Blockade of HERG cardiac K+ current by antifungal drug miconazole

Kikuchi, Kan; Nagatomo, Toshihisa; Abe, Haruhiko; Kawakami, Kyojiro; Duff, Henry J.; Makielski, Jonathan C.; January, Craig T.; Nakashima, Yasuhide

doi:10.1038/sj.bjp.0706095

Cited by 43 publications

(39 citation statements)

References 33 publications

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“…PPB are either from published data (plain text) or measured in our laboratories (bold italics). [22]; c: [23]; d: [24,25]; e: [26]; f: [27]; g: [28]; h: [19]; i: [29]; j: [30]; k: [31]; l: [32]; m: [33]; n: [34]; o: [35]; p: [36]; q: [37]; r: [38]; s: [39]; t: [40]; u: [41]; v: [42]; w: [43]; x: [44]; y: [45]; z: [46]; aa: [47]; bb: [48]; cc: [49]; dd: [50]; ee: [51]; ff: [52]; gg: [53]; hh: [54]; ii: [55]; jj: [56]; kk: [57]; ll: [58]; mm: [59]; nn: [60]; oo: [61]; pp: [62]; qq: [63]; rr: [64]; ss: [65]; tt: [66]; uu: [67]; vv: [68]; ww: …”

Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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“…However, recent studies suggest that azole antifungal agents such as miconazole, ketoconazole, fluconazole, and itraconazole are associated with acquired long QT (LQT) syndrome and ventricular arrhythmias. [1][2][3] Ventricular arrhythmias caused by antifungal agents seem to be related to the human-ether-a-go-go-related gene (HERG) channels. Kikuchi et al 3) reported that the cardiac HERG K + current is inhibited by miconazole.…”

mentioning

confidence: 99%

Blockade of K+ and Ca2+ Channels by Azole Antifungal Agents in Neonatal Rat Ventricular Myocytes

Sung

Kim

Won

et al. 2012

Biological & Pharmaceutical Bulletin

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Some azole antifungal agents induce long QT syndrome and arrhythmias. Although composite functions of ion channels in cardiomyocytes contribute to the shaping of action potentials, information on the effects of azole antifungal agents on ion currents, except human-ether-a-go-go-related gene (HERG) K currents, is largely lacking. Antibiotics are widely used throughout the world. However, despite their therapeutic effectiveness, some promising antibiotics have been withdrawn from the market due to their life-threatening side effects such as ventricular arrhythmias. Among antibiotics, azole family antifungal agents have been considered relatively safe. However, recent studies suggest that azole antifungal agents such as miconazole, ketoconazole, fluconazole, and itraconazole are associated with acquired long QT (LQT) syndrome and ventricular arrhythmias. 1-3)Ventricular arrhythmias caused by antifungal agents seem to be related to the human-ether-a-go-go-related gene (HERG) channels. Kikuchi et al. 3) reported that the cardiac HERG K + current is inhibited by miconazole. Inhibition of HERG and voltage-gated K + channels (Kv1.5) by ketoconazole has also been reported. 4) Fluconazole also blocks HERG K + channels. 5)Itraconazole has been reported to cause frequent premature ventricular contractions in young males. 6) These reports demonstrate that azole antifungal agents may cause arrhythmias by impairing function of cardiac ion channels such as HERG K + channels. However, information about the effects of azole antifungal agents on cardiac ion channels other than HERG are largely lacking. Cardiac rhythm and contractility are regulated by composite functions of cardiomyocyte ion channels. The functions of various K + currents such as rapid (IK r ) and slowly (IK s ) activating delayed-rectifier K + current (IK dr ) are important for repolarization of mammalian cardiac ventricular cells. 7) Particularly, the role of IK r (encoded by HERG) is important during repolarization from the plateau (phase 2) of the action potential. 8,9) In this regard, HERG is recommended as an important safety screening target during drug development. However, coordinated functions of various ion channels are essential for normal shaping of action potentials in addition to HERG K + channels. For example, currents through inward rectifier K + channels (IK ir ) contribute to stabilizing the resting membrane potential (phase 4) and completing phase 3 repolarization. 10)Inhibiting IK ir depolarizes the diastolic potential and prolongs action potential duration. 11) Besides the K + channels, slowing the inactivation of voltage-gated Na + or Ca 2+ currents may also contribute to prolong the action potential and to generate LQT or torsade de pointes. 12,13) In this study, we examined the effects of four azole antifungal agents (miconazole, ketoconazole, fluconazole, and itraconazole) on K + and voltage-gated L-type Ca 2+ currents (ICa L ) in ventricular myocytes from rat neonates using wholecell voltage clamping. Both miconazole and ketoconazole s...

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“…These properties are similar to those of mesoridazine 32) and miconazole. 33) In summary, IM is a potent blocker of HERG channels, and it blocks the channels in a state-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

Zhao

et al. 2013

Biological & Pharmaceutical Bulletin

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Imatinib mesylate (IM), a widely prescribed powerful tyrosine kinase inhibitor, has been associated with increased risk of heart failure and is known to induce cell apoptosis and death in isolated cardiomyocytes. In addition to acquired long QT syndrome, pharmacological inhibition of human ether-à-go-go-related gene (HERG) channel has been reported to involve in apoptosis. The present study was undertaken to characterize the biophysical properties of IM on HERG and the molecular determinants of HERG blockade using mutant channels (

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Blockade of HERG cardiac K⁺ current by antifungal drug miconazole

Cited by 43 publications

References 33 publications

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Blockade of K<sup>+</sup> and Ca<sup>2+</sup> Channels by Azole Antifungal Agents in Neonatal Rat Ventricular Myocytes

Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

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