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The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

Lixia Jia1, Marieke W Veldkamp1, Arie O Verkerk1,2

  • 1Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.

Europace : European Pacing, Arrhythmias, and Cardiac Electrophysiology : Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology
|July 11, 2023
PubMed
Abstract

Insights

Tramadol significantly inhibits cardiac sodium channel (Nav1.5) currents, potentially increasing sudden cardiac death risk. Fentanyl and codeine do not affect these critical cardiac channels.

Area of Science:

  • Cardiovascular Pharmacology
  • Cardiac Electrophysiology
  • Molecular Cardiology

Background:

  • Opioid analgesics are linked to increased risk of sudden cardiac death.
  • This risk may stem from opioid interactions with cardiac sodium channels (Nav1.5).

Purpose of the Study:

  • To investigate the effects of tramadol, fentanyl, and codeine on the human cardiac sodium channel Nav1.5.
  • To determine the impact of these opioids on cardiac action potential properties.

Main Methods:

  • Whole-cell patch-clamp electrophysiology was used to assess effects on Nav1.5 currents in HEK293 cells.
  • Action potential properties were studied in isolated rabbit ventricular cardiomyocytes.
  • Concentration-dependent inhibition and effects on channel gating parameters were evaluated.

Main Results:

  • Tramadol concentration-dependently inhibited Nav1.5 current, with significant effects at near-physiological potentials (IC50 values ranging from 4.5 to 378.5 µm).
  • Tramadol altered Nav1.5 channel gating, causing hyperpolarizing shifts in activation/inactivation and delayed recovery.
  • Fentanyl and codeine demonstrated no significant effects on Nav1.5 current, even at high concentrations.

Conclusions:

  • Tramadol exerts a significant inhibitory effect on cardiac Nav1.5 currents, particularly under conditions mimicking physiological membrane potentials.
  • These findings suggest a potential mechanism for opioid-induced cardiotoxicity.
  • Fentanyl and codeine do not appear to interact with Nav1.5 channels, indicating a differential cardiotoxic potential among opioids.
Keywords:
Action potentialNav1.5 currentOverdoseRisk associationSudden cardiac deathTramadol

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