Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle

Tamás Árpádffy-Lovas; István Baczkó; Beáta Baláti; Miklós Bitay; Norbert Jost; Csaba Lengyel; Norbert Nagy; János Takács; András Varró; László Virág

doi:10.3389/fphar.2020.00479

Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle

Front Pharmacol. 2020 Apr 30:11:479. doi: 10.3389/fphar.2020.00479. eCollection 2020.

Authors

Tamás Árpádffy-Lovas^{1

2}, István Baczkó^{1

2}, Beáta Baláti¹, Miklós Bitay³, Norbert Jost^{1

2

4}, Csaba Lengyel⁵, Norbert Nagy^{1

4}, János Takács¹, András Varró^{1

2

4}, László Virág^{1

2}

Affiliations

¹ Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.
² Department of Pharmacology and Pharmacotherapy, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary.
³ Department of Cardiac Surgery, Faculty of Medicine, University of Szeged, Szeged, Hungary.
⁴ MTA-SZTE Research Group for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
⁵ First Department of Internal Medicine, University of Szeged, Szeged, Hungary.

Abstract

Introduction: Re-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species.

Methods: Action potentials were recorded in preparations obtained from rat, guinea pig, rabbit, and dog hearts; and from undiseased human donor hearts using the conventional microelectrode technique. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5,000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1,000 ms BCL.

Results: Marked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective I_Kr inhibitors E-4031 and sotalol increased overall APD and slowed the restitution kinetics, while I_Ks inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics.

Discussion: Frequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of I_to in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of I_Na, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as I_Na or I_to, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.

Keywords: action potential; arrhythmia; cardiac electrophysiogy; electrical restitution; human ventricle.