Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans

Walfridsson, Håkan; Anfinsen, Ole-Gunnar; Berggren, Anders; Frison, Lars; Jensen, Steen M.; Linhardt, Gunilla; Nordkam, Ann-Christin; Sundqvist, Monika; Carlsson, Leif

doi:10.1093/europace/euu192

Cited by 33 publications

(27 citation statements)

References 22 publications

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Section: Discussionmentioning

confidence: 99%

“…It has been reported that NTC‐801 (50), a benzopyrene derivative, and AZD2927 (51), a benzamide‐related compound, can selectively inhibit I KACh at submicromolar concentrations. However, the drugs failed to revert paroxysmal AF and atrial flutter, respectively, in patients (50, 51). The results are not surprising, given the fact that I KACh is not constitutively active in patients with paroxysmal AF (52), let alone in atrial flutter whose mechanism differs from that of AF (53).…”

Section: Discussionmentioning

confidence: 99%

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Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

et al. 2018

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The acetylcholine-activated inward rectifier potassium current ( I) is constitutively active in persistent atrial fibrillation (AF). We tested the hypothesis that the blocking of I with the small molecule chloroquine terminates persistent AF. We used a sheep model of tachypacing-induced, persistent AF, molecular modeling, electrophysiology, and structural biology approaches. The 50% inhibition/inhibitory concentration of I block with chloroquine, measured by patch clamp, was 1 μM. In optical mapping of sheep hearts with persistent AF, 1 μM chloroquine restored sinus rhythm. Molecular modeling suggested that chloroquine blocked the passage of a hydrated potassium ion through the intracellular domain of Kir3.1 (a molecular correlate of I) by interacting with residues D260 and F255, in proximity to I228, Q227, and L299. HN heteronuclear single-quantum correlation of purified Kir3.1 intracellular domain confirmed the modeling results. F255, I228, Q227, and L299 underwent significant chemical-shift perturbations upon drug binding. We then crystallized and solved a 2.5 Å X-ray structure of Kir3.1 with F255A mutation. Modeling of chloroquine binding to the mutant channel suggested that the drug's binding to the pore becomes off centered, reducing its ability to block a hydrated potassium ion. Patch clamp validated the structural and modeling data, where the F255A and D260A mutations significantly reduced I block by chloroquine. With the use of numerical and structural biology approaches, we elucidated the details of how a small molecule could block an ion channel and exert antiarrhythmic effects. Chloroquine binds the I channel at a site formed by specific amino acids in the ion-permeation pathway, leading to decreased I and the subsequent termination of AF.-Takemoto, Y., Slough, D. P., Meinke, G., Katnik, C., Graziano, Z. A., Chidipi, B., Reiser, M., Alhadidy, M. M., Ramirez, R., Salvador-Montañés, O., Ennis, S., Guerrero-Serna, G., Haburcak, M., Diehl, C., Cuevas, J., Jalife, J., Bohm, A., Lin,Y.-S., Noujaim, S. F. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

et al. 2018

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“…Besides a role of I K1 in AF, also constitutive I KACh activity has been associated with AF in humans and was subsequently suggested as a potential target in AF treatment . Indeed, I KACh inhibition in dogs with rapid atrial pacing induced AF results in prolongation of the effective refractory period and cardioversion to SR . Currently, there is no evidence that PA‐6 inhibits I KACh , but previous studies reported that I KACh action is reduced by some anesthetic agents .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of pentamidine analogue 6 in dogs with chronic atrial fibrillation

Szatmári

Yuan

Herwijnen

et al. 2018

Veterinary Internal Medicne

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BackgroundThe inward rectifier inhibitor pentamidine analogue 6 (PA‐6) is effective in cardioversion of goats with persistent rapid pacing induced atrial fibrillation (AF) and is not proarrhythmic in dogs with experimental chronic 3rd‐degree AV block. Efficacy and safety in the clinical setting are unknown.HypothesisThat PA‐6 would be effective in converting AF to sinus rhythm (SR) in dogs with naturally occurring AF, without the presence of overt adverse effects.AnimalsTen client‐owned large and giant breed dogs.MethodsAnimals with persistent or permanent AF were recruited for our prospective study. PA‐6 was administered IV as a bolus of 2.5 mg/kg 10 min−1 followed by a maintenance infusion of 0.04 mg/kg min−1 for a maximum of 50 minutes in conscious dogs. Standard 6 lead limb ECG was recorded during the infusion. Visible and audible signs of adverse effects were scored during the entire procedure.ResultsPA‐6 did not induce changes in QRS duration (54.7 ± 4.6 versus 56.7 ± 6.1 ms, P = .42), QTc interval (241.1 ± 19.5 versus 258.7 ± 19.8 ms, P = .061) or RR interval (363.4 ± 84.6 versus 440.8 ± 96.3 ms, P = .072) at the end of the bolus. No cardioversion to SR was observed in any dog. Three dogs displayed no adverse effects. Five dogs had premature ventricular depolarizations during PA‐6 infusion on the ECG. Respiratory distress with laryngeal stridor, subtle muscle twitching, and mild generalized muscular weakness were noncardiac adverse effects observed in 5 dogs. Adverse effects resolved spontaneously.Conclusions and Clinical importanceChronic naturally occurring AF in large and giant breed dogs could not be cardioverted to SR by PA‐6.

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“…Pharmacological block of I K,ACh in in vitro and ex vivo experiments showed promising antiarrhythmic effects. However, recent studies have found I K,ACh block to be ineffective both in increasing the left-atrial ERP in vivo ( Walfridsson et al, 2015 ) and reducing AF burden in clinical trials ( Podd et al, 2016 ). Pharmacological effects and pathways activated by acetylcholine that are currently not implemented in the existing computational models (e.g., crosstalk with CaMKII and β-adrenergic stimulation) might explain the disagreement between in vitro , in silico , and clinical studies.…”

Section: Computational Pharmacology In Afmentioning

confidence: 99%

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

et al. 2018

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The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.

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Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans

Abstract: Based on the present series of experiments, an important role of IKACh in human atrial electrophysiology, as well as its potential as a viable target for effective management of AF, may be questioned.

Cited by 33 publications

References 22 publications

Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

Efficacy of pentamidine analogue 6 in dogs with chronic atrial fibrillation

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

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