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.
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.
Authors: Zsófia Kohajda; Nikolett Farkas-Morvay; Norbert Jost; Norbert Nagy; Amir Geramipour; András Horváth; Richárd S Varga; Tibor Hornyik; Claudia Corici; Károly Acsai; Balázs Horváth; János Prorok; Balázs Ördög; Szilvia Déri; Dániel Tóth; Jouko Levijoki; Piero Pollesello; Tuula Koskelainen; Leena Otsomaa; András Tóth; István Baczkó; István Leprán; Péter P Nánási; Julius Gy Papp; András Varró; László Virág Journal: PLoS One Date: 2016-11-10 Impact factor: 3.240
Authors: Igor V Kubasov; Andrei Stepanov; Danila Bobkov; Przemysław B Radwanski; Maxim A Terpilowski; Maxim Dobretsov; Sandor Gyorke Journal: Front Physiol Date: 2018-02-13 Impact factor: 4.566
Authors: Carlos M G de Godoy; Ênio R Vasques; Afonso Caricati-Neto; José G P Tavares; Beatriz J Alves; Juliana Duarte; Regiane Miranda-Ferreira; Marcelo A Lima; Helena B Nader; Ivarne L Dos Santos Tersariol Journal: Front Cardiovasc Med Date: 2018-06-07