Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic pore

Amorós, Irene; Dolz-Gaitón, Pablo; Gómez, Ricardo; Matamoros, Marcos; Barana, Adriana; Fuente, Marta González de la; Núñez, Mercedes; Pérez-Hernández, Marta; Moraleda, Ignacio; Galvez, Enrique J.; Iriepa, Isabel; Tamargo, Juan; Caballero, Ricardo; Delpón, Eva

doi:10.1016/j.bcp.2013.04.023

Cited by 18 publications

(28 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Memantine is a blocker of glutamate receptor channels but also suppresses Kir current amplitude in apparent competition with spermine, causing cell depolarization (100). The antiarrhythmic drug propafenone blocks human cardiac Kir2 channels, apparently by decreasing the negative electrostatic charge sensed by polyamines within the cytoplasmic pore (101). Propafenone-induced block was markedly increased at lower intracellular [K ϩ ] and decreased at more positive voltages, resulting in effective reduction of inward rectification, consistent with propafenone binding within the cytoplasmic domain in such a way that it decreased the net negative charge sensed by K ϩ ions and polyamines.…”

Section: Clinical Relevance Of Inward Rectificationmentioning

confidence: 87%

Polyamines and potassium channels: A 25-year romance

Nichols

Lee

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Clinical Relevance Of Inward Rectificationmentioning

confidence: 87%

Polyamines and potassium channels: A 25-year romance

Nichols

Lee

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Propafenone blocks I CaL with an IC 50 of 1.5–1.7 μM in mammalian cardiac myocytes (Fei et al, 1993; Hancox and Mitcheson, 1997). In human atrial myocytes, propafenone has been shown to block I to with an IC 50 of 4.8 μM (Gross and Castle, 1998; Seki et al, 1999) and I K1 with an IC 50 of 16.8 μM (Amorós et al, 2013). Finally, I Kur is blocked with an IC 50 of 4.4 μM (Franqueza et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

2019

View full text Add to dashboard Cite

Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.

show abstract

“…Forty-eight hours after transfection, cells were incubated with polystyrene microbeads precoated with anti-CD8 antibody. 10,15,16…”

Section: Human Atrial and Guinea Pig Myocyte Isolationmentioning

confidence: 99%

“…Currentvoltage (I -V ) curves were corrected according to the calculated liquid junction potential. 10,15,16…”

Section: Macroscopic Current Recordingsmentioning

confidence: 99%

Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents

Gómez

Caballero

Barana

et al. 2014

Cardiovascular Research

Self Cite

View full text Add to dashboard Cite

show abstract

Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic pore

Cited by 18 publications

References 35 publications

Polyamines and potassium channels: A 25-year romance

Polyamines and potassium channels: A 25-year romance

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents

Contact Info

Product

Resources

About