Abstract
The transient outward current (Ito) plays important roles in action potential (AP) morphology and arrhythmogenesis in cardiac diseases, such as ischemia and the Brugada syndrome. It is well accepted that early afterdepolarizations (EADs) occur under conditions of reduced repolarization reserve, which can result from either increased inward currents or reduced outward currents. Here we show the novel finding that Ito, an outward current, promotes EADs in rabbit ventricular myocytes, raising the question: how does an outward current promote EADs? To answer this question, we carried out experimental studies in isolated rabbit ventricular myocytes, theoretical analysis, and computer simulations. In myocyte experiments, exposure to 0.2-1 mM H2O2 at slow pacing rates induced EADs, which were eliminated by selectively blocking Ito with 2 mM 4-aminopyridine. Pre-treating myocytes with 4-aminopyridine prolonged AP, but likewise prevented H2O2-induced EADs. Voltage-clamp experiments showed that besides promoting late ICa,L and late INa, H2O2 also increased the maximum conductance, slowed the inactivation and accelerated the recovery from inactivation of Ito. When the cells were clamped with AP morphologies corresponding to the absence and presence of Ito, Ito significantly enhanced the Ca current, promoting its reactivation as the mechanism induced EADs. In a computer model of the rabbit ventricular AP, we also showed that the presence of Ito promoted EADs. The rate of Ito inactivation played a critical role: if too fast, no EADs occurred, and if too slow, AP duration became too short and no EADs occurred either. The underlying dynamical mechanisms were revealed by bifurcation theory of EADs previously developed by our group (Tran et al, Phys. Rev. Lett. 2009; 102:258103).
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