Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling

Hydrogen peroxide (H&sub2;O&sub2;)-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.

H&sub2;O&sub2; induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.

Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H&sub2;O&sub2; (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.

H&sub2;O&sub2; perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H&sub2;O&sub2;-induced afterdepolarizations. Additional application of Gö 6983 with H&sub2;O&sub2; effectively suppressed H&sub2;O&sub2;-induced afterdepolarizations. H&sub2;O&sub2; increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H&sub2;O&sub2; also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H&sub2;O&sub2;-induced enhancement of Ito. Conclusions: H&sub2;O&sub2; induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.