Early afterdepolarizations produced by oxidative stress and stretch activated conductance in rat ventricular cells

Abstract

Objective: To investigate the hypothesis that acute oxidative stress and abnormal stretch of the myocardium may contribute to the production of early-afterdepolarizations (EADs). Introduction: Mechanical stretch and oxidative stress have been shown to prolong action potential durations and produce EADs. Physically stretching isolated cardiac cells is technically difficult. To study the role of stretch and oxidative stress in arrhythmia development, we have incorporated a model of mechanical stretch into isolated rat ventricular cells. Methods: We adapted our coupling clamp circuit so that a model ionic current representing stretch-activated currents was injected into isolated rat ventricular cells and added as an additional ionic current in real-time. This current was calculated as ISAC GSAC*(Vm-ESAC), where GSAC is the stretch activated conductance, Vm is the membrane potential and ESAC is the reversal potential. Results: In control, application of GSAC did not produce sustained activity or EADs, although turn-on of GSAC did produce some transient activity at high levels (6.0 0.4 nS, n 7). In H2O2 solution, used to induce acute oxidative stress, the action potential prolonged but did not have EADs in the absence of GSAC. However, the combination of GSAC and H2O2 consistently produced EADs at lower levels of GSAC (3.2 0.5 nS, n 7, p 0.05). Pacing the cell at a faster rate also prolonged the action potential and promoted the development of EADs. Conclusions: We conclude that the effects of mechanical stretch on the production of cardiac arrhythmias from EADs may be enhanced in the presence of acute oxidative stress.