Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2＋ overload

Aim： To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca2＋ overload in ventricular myocytes and to explore the underlying mechanisms. Methods： 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 Ca2＋ （[Ca2＋]i）. Ca2＋/calmodulin-dependent protein kinases II （CaMKII） activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na＋ and Ca2＋ currents were examined using whole-cell recording in myocytes. Results： H2O2 markedly prolonged Ca2＋ 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 [Ca2＋]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na＋ current （INa,L） and L-type Ca2＋ current （ICa,L） in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol. Conclusion： Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2＋ overload through inhibition of INa,L/ICa,L, reduction of ROS generation, and prevention of CaMKII activation.