Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b

Abstract

Introduction: 690 Discussion: 1481 Abbreviations: ANOVA, analysis of variance; APD, action potential duration; FBS, fetal bovine serum; HEK, human embryonic kidney; hERG, human ether a-go-go related gene; IC 50 , half maximal inhibitory concentration; I hERG , hERG current; I Kr , rapidly activating delayed rectifier potassium current; [K + ] o , extracellular potassium concentration; LQTS, long QT syndrome; MEM, minimum essential medium; S.D., standard deviation; τ f-deact , fast time constant of deactivation; τ s-deact , slow time constant of deactivation; WT, wild-type.

Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

“…The authors also demonstrated that block by N-methyl-verapamil, a permanently charged analogue of verapamil, was not sensitive to changes in pH, confirming that the effect on block was specifically due to the charge on the drug molecule (Zhang et al 1999 ). Similar explanations have also been posed for other drugs such as flecainide (Du et al 2011 ), ibogaine (Thurner et al 2014 ), fentanyl (Tschirhart and Zhang 2020 ) and hydroxychloroquine (TeBay et al 2021 ) supporting the case that this is a common mechanism for the effect of pH on a drug’s potency to bock ERG.…”

“…Here we will focus on studies that have specifically addressed potassium dependence of a drug’s potency to block hERG. Across the literature, reports of the influence of K + on potency to block hERG across drugs is broadly consistent, with increasing extracellular potassium reducing the potency of block (Barrows et al 2009 ; Busch et al 1998 ; Lin et al 2007 , 2008 , 2005c ; Lin and Papazian 2007 ; Mergenthaler et al 2001 ; TeBay et al 2021 ; Wang et al 1997 ; West et al 1997 ; Yang et al 2004 ) and decreased potassium concentration increasing potency of block (Lin et al 2005a ; TeBay et al 2021 ; Tschirhart and Zhang 2020 ). Two potential mechanisms have been proposed to explain this.…”

“…In the latter case, early experiments showed that a reduction in pH to 6.8 could significantly reduce hERG block by dofetilide (West et al 1997 ). Across numerous subsequent reports, there is broad consensus that extracellular acidification reduces hERG block by a range of compounds (Du et al 2011 ; Lin et al 2005a , b , 2008 ; TeBay et al 2021 ; Thurner et al 2014 ; Tschirhart and Zhang 2020 ; Wang et al 2016 ; Zhang et al 1999 ), with alkalisation enhancing drug block (Lin et al 2005a ; Thurner et al 2014 ; Tschirhart and Zhang 2020 ; Zhang et al 1999 ). There is however some complexity to this relationship since quite different results were seen when the extracellular solution was acidified using sodium acetate rather than hydrochloric acid.…”

Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

“…Congenital diseases may eventually manifest during adulthood in response to specific stresses, remaining undiscovered until a dramatic or fatal episode occurs, even in agonistic athletes routinely submitted to ECG to practice [102][103][104][105][106][107][108][109][110][111]. Acquired rhythm pathologies might be induced by several causes, among which drug cardiotoxicity, cardiomyopathies, myocarditis or systemic infections, valve diseases, and interventional/surgical maldeployment of cardiac valve replacements [112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128].…”

Editorial: 50 Years of Opioid Research and the International Narcotics Research Conference

“…Eacret et al focus on the relationship between sleep and opioids, and outline the mechanisms underlying the reciprocal feed-forward interaction between these sleep disruption and opioid use (Eacret et al, 2020). Interestingly, some synthetic opioids might also act outside of opioid receptors, as shown by Tschirhart and Zhang in their study that described how metabolic changes can potentiate the inhibition of specific potassium channels by fentanyl (Tschirhart and Zhang, 2020).…”