Abstract
To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca(2+) overload in ventricular myocytes and to explore the underlying mechanisms. Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca(2+) ([Ca(2+)]i). Ca(2+)/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na(+) and Ca(2+) currents were examined using whole-cell recording in myocytes. H2O2 markedly prolonged Ca(2+) transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca(2+)]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na(+) current (I(Na,L)) and L-type Ca(2+) current (I(Ca,L)) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol. Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca(2+) overload through inhibition of I(Na,L)/I(Ca,L), reduction of ROS generation, and prevention of CaMKII activation.
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