Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents

Abstract

Based on recent findings, an increased late sodium current (I_Na,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I_Na,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I_Na,late in heart diseases, and also discusses how the upregulated I_Na,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about I_Na,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.

Keywords: antiarrhythmic drugs; arrhythmias; late sodium current; sodium channel inhibitors; voltage gated sodium channel.

Figure 1

The early and the late component of the sodium current under physiological (A) and pathological (B) conditions. Upper panels: membrane potential; lower panels: sodium current. I_Na,early, early (peak) component of the sodium current; I_Na,late, late (sustained) component of the sodium current.

Figure 2

How can an impaired sodium homeostasis of cardiac myocytes lead to arrhythmias? AP, action potential; NHE, Na⁺/H⁺ exchanger; [Na⁺]_i, intracellular sodium concentration; NCX, Na⁺/Ca²⁺ exchanger; [Ca²⁺]_i, intracellular calcium concentration; SR, sarcoplasmic reticulum; CaMKII, calcium/calmodulin dependent protein kinase II.