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.
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.
Vié
Bruno
B
Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres Cedex, France.
Sablayrolles
Sylvie
S
Létienne
Robert
R
Vacher
Bernard
B
Darmellah
Amaria
A
Bernard
Monique
M
Feuvray
Danielle
D
Le Grand
Bruno
B
D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology* / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008244:Lysophosphatidylcholines / Q000037:antagonists & inhibitors / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use*; D012979:Sodium Radioisotopes; D020257:Ventricular Remodeling / Q000187:drug effects*; D014702:Veratrine / Q000494:pharmacology
C541955:3-(3-(2-methoxyphenylthio)-2-methylpropyl)amino-3,4-dihydro-2H-1,5-benzoxathiepine; D001582:Benzothiepins; D008244:Lysophosphatidylcholines; D026941:Sodium Channel Blockers; D012979:Sodium Radioisotopes; D012964:Sodium; D014702:Veratrine