Contribution of ATP to oxidative stress-induced changes in action potential of isolated cardiac myocytes.
The role of ATP in oxidative stress-mediated changes in the cardiac action potential was investigated in isolated adult rat cardiac myocytes. Superfusion with H2O2 led to a decrease in the energy charge and depletion of nonprotein thiols and elicited hypercontracture of the myocytes. Treatment with 3-aminobenzamide (3-AB), an inhibitor of protein ribosylation, increased the lifetime of H2O2-exposed myocytes and attenuated depletion of ATP and nonprotein thiols. H2O2-mediated DNA strand breaks were increased in the presence of 3-AB. On exposure to H2O2, myocytes patch clamped with 1 mM ATP in the pipette initially displayed prolonged action potential durations (APD), which were later markedly abbreviated and accompanied by the activation of ATP-sensitive K+ currents (I(K,ATP)). The late decrease in APD was inhibited by glibenclamide (which inhibits I(K,ATP)), but the initial prolongation of the action potential was exacerbated. Treatment with 3-AB or recordings with 10 mM ATP in the patch pipette caused an initial delay in the expression of H2O2-induced changes, but later caused a more pronounced and sustained increase in APD. These interventions delayed the activation of I(K,ATP). Thus enhanced ribosylation (presumably due to activation of DNA repair) appears to be a significant source of ATP depletion under oxidative stress that, via activation of I(K,ATP), mediates oxidative modifications in the action potential.
Bhatnagar
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Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77555-1067, USA.
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000166:cytology; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide