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  • Title: The effect of SN-6, a novel sodium-calcium exchange inhibitor, on contractility and calcium handling in isolated failing rat ventricular myocytes.
    Author: Gandhi A, Siedlecka U, Shah AP, Navaratnarajah M, Yacoub MH, Terracciano CM.
    Journal: Cardiovasc Ther; 2013 Dec; 31(6):e115-24. PubMed ID: 24106913.
    Abstract:
    BACKGROUND AND PURPOSE: Specific Na(+) /Ca(2+) exchanger (NCX) inhibition is a potential strategy to correct reduced contractility and depleted sarcoplasmic reticulum (SR) Ca(2+) content in heart failure (HF). SN-6, a benzyloxyphenyl derivative and proposed selective NCX inhibitor, could be used for this purpose. This study aimed to evaluate the effects of SN-6 on contractility and Ca(2+) handling in normal and failing rat cardiomyocytes. EXPERIMENTAL APPROACH: HF was induced in rats by coronary artery ligation. Left ventricular myocytes were isolated and superfused with increasing concentrations of SN-6. KEY RESULTS: Sarcomere shortening, induced by field-stimulation, was reduced in amplitude with increasing concentrations of SN-6 compared with control solution. This effect was greater in failing cells. Kinetics of contractility (time to 90% peak and time to 50% relaxation) were significantly faster. Despite this, intracellular Ca(2+) transients demonstrated no change in the peak amplitude at low concentrations of SN-6, suggesting that SN-6 may affect myofilament sensitivity to Ca(2+) . Ten micro molar SN-6 significantly reduced peak Ca(2+) amplitude by 61.57% and 64.73% in normal and failing cells, respectively. Diastolic Ca(2+) was significantly increased at 1 μM SN-6. SR Ca(2+) content, assessed by rapid application of caffeine, was reduced in failing cells with 1 μM SN-6. Peak ICa , measured by whole-cell patch clamping, was significantly reduced in normal and failing myocytes at 1 μM SN-6. CONCLUSIONS AND IMPLICATIONS: Our data suggest that SN-6 is not a selective inhibitor of NCX and impairs contractility and Ca(2+) handling. Its use, together with similar putative NCX blockers, in correcting the contractile abnormalities of heart failure requires further studies.
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