Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of HERG1b

Abstract

Human ether-a-go-go-related gene (hERG) encodes the poreforming subunit of the rapidly activating delayed rectifier potassium current (IKr) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome, which can lead to ventricular arrhythmias and sudden death. Illicit fentanyl use is associated with sudden death. We have demonstrated that fentanyl blocks hERG current (IhERG) at concentrations that overlap with the upper range of postmortem blood concentrations in fentanyl-related deaths. Since fentanyl can cause respiratory depression and electrolyte imbalances, in the present study we investigated whether certain pathologic circumstances exacerbate fentanyl-induced block of IhERG. Our results show that chronic hypoxia or hypokalemia additively reduced IhERG with fentanyl. As well, high pH potentiated the fentanyl-mediated block of hERG channels, with an IC50 at pH 8.4 being 7-fold lower than that at pH 7.4. Furthermore, although the full-length hERG variant, hERG1a, has been widely used to study hERG channels, coexpression with the short variant, hERG1b (which does not produce current when expressed alone), produces functional hERG1a/1b channels, which gate more closely resembling native IKr. Our results showed that fentanyl blocked hERG1a/1b channels with a 3-fold greater potency than hERG1a channels. Thus, in addition to a greater susceptibility due to the presence of hERG1b in the human heart, hERG channel block by fentanyl can be exacerbated by certain conditions, such as hypoxia, hypokalemia, or alkalosis, whichmay increase the risk of fentanyl-induced ventricular arrhythmias and sudden death.