Document Detail

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.
MedLine Citation:
PMID:  19515969     Owner:  NLM     Status:  MEDLINE    
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.
Bruno Vié; Sylvie Sablayrolles; Robert Létienne; Bernard Vacher; Amaria Darmellah; Monique Bernard; Danielle Feuvray; Bruno Le Grand
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2009-06-10
Journal Detail:
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:
Created Date:  2009-08-21     Completed Date:  2009-09-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  696-703     Citation Subset:  IM    
Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres Cedex, France.
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MeSH Terms
Benzothiepins / pharmacology*,  therapeutic use*
Diabetes Mellitus, Experimental / metabolism
Guinea Pigs
Lysophosphatidylcholines / antagonists & inhibitors,  toxicity
Magnetic Resonance Spectroscopy
Myocardial Contraction / drug effects
Myocardial Infarction / drug therapy,  pathology
Myocardial Ischemia / drug therapy*,  pathology
Myocytes, Cardiac / drug effects
Rats, Sprague-Dawley
Rats, Wistar
Sodium / metabolism*
Sodium Channel Blockers / pharmacology*,  therapeutic use*
Sodium Radioisotopes / diagnostic use
Ventricular Remodeling / drug effects*
Veratrine / pharmacology
Reg. No./Substance:
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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