Human ether-a-go-go–related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (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, 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 pathologic circumstances exacerbate fentanyl-induced block of I_hERG. Our results show 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, 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 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.

中文翻译：

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缺氧，低钾血症，碱中毒和hERG1b的存在加剧了芬太尼诱导的hERG通道阻滞。

人与人有关的基因（hERG）编码快速激活的延迟整流钾电流（I _Kr）的成孔亚基，对心脏动作电位的复极化很重要。药物诱导的hERG通道功能破坏是获得性长QT综合征的主要原因，可导致室性心律不齐和猝死。非法使用芬太尼会导致猝死。我们已经证明，芬太尼在与芬太尼相关的死亡中的死后血液浓度上限重叠的浓度范围内会阻断hERG电流（I _hERG）。由于芬太尼可导致呼吸抑制和电解质失衡，因此在本研究中，我们调查了某些病理情况是否会加剧芬太尼诱导的I受体阻滞_hERG的。我们的结果表明，慢性低氧或低血钾症会与芬太尼共同降低I _hERG。同样，高pH值增强了芬太尼介导的hERG通道阻滞，pH 8.4时的IC ₅₀比pH 7.4时低7倍。此外，尽管全长hERG变体hERG1a已广泛用于研究hERG通道，但与短变体hERG1b（单独表达时不产生电流）的共表达可产生功能性hERG1a / 1b通道，其门控更紧密类似于本地人I _Kr。我们的结果表明，芬太尼阻断hERG1a / 1b通道的效力比hERG1a通道高3倍。因此，除了由于人类心脏中存在hERG1b而引起的更大敏感性之外，某些条件（例如缺氧，低钾血症或碱中毒）还会加剧芬太尼对hERG通道的阻断，这可能会增加芬太尼诱导的心室风险心律失常和猝死。