Interaction of the antiarrhythmic drug Amiodarone with the sodium channel Nav1.5 depends on the extracellular pH

Abstract

Introduction: Amiodarone (AMD) is a clinically used drug to treat arrhythmias with significant effect upon the cardiac sodium channel Na_v1.5. AMD has a pKa of 6.56, and changes in extracellular pH (pHe) may alter its pharmacological properties. Here we explored how changes in pHe impacts the pharmacological properties of AMD upon human-Na_v1.5-sodium-current (I_Na) and in ex vivo rat hearts.

Methods: Embryonic-human-kidney-cells (HEK293) were used to transiently express the human alpha-subunit of Na_V1.5 channels and the isolated heart of Wistar rats were used. Patch-Clamp technique was deployed to study I_Na and for electrocardiogram (ECG) evaluation the ex vivo heart preparation in the Langendorff system was applied.

Results: The potency of AMD upon peak I_Na was ∼25x higher in pHe 7.0 when compared to pHe 7.4. Voltage dependence for activation did not differ among all groups. AMD shifted the steady-state inactivation curve to more hyperpolarized potentials, with similar magnitudes for both pHes. The recovery from I_Na inactivation was delayed in the presence of AMD with similar profile in both pHes. Interestingly, the use-dependent properties of AMD was distinct at pHe 7.0 and 7.4. Finally, AMD was able to change the ex vivo ECG profile, however at pHe 7.0+AMD a larger increase in the RR and QRS duration and in the QT interval when compared to pHe 7.4 was found.

Conclusions: The pharmacological properties of AMD upon Na_V1.5 and isolated heart preparation depends on the pHe and its use in vivo during extracellular acidosis may cause a distinct biological response in the heart tissue.

Keywords: Acidosis; Amiodarone; Antiarrhythmic drugs; Sodium channel.