Abstract
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 (IC50 = 0.14 μM) in isolated atria. Second, F 15845 from 1 μM 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 23Na-nuclear magnetic resonance spectroscopy. F 15845 (0.3 μM) 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 μg/l with vehicle versus 271 ± 63 μg/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.
Footnotes
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B.V. and S.S. contributed equally to this study.
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All of the authors with the exception of D.F., A.D., and M.B. are employees of Pierre Fabre Laboratory.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.153122.
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ABBREVIATIONS: F 15845, 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate; NMR, nuclear magnetic resonance; LPC, lysophosphatidylcholine; TmDOTP5-, thulium(III)-1,4,7,10-tetraazacyclododecane-N,NI,NII,NIII-tetra-(methylene phosphonate); dP/dtmax, maximum positive and negative first derivative of left ventricular pressure; PEG, polyethylene glycol.
- Received March 5, 2009.
- Accepted June 9, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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