Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart.

Reactive oxygen species have been shown to prolong cardiac action potential duration resulting in afterdepolarizations, the cellular basis of triggered arrhythmias. As previously shown, protein kinase A type I I) is readily activated by oxidation of its regulatory subunits. However, the relevance of this mechanism of activation for cardiac pathophysiology is still elusive. In this study, we investigated the effects of oxidation-activated I on cardiac electrophysiology. Ventricular cardiomyocytes were isolated from redox-dead Cys17Ser knock-in (KI) and wild-type (WT) mice and exposed to H₂O₂ (200 µmol/L) or vehicle (Veh) solution. In WT myocytes, exposure to H₂O₂ significantly increased oxidation of the regulatory subunit I (RI) and thus its dimerization (threefold increase in duanyu1529 RI dimer). Whole cell current clamp and voltage clamp were used to measure cardiac action potentials (APs), transient outward potassium current (I_to) and inward rectifying potassium current (I_K1), respectively. In WT myocytes, H₂O₂ exposure significantly prolonged AP duration due to significantly decreased I_to and I_K1 resulting in frequent early afterdepolarizations (EADs). Preincubation with the inhibitor Rp-8-Br-cAMPS (10 µmol/L) completely abolished the H₂O₂-dependent decrease in I_to and I_K1 in WT myocytes. Intriguingly, H₂O₂ exposure did not prolong AP duration, nor did it decrease I_to, and only slightly enhanced EAD frequency in KI myocytes. Treatment of WT and KI cardiomyocytes with the late I_Na inhibitor TTX (1 µmol/L) completely abolished EAD formation. Our results suggest that redox-activated duanyu1529 may be important for H₂O₂-dependent arrhythmias and could be important for the development of specific antiarrhythmic drugs.NEW & NOTEWORTHY Oxidation-activated duanyu1529 type I inhibits transient outward potassium current (I_to) and inward rectifying potassium current (I_K1) and contributes to APD prolongation as well as generation of early afterdepolarizations in murine ventricular cardiomyocytes.

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