Effect of antiarrhythmic drugs on small conductance calcium – activated potassium channels

Simó-Vicens, Rafel; Sauter, Daniel; Grunnet, Morten; Diness, Jonas Goldin; Bentzen, Bo Hjorth

doi:10.1016/j.ejphar.2017.03.039

Cited by 11 publications

(11 citation statements)

References 17 publications

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“…Automated patch clamp (QPatch 16, Sophion, Denmark) on SK-expressing HEK293 cell lines was conducted as previously described (Simó-Vicens et al, 2017b). Briefly, SK currents were elicited by voltage-ramps starting at −80 mV and finishing at +80 mV from a holding potential of 0 mV.…”

Section: Methodsmentioning

confidence: 99%

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

et al. 2018

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A variety of polycyclic pyridines have been proposed as inhibitors of the small conductance calcium-activated potassium (SK) channel. To this group belongs 2,6-bis(2-benzimidazolyl)pyridine (BBP), a commercially and readily available small organic compound which has earlier been described in a broad range of chemical and biological uses. Here, we show how BBP can also be used as a potent and specific SK channel blocker in vitro. The potency of BBP was measured using automatic patch clamp on all three SK channel subtypes, resulting in similar IC50 of 0.4 μM. We also assessed the selectivity of BBP on a panel of calcium-activated and voltage-activated potassium channels using two-electrode voltage clamp, automatic and manual patch clamp. BBP did not have any effect on IK, Kir2.1, Kir3.1+Kir3.4, Kv1.5, Kv4.3/KCHIP2 and Kv7.1/KCNE1 currents and was 4.8-fold and 46-fold more potent on all SK channel subtypes vs. BK and hERG channels, respectively. Moreover, we were able to identify H491 as a critical amino acid for the pharmacological effect of BBP on the SK channel. From a medicinal chemistry perspective, BBP could be used as a starting point for the design of new and improved SK inhibitors.

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Section: Methodsmentioning

confidence: 99%

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

et al. 2018

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“…Because apamin cannot be applied to humans, other compounds with different mechanisms of SK-channel inhibition, including modulation of the Ca 2+ sensor (e.g., NS8593) and direct channel pore block (e.g., UCL1684 and ICAGEN) [36] have been developed. Currently used AADs do not appear to target SK channels, with only dofetilide and propafenone showing some inhibition at suprapharmacological concentrations [90]. Interestingly, an SK-channel activator (NS309) has recently been described to attenuate Ca 2+ -dependent arrhythmia in hypertrophic rat hearts by regulating SK channels on the mitochondrial membrane, thereby reducing mitochondrial production of reactive oxygen species that promote RyR2 dysfunction [91].…”

Section: Promising Antiarrhythmic Targets and Agentsmentioning

confidence: 99%

Investigational antiarrhythmic agents: promising drugs in early clinical development

Heijman

Ghezelbash

Dobrev

2017

Expert Opinion on Investigational Drugs

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Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy. Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K-channels, the late Na-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca-activated K-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development. Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.

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“…A high coverage can be obtained because it is shaped as a sphere. Several reports indicate high success rates when FIRM-identified sources were ablated [66][67][68] but later studies failed to reproduce these findings. [69][70][71][72][73] The algorithm is not disclosed but it is reported that the electrograms are converted into a phase signal.…”

Section: Chapter 1 16mentioning

confidence: 99%

“…[69][70][71][72][73] The algorithm is not disclosed but it is reported that the electrograms are converted into a phase signal. [65][66][67] Based on the low density of electrodes, potential poor contact and signal processing steps there are some concerns about the specificity of rotor identification with this method. 74,75 In c hapter 6 we developed an algorithm to covert raw electrograms into a phase signal.…”

Section: Chapter 1 16mentioning

confidence: 99%

“…65 Recently, it was shown that vernakalant also inhibits IK2p2.1 at clinical relevant concentrations but not ISK (figure 1). 67 Earlier studies on vernakalant have emphasized its ability to inhibit IKur and high atrial specificity was assigned to vernakalant because of a high potency for the atrial specific currents. [68][69][70] Vernakalant led, indeed, to an atrial-preferential refractory period prolongation in patients.…”

Section: P Otential Targets For New Antiarrhythmic Drugs For the Treamentioning

confidence: 99%

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Dynamics of propagation patterns and anti-arrhythmic mechanisms during atrial fibrillation

Hunnik¹

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People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. 26. Mandzia, J. L. & Hill, M. D. Acute stroke management in patients with known or suspected atrial fibrillati on.

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Effect of antiarrhythmic drugs on small conductance calcium – activated potassium channels

Cited by 11 publications

References 17 publications

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

Investigational antiarrhythmic agents: promising drugs in early clinical development

Dynamics of propagation patterns and anti-arrhythmic mechanisms during atrial fibrillation

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