-dependently reduced veratrine-induced diastolic contracture (IC(50) = 0.14 microM) in isolated atria. Second, F 15845 from 1 microM preserved viability in 54.2 +/- 12.5% of isolated cardiomyocytes exposed to lysophosphatidylcholine. Third, the effect of F 15845 on intracellular Na(+) of isolated hearts from control and diabetic db/db mice was monitored using (23)Na-nuclear magnetic resonance spectroscopy. F 15845 (0.3 microM) significantly counteracted [Na(+)](i) increase during no-flow ischemia in control mouse hearts. In diabetic db/db mouse hearts, the reduction in [Na(+)](i) was delayed relative to control. However, it was more marked and maintained upon reperfusion. The cardioprotective properties after myocardial infarction associated with short- (24-h) and long-term (14-day) reperfusion were measured in anesthetized rats. After 24-h reperfusion, F 15845 (5 mg/kg) significantly reduced infarct size (32.4 +/- 1.7% with vehicle and 24.2 +/- 3.4% with F 15845; P < 0.05) and decrease of troponin I levels (524 +/- 93 microg/l with vehicle versus 271 +/- 63 microg/l with F 15845; P < 0.05). It is important that F 15845 limits the long-term expansion of infarct size (35.2 +/- 2.6%, n = 19 versus 46.7 +/- 1.6%, n = 27 in the vehicle group; P < 0.001). Overall, F 15845 attenuates [Na(+)](i) and prevents (or reverses) contractile and biochemical dysfunction in ischemic and remodeling heart. F 15845 constitutes a new generation of cardioprotective agent. |
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Authors:
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Bruno Vié; Sylvie Sablayrolles; Robert Létienne; Bernard Vacher; Amaria Darmellah; Monique Bernard; Danielle Feuvray; Bruno Le Grand |
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Publication Detail:
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Type: In Vitro; Journal Article Date: 2009-06-10 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 330 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-08-21 Completed Date: 2009-09-21 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 696-703 Citation Subset: IM |
Affiliation:
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Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres Cedex, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzothiepins / pharmacology*, therapeutic use* Diabetes Mellitus, Experimental / metabolism Guinea Pigs Lysophosphatidylcholines / antagonists & inhibitors, toxicity Magnetic Resonance Spectroscopy Male Mice Myocardial Contraction / drug effects Myocardial Infarction / drug therapy, pathology Myocardial Ischemia / drug therapy*, pathology Myocytes, Cardiac / drug effects Rats Rats, Sprague-Dawley Rats, Wistar Sodium / metabolism* Sodium Channel Blockers / pharmacology*, therapeutic use* Sodium Radioisotopes / diagnostic use Ventricular Remodeling / drug effects* Veratrine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/3-(3-(2-methoxyphenylthio)-2-methylpropyl)amino-3,4-dihydro-2H-1,5-benzoxathiepine; 0/Benzothiepins; 0/Lysophosphatidylcholines; 0/Sodium Channel Blockers; 0/Sodium Radioisotopes; 62-59-9/Veratrine; 7440-23-5/Sodium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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