Oxidative stress-induced afterdepolarizations and protein kinase C signaling

Background: Hydrogen peroxide (H₂O₂)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H₂O₂ (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 µM), was applied to test the involvement of PKC. Results: H₂O₂ perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H₂O₂-induced afterdepolarizations. Additional application of Gö 6983 with H₂O₂ effectively suppressed H₂O₂-induced afterdepolarizations. H₂O₂ increased the late sodium current (I_Na,L) (n = 7, p < 0.01) and the L-type calcium current (I_Ca,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H₂O₂ also increased the transient outward potassium current (I_to) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H₂O₂-induced enhancement of I_to. Conclusions: H₂O₂ induced afterdepolarizations via the activation of PKC and the enhancement of I_Ca,L and I_Na,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.