Fentanyl-induced block of hERG channels is exacerbated by hypoxia, hypokalemia, alkalosis, and the presence of hERG1b.

Human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (I_Kr) important for repolarization of cardiac action potentials. Drug-induced disruption of hERG channel function is a main cause of acquired long QT syndrome (LQTS), 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 (I_hERG) 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 pathological circumstances exacerbate fentanyl-induced block of I_hERG Our results showed that chronic hypoxia or hypokalemia additively reduced I_hERG 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, while 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 I_Kr 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, which may increase the risk of fentanyl-induced ventricular arrhythmias and sudden death. SIGNIFICANCE STATEMENT: This work demonstrates that heterologously expressed hERG1a/1b channels, which more closely resemble I_Kr in the human heart, are blocked by fentanyl with a 3-fold greater potency than the previously studied hERG1a expressed alone. Additionally, chronic hypoxia, hypokalemia, and alkalosis can increase the block of hERG current by fentanyl, potentially increasing the risk of cardiac arrhythmias and sudden death.