Conductance Changes of Na+ Channels during the Late Na+ Current Flowing under Action Potential Voltage Clamp Conditions in Canine, Rabbit, and Guinea Pig Ventricular Myocytes

Balázs Horváth; Zsigmond M Kovács; Csaba Dienes; József Óvári; Norbert Szentandrássy; János Magyar; Tamás Bányász; András Varró; Péter P Nánási

doi:10.3390/ph16040560

Conductance Changes of Na⁺ Channels during the Late Na⁺ Current Flowing under Action Potential Voltage Clamp Conditions in Canine, Rabbit, and Guinea Pig Ventricular Myocytes

Pharmaceuticals (Basel). 2023 Apr 7;16(4):560. doi: 10.3390/ph16040560.

Authors

Affiliations

¹ Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
² Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary.
³ Division of Sport Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
⁴ Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary.
⁵ Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, 4032 Debrecen, Hungary.

Abstract

Late sodium current (I_Na,late) is an important inward current contributing to the plateau phase of the action potential (AP) in the mammalian heart. Although I_Na,late is considered as a possible target for antiarrhythmic agents, several aspects of this current remained hidden. In this work, the profile of I_Na,late, together with the respective conductance changes (G_Na,late), were studied and compared in rabbit, canine, and guinea pig ventricular myocytes using the action potential voltage clamp (APVC) technique. In canine and rabbit myocytes, the density of I_Na,late was relatively stable during the plateau and decreased only along terminal repolarization of the AP, while G_Na,late decreased monotonically. In contrast, I_Na,late increased monotonically, while G_Na,late remained largely unchanged during the AP in guinea pig. The estimated slow inactivation of Na⁺ channels was much slower in guinea pig than in canine or rabbit myocytes. The characteristics of canine I_Na,late and G_Na,late were not altered by using command APs recorded from rabbit or guinea pig myocytes, indicating that the different shapes of the current profiles are related to genuine interspecies differences in the gating of I_Na,late. Both I_Na,late and G_Na,late decreased in canine myocytes when the intracellular Ca²⁺ concentration was reduced either by the extracellular application of 1 µM nisoldipine or by the intracellular application of BAPTA. Finally, a comparison of the I_Na,late and G_Na,late profiles induced by the toxin of Anemonia sulcata (ATX-II) in canine and guinea pig myocytes revealed profound differences between the two species: in dog, the ATX-II induced I_Na,late and G_Na,late showed kinetics similar to those observed with the native current, while in guinea pig, the ATX-II induced G_Na,late increased during the AP. Our results show that there are notable interspecies differences in the gating kinetics of I_Na,late that cannot be explained by differences in AP morphology. These differences must be considered when interpreting the I_Na,late results obtained in guinea pig.

Keywords: action potential voltage clamp; late Na+ current; mammalian heart; ventricular myocytes; ventricular repolarization.

Abstract

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