Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels

Haechl, Nicholas; Ebner, Janine; Hilber, Karlheinz; Todt, Hannes; Koenig, Xaver

doi:10.33594/000000119

Cited by 31 publications

(28 citation statements)

References 41 publications

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“…Similarly it increased action potential duration in an isolated rabbit heart by 16% (at 5 µM), while lower concentrations were ineffective [ 46 ] and increased APD in fetal mouse hearts [ 43 ]. The fact that in all these studies resting membrane potential was unchanged despite prolongation of APD further corroborates that this effect was mediated by I Kr inhibition [ 41 , 42 , 43 ]. Studies indicate that ivabradine at 10 μM blocks approximately 20–60% of I Kr [ 47 ] and 80% of HCN4 current [ 43 ].…”

Section: Effect Of Ivabradine On Ion Channelssupporting

confidence: 64%

“…Delpon et al found that the hKv1.5 was blocked by the drug in a concentration-dependent way with IC 50 29.0 ± 1.9 μM, therefore at doses higher than those required to block HCN channels [ 40 ]. Moreover, in the clinically relevant doses ivabradine did not affect calcium channels [ 41 ] and inhibited sodium channels at high concentrations (IC 50 30 ± 3 μM) [ 6 , 41 ].…”

Section: Effect Of Ivabradine On Ion Channelsmentioning

confidence: 99%

“…However, recent data indicates that ivabradine also inhibits the rapidly activating delayed rectifier potassium current ( I Kr ) (IC 50 of ≈2–6.8 μM) [ 41 , 42 , 43 ]. This current is critical for cardiac action potential repolarization and is encoded by the human ether-a-go-go-related gene (hERG).…”

Section: Effect Of Ivabradine On Ion Channelsmentioning

confidence: 99%

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Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Oknińska

Paterek

Zambrowska

et al. 2021

JCM

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Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.

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Section: Effect Of Ivabradine On Ion Channelssupporting

confidence: 64%

Section: Effect Of Ivabradine On Ion Channelsmentioning

confidence: 99%

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Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Oknińska

Paterek

Zambrowska

et al. 2021

JCM

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“…The inhibition of I Na may contribute to antiarrhythmic but not APD-prolonging effect. In previous studies, ivabradine showed no effect or prolonging or shortening effect on APD in wild type cells (Table 1) (Koncz et al, 2011;Haechl et al, 2019). It seems that ivabradine effect on APD mainly resulted from its effect on I Kr .…”

Section: Discussionmentioning

confidence: 79%

“…Besides hERG current, I Na , but not I Ca-L , I Ks and I K1 can be inhibited by ivabradine (Supplementary Table 1) (Haechl et al, 2019;Demontis et al, 2009). The inhibition of I Na may contribute to antiarrhythmic but not APD-prolonging effect.…”

Section: Discussionmentioning

confidence: 99%

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Huang

Liao

et al. 2021

Front. Pharmacol.

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Aims: The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated.Methods: This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics.Results: Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (IKr) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of IKr similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs.Conclusion: The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.

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Multitargeting in cardioprotection: An example of biaromatic compounds

Mokrov

2023

Archiv der Pharmazie

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A multitarget drug design approach is actively developing in modern medicinal chemistry and pharmacology, especially with regard to multifactorial diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. A detailed study of many well‐known drugs developed within the single‐target approach also often reveals additional mechanisms of their real pharmacological action. One of the multitarget drug design approaches can be the identification of the basic pharmacophore models corresponding to a wide range of the required target ligands. Among such models in the group of cardioprotectors is the linked biaromatic system. This review develops the concept of a “basic pharmacophore” using the biaromatic pharmacophore of cardioprotectors as an example. It presents an analysis of possible biological targets for compounds corresponding to the biaromatic pharmacophore and an analysis of the spectrum of biological targets for the five most known and most studied cardioprotective drugs corresponding to this model, and their involvement in the biological effects of these drugs.

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Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 31 publications

References 41 publications

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Multitargeting in cardioprotection: An example of biaromatic compounds

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