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Sacherer, M.
Modulation der Ca2+ Freisetzung aus dem sarkoplasmatischen Retikulum durch Digitalis und JTV519 in Herzmuskelzellen der Maus.
[ Diplomarbeit/Master Thesis ] Graz Medical University; 2009. pp.69. [OPEN ACCESS]
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Authors Med Uni Graz:: Sacherer Michael
Advisor:: Heinzel Frank; Pieske Burkert Mathias
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Abstract:: Background: In heart failure, diastolic Ca2+ leak from the intracellular Ca2+ stores (sarcoplasmic reticulum, SR) into the cytosol through the sarcoplasmic Ca2+ release channel (ryanodine receptor, RyR) is involved in contractile dysfunction and arrhythmogenesis in cardiomyocytes. SR Ca2+ overload or altered RyR gating following beta-adrenoceptor - protein kinase A (PKA)- mediated RyR phosphorylation have been implicated with increased Ca2+ leak from the RyR. JTV519 (K201), a 1,4- benzothiazepine derivate has shown to be an effective suppressant of cardiac cell death due to Ca2+ overload. JTV519 was shown to be antiarrhythmic possibly related to its direct action on the RyR. Whether JTV519 is only effective in conditions where the RyR is pathologically modified by phosphorylation is currently unclear. Experimental approach: We assessed systolic Ca2+ release, diastolic Ca2+ leak (visualized as Ca2+ sparks) and SR Ca2+ content in intact isolated mouse cardiomyocytes using fast confocal line scan imaging (Ca2+ indicator Fluo4-AM). To increase cellular [Ca2+] and induce SR Ca2+ overload independent of PKA- activation we used ouabain (100M), an inhibitor of the sarcolemmal Na+/ K+- ATPase. A subset of cells was pretreated with 1M JTV519. Results: Ouabain increased the systolic Ca2+ transient and SR Ca2+ content in mouse cardiomyocytes. Ouabain increased the incidence of Ca2+ sparks dramatically. JTV519 (1M) significantly reduced Ca2+ spark frequency. However, JTV519 also attenuated the increase in systolic Ca2+ and the increase in SR Ca2+ load induced by ouabain. Conclusion: In cardiomyocytes treated with ouabain, JTV519 decreases the incidence of arrhythmogenic diastolic Ca2+ leak. In our mouse model the protection from diastolic Ca2+ leak with JTV519 occurs partly at the expense of inotropy.