TY - JOUR
T1 - The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells
AU - Jia, Lixia
AU - Veldkamp, Marieke W.
AU - Verkerk, Arie O.
AU - Tan, Hanno L.
N1 - Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation program (grant number 733381); the European Cooperation in Science and Technology (grant number CA19137); the China Scholarship Council; and Netherlands Cardio Vascular Research Initiative (grant numbers CVON-2017-15 and CVON-2018-30). Publisher Copyright: © The Author(s) 2023.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Aims: Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. Methods and results: Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential -120mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33 μm. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential -90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μm, while it was 16 ± 4.8 μm during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. Conclusion: Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.
AB - Aims: Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. Methods and results: Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential -120mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33 μm. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential -90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μm, while it was 16 ± 4.8 μm during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. Conclusion: Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.
KW - Action potential
KW - Na 1.5 current
KW - Overdose
KW - Risk association
KW - Sudden cardiac death
KW - Tramadol
UR - http://www.scopus.com/inward/record.url?scp=85166442476&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/europace/euad209
DO - https://doi.org/10.1093/europace/euad209
M3 - Article
C2 - 37433113
SN - 1099-5129
VL - 25
JO - EP Europace
JF - EP Europace
IS - 9
M1 - euad209
ER -