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TRANSLATIONAL PHYSIOLOGY

Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress

Department of Pediatrics, Emory University, Atlanta, Georgia

Submitted 4 August 2008 ; accepted in final form 11 March 2009

Mechanical stretch and oxidative stress have been shown to prolong action potential duration (APD) and produce early afterdepolarizations (EADs). Here, we developed a simulation model to study the role of stretch-activated channel (SAC) currents in triggering EADs in ventricular myocytes under oxidative stress. We adapted our coupling clamp circuit so that a model ionic current representing the actual SAC current was injected into ventricular myocytes and added as a real-time current. This current was calculated as I_SAC = G_SAC * (V_m – E_SAC), where G_SAC is the stretch-activated conductance, V_m is the membrane potential, and E_SAC is the reversal potential. In rat ventricular myocytes, application of G_SAC did not produce sustained automaticity or EADs, although turn-on of G_SAC did produce some transient automaticity at high levels of G_SAC. Exposure of myocytes to 100 µM H₂O₂ induced significant APD prolongation and increase in intracellular Ca²⁺ load and transient, but no EAD or sustained automaticity was generated in the absence of G_SAC. However, the combination of G_SAC and H₂O₂ consistently produced EADs at lower levels of G_SAC (2.6 ± 0.4 nS, n = 14, P < 0.05). Pacing myocytes at a faster rate further prolonged APD and promoted the development of EADs. SAC activation plays an important role in facilitating the development of EADs in ventricular myocytes under acute oxidative stress. This mechanism may contribute to the increased propensity to lethal ventricular arrhythmias seen in cardiomyopathies, where the myocardium stretch and oxidative stress generally coexist.

arrhythmia mechanisms; action potential; patch clamp