Abstract
The late sodium current [INa,late] can play an important role in generating arrhythmogenic afterdepolarisations in cardiac myocytes. However the profile of INa,late during the action potential [AP] has not yet been directly measured. The goal of the present study was to directly record and describe the profile of INa,late as it could be observed in situ (in a physiological milieu, during AP, with undisturbed cellular calcium homeostasis).METHODS: Our newly developed ‘Onion-Peeling’ technique (a variant of action potential voltage-clamp) was utilised to dissect out INa,late during AP by using tetrodotoxin. The experiments were done on isolated guinea pig ventricular myocytes at 36 °C. In one set of experiments no exogenous calcium buffer was used in the internal solution, which enabled intracellular calcium cycling during AP. In the other set of recordings intracellular calcium concentration was clamped with BAPTA. The intracellular calcium concentration was measured by using Fura-2.RESULTS: The tetrodotoxin-sensitive current first displayed a large peak during the AP upstroke attributable to the fast sodium current, and then showed a sustained current throughout the AP due to INa,late. With cycling calcium, INa,late showed a gradual increase during the AP plateau phase and then peaked during the fast repolarising phase. When the intracellular calcium was clamped, INa,late showed larger current density throughout the AP time course but the overall current profile remained similar.CONCLUSION: The INa,late profile directly recorded in situ by using the ‘Onion-Peeling’ method is different from what previously predicted by model simulations based on the data obtained using conventional voltage-clamp under simplified conditions (ion substitution, calcium buffering, rectangular voltage pulses). The observed high INa,late density during the AP repolarising phase underlies the arrhythmogenic role of the current.
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