Abstract
Slowly inactivating Na+ channels conducting “late” Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.
Highlights
The long-lasting plateau phase of the cardiac action potential is supported by L-type Ca2+ current [1], but slowly inactivating Na+ channels conducting “late” Na+ current (INa,late) contribute to the plateau phase and are related to ventricular arrhythmogenesis under pathological conditions [2,3,4]
This finding is of clinical interest, because enhancement of INa,late in atrial fibrillation (AF) could contribute to the maintenance of the arrhythmia via increased Na+ influx during the action potentials (APs) plateau phase leading to Ca2+ overload via modulation of NCX activity [15,16]
In order to test whether the clamp protocol for testing persisting membrane current at -30 mV as deviation from the extrapolated straight line between -110 mV (-120 mV) and -80 mV is sensitive enough for detecting INa,late, we studied cardiomyocytes from ΔKPQ mice in which INa,late has been detected previously [8,22]
Summary
The long-lasting plateau phase of the cardiac action potential is supported by L-type Ca2+ current [1], but slowly inactivating Na+ channels conducting “late” Na+ current (INa,late) contribute to the plateau phase and are related to ventricular arrhythmogenesis under pathological conditions [2,3,4]. In a mouse model of LQT3 (ΔKPQ), the increase in late Na+ current results in the prolongation of action potential (AP) duration in both ventricular and atrial tissues [8,9], suggesting that, in addition to its role in the ventricle, INa,late can modulate atrial repolarization. A recent study reported the presence in human right atrial myocytes of late Na+ currents with larger amplitude in cells from patients with chronic AF [14] This finding is of clinical interest, because enhancement of INa,late in AF could contribute to the maintenance of the arrhythmia via increased Na+ influx during the AP plateau phase leading to Ca2+ overload via modulation of NCX activity [15,16]. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria (reviewed in [19])
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