Electrical Restitution and ItsModifications by AntiarrhythmicDrugs in Undiseased HumanVentricular Muscle
2020
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 IKr inhibitors E-4031
and sotalol increased overall APD and slowed the restitution kinetics, while IKs 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 Ito in restitution. APD prolonging drugs slowed restitution, while
mexiletine, a known inhibitor of INa, shortened basic APD but also slowed restitution.
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