Ethnic-Related Sodium Voltage-Gated Channel α Subunit 5 Polymorphisms Shape the In Vitro Pharmacological Action of Amiodarone upon Na_v1.5

Abstract

Nav1.5-derived Na + current (I Na ) exerts a pivotal role in the depolarization phase of cardiomyocytes' action potential, and therefore, changes in I Na can contribute to fatal arrhythmias. Nav1.5 displays naturally occurring ethnic-related polymorphisms, which might alter the functioning and pharmacology of the channel. Some studies have shown how single nucleotide polymorphism can change the response to antiarrhythmic drugs. Investigations on the role of Nav1.5 in arrhythmogenesis, associated with its functional polymorphisms, are currently growing, as well as the possible variability in the antiarrhythmic pharmacotherapy among ethnic-groups. The influence of the ethnic-related polymorphisms (S524Y, S1103Y, R1193Q, V1951L) on the responsiveness, selectivity, and pharmacological efficacy of the clinically used antiarrhythmic, amiodarone (AMIO), is not completely known. Our objectives were to analyze biophysical and pharmacological aspects of four ethnic-related polymorphisms before and after exposure to AMIO. Polymorphisms caused reduced AMIO potency compared to wild-type (WT) that can vary up to 4x between them.AMIO shifted the voltage dependency for current inactivation, without significant effect in voltage-dependent activation to a similar extend in WT and polymorphisms.The recovery from inactivation was altered between the polymorphisms when compared to WT. Finally, the use-dependency of AMIO differed between studied groups, especially at a more depolarized cell membrane. Thus, our work may guide future studies focusing on the efficiency of AMIO in treating different arrhythmias and to establish more individualized guidelines for its use depending on the Nav1.5polymorphism, after validating our findings using in vivo studies.

Evaluation of right atrium structure and function in a rat model of monocrotaline‐induced pulmonary hypertension: Exploring the possible antiarrhythmic properties of amiodarone

“…However, it is known that amiodarone is a multichannel blocker, with clear action against a variety of ion channel (e.g. calcium and sodium channels) 40,41 and also action against β adrenoceptor and muscarinic receptor 42 . Therefore, the potential in vivo net effect of amiodarone depends on a set of parameters, including: (a) the total plasma concentration of the drug 21 ; (b) the fine balance of ion channels found in the tissue, especially in diseases that alters the expression of a variety of ion channels, as that observed in MCT‐PH rats 6 ; (c) the influence of amiodarone on the ion channel expression after long‐term treatment with the drug 39 ; (d) non‐cardiac effects of the drug 43 ; and (e) unknown factors.…”

The insecticide β-Cyfluthrin induces acute arrhythmic cardiotoxicity through interaction with NaV1.5 and ranolazine reverses the phenotype

“…Human embryonic kidney cells (HEK-293) exhibiting no constitutive macroscopic functional sodium current (I Na ) were used in the voltage-clamp experiments as previously described [26]. Cells were cultured in Dulbecco's Modified Eagle's Medium…”