Role of Cardiac IKs Current in Repolarization Reserve Process During Late Sodium Current (INaL) Activation

Printemps, Richard; Salvetat, Céline; Faivré, Jean-François; Grand, Marie Le; Bois, Patrick; Maati, Hamid Moha Ou

doi:10.26502/fccm.92920065

Cited by 6 publications

(7 citation statements)

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“…U04270 ) was cloned into pcDNA3.1-Zeo (Invitrogen, Carlsbad, CA, USA) vector. 14 , 15 IKs and IKr were examined for channel expression by whole-cell configuration of patch clamp technique.…”

Section: Methodsmentioning

confidence: 99%

“…The cells are seeded in 35 mm Petri dishes to obtain a confluence of about 50% on the day of the experiment. 14 , 15 …”

Section: Methodsmentioning

confidence: 99%

“…Current-voltage relationships (IKs) were obtained by stepping the membrane voltage for 5.5 s at voltages between −70 and + 90 mV in 20 mV increments, and tail currents were generated by the following repolarization to −40 mV (for 3 s). 15 Cells were superfused with vehicle until stabilization, then with H. bonariensis extract at 0.5 mg/ml (n = 5) until steady state, followed by a washout period with vehicle. Note that preliminary results obtained in our laboratory indicate that 0.5 mg/ml reduces blood pressure in anesthetized rabbit by more than 30% (not shown).…”

Section: Methodsmentioning

confidence: 99%

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Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Kaboua

Mouzou²,

Pakoussi³

et al. 2022

Journal of Traditional and Complementary Medicine

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Section: Methodsmentioning

confidence: 99%

“…The cells are seeded in 35 mm Petri dishes to obtain a confluence of about 50% on the day of the experiment. 14 , 15 …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Kaboua

Mouzou²,

Pakoussi³

et al. 2022

Journal of Traditional and Complementary Medicine

Self Cite

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“…2.1 (Busch, A. et al, 1996) Guinea-pig KCNQ1/KCNE1 6.51 (Printemps et al, 2019) Guinea-pig ventricular myocytes (IKs)…”

Section: Limitations Of the Studymentioning

confidence: 99%

Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish I_Ks to I_Ks inhibitors and activators

Haverinen

Hassinen

Vornanen

2021

Preprint

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In cardiac myocytes, the slow component of the delayed rectifier K+ current (IKs) ensures repolarization of action potential during beta-adrenergic activation or when other repolarizing K+ currents fail. As a key factor of cardiac repolarization IKs should be present in model species used for cardiovascular drug screening, preferably with pharmacological characteristics similar to those of the human IKs. To this end, we investigated the effects of inhibitors and activators of the IKs on KCNQ1 and KCNQ1+KCNE1 channels of the zebrafish, an important model species, in Chinese hamster ovary cells. Inhibitors of IKs, chromanol 293B and HMR-1556, inhibited zebrafish IKs channels with approximately similar potency as that of mammalian IKs. Chromanol 293B concentration for half-maximal inhibition (IC50) of zebrafish IKs was at 13.1±5.8 and 13.4±2.8 μM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. HMR-1556 was a more potent inhibitor of zebrafish IKs with IC50=0.1±0.1 μM and 1.5±0.8 μM for KCNQ1 and KCNQ1+KCNE1 channels, respectively. R-L3 and mefenamic acid, generally identified as IKs activators, both inhibited zebrafish IKs. R-L3 almost completely inhibited zebrafish IKs generated by KCNQ1 and KCNQ1+KCNE1 channels with similar affinity (IC50 1.1±0.4 and 1.0±0.4 μM, respectively). Mefenamic acid partially blocked zebrafish KCNQ1 (IC50=9.5±4.8 μM) and completely blocked KCNQ1+KCNE1 channels (IC50=3.3±1.8 μM). Although zebrafish IKs responds to IKs inhibitors in the same way as mammalian IKs, its response to activators is atypical, probably due to the differences in the binding domain of KCNE1 to KCNQ1. Therefore, care must be taken when translating the results from zebrafish to humans.

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“…Quantifying the corresponding ion-specific conductance profile would more fully describe a cardiomyocyte’s repolarization reserve and elucidate how variability in ion-channel densities translates to RRC values. While repolarization reserve has been studied, most efforts made to describe this phenomenon have quantified effects of individual ion channel conductances (Xiao et al, 2008; Jost et al, 2005; Varshneya et al, 2018; Silva and Rudy, 2005; Printemps et al, 2019; Ishihara et al, 2009; Jost et al, 2013; Biliczki et al, 2002). For example, the slow delayed rectifier potassium current (I Ks ) (Xiao et al, 2008; Jost et al, 2005; Varshneya et al, 2018; Silva and Rudy, 2005) and the inward rectifier current (I K1 ) (Ishihara et al, 2009; Jost et al, 2013; Biliczki et al, 2002) have been independently demonstrated to provide the necessary repolarizing current to prevent proarrhythmia in the presence of rapid delayed rectifier potassium current (I Kr ) block.…”

Section: Introductionmentioning

confidence: 99%

Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve

Fullerton,

Clark,

Krogh-Madsen

et al. 2023

Preprint

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Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents. However, it is important to understand the interplay between all major ion channel conductances, as repolarization reserve is dependent on the balance between all ion currents in a cardiomyocyte. Here, a genetic algorithm was designed to derive a profile of nine ion-channel conductances that optimizes repolarization reserve in a mathematical cardiomyocyte model. Repolarization reserve was quantified using a previously defined metric, repolarization reserve current, i.e., the minimum constant current to prevent normal action potential repolarization in a cell. The optimization improved repolarization reserve current by 77 % compared to baseline in a human adult ventricular myocyte model and increased resistance to arrhythmogenic insult. The optimized conductance profile was characterized by increased repolarizing current conductances, but also uncovered a previously un-reported behavior by the late sodium current. Simulations demonstrated that upregulated late sodium increased action potential duration, without compromising repolarization reserve current. The finding was generalized to multiple models. Ultimately, this computational approach in which multiple currents were studied simultaneously illuminated mechanistic insights into how the metric’s magnitude could be increased, and allowed for the unexpected role of late sodium to be elucidated.NEW & NOTEWORTHYGenetic algorithms are typically used to fit models or extract desired parameters from data. Here, we utilize the tool to produce a ventricular cardiomyocyte model with increased repolarization reserve. Since arrhythmia mitigation is dependent on multiple cardiac ion-channel conductances, study using a comprehensive, unbiased, and systems-level approach is important. This use of this optimization strategy allowed us to find a robust profile that illuminated unexpected mechanistic determinants of key ion-channel conductances in repolarization reserve.

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Role of Cardiac IKs Current in Repolarization Reserve Process During Late Sodium Current (INaL) Activation

Cited by 6 publications

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Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish I_Ks to I_Ks inhibitors and activators

Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve

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Role of Cardiac IKs Current in Repolarization Reserve Process During Late Sodium Current (INaL) Activation

Cited by 6 publications

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Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Hydrocotyle bonariensis Comm ex Lamm (Araliaceae) leaves extract inhibits IKs not IKr potassium currents: Potential implications for anti-arrhythmic therapy

Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish IKs to IKs inhibitors and activators

Optimization of a Cardiomyocyte Model Illuminates Role of Increased INaLin Repolarization Reserve

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Effect of channel assembly (KCNQ1 or KCNQ1 + KCNE1) on the response of zebrafish I_Ks to I_Ks inhibitors and activators

Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve