Dataset Information

Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca2+-Activated K+ Channels in Pigs.

ABSTRACT: BACKGROUND:Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. METHODS AND RESULTS:A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. CONCLUSIONS:SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

SUBMITTER: Diness JG

PROVIDER: S-EPMC5647113 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels in Pigs.

Diness Jonas Goldin JG Skibsbye Lasse L Simó-Vicens Rafel R Santos Joana Larupa JL Lundegaard Pia P Citerni Carlotta C Sauter Daniel Rafael Peter DRP Bomholtz Sofia Hammami SH Svendsen Jesper Hastrup JH Olesen Søren-Peter SP Sørensen Ulrik S US Jespersen Thomas T Grunnet Morten M Bentzen Bo Hjorth BH

Circulation. Arrhythmia and electrophysiology 20171001 10

<h4>Background</h4>Evidence has emerged that small-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses.<h4>Methods and results</h4>A total of 43 pigs were used for the studies. AF reversion in conscious long-term tach ...[more]

PMID: 29018164

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Project description:Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current ( IKAS) is encoded by Ca2+-activated K+ channel subfamily N ( KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

Dataset Information

Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca2+-Activated K+ Channels in Pigs.

Publications

Termination of Vernakalant-Resistant Atrial Fibrillation by Inhibition of Small-Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channels in Pigs.

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