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| Fältnamn | Indikatorer | Metadata |
|---|---|---|
| 000 | 04174naa a2200601 4500 | |
| 001 | oai:gup.ub.gu.se/293971 | |
| 003 | SwePub | |
| 008 | 240528s2020 | |||||||||||000 ||eng| | |
| 024 | 7 | a https://gup.ub.gu.se/publication/2939712 URI |
| 024 | 7 | a https://doi.org/10.3389/fphar.2020.006102 DOI |
| 040 | a (SwePub)gu | |
| 041 | a eng | |
| 042 | 9 SwePub | |
| 072 | 7 | a ref2 swepub-contenttype |
| 072 | 7 | a art2 swepub-publicationtype |
| 100 | 1 | a Bentzen, B. H.4 aut |
| 245 | 1 0 | a Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man |
| 264 | c 2020-05-06 | |
| 264 | 1 | b Frontiers Media SA,c 2020 |
| 520 | a Aims Small conductance Ca2+-activated K+ channels (SK channels, K(Ca)2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of K(Ca)2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue. Methods and Results Whole-cell and inside-out patch-clamp recordings of heterologously expressed K(Ca)2 channels revealed that AP30663 inhibits K(Ca)2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the K(Ca)2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7 +/- 5.4% and 189.9 +/- 18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue. Conclusions AP30663 is a novel negative allosteric modulator of K(Ca)2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man. | |
| 650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe |
| 650 | 7 | a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng |
| 653 | a atrial fibrillation | |
| 653 | a ion channels | |
| 653 | a anti-arrhythmic drugs | |
| 653 | a SK channels | |
| 653 | a K(Ca)2 | |
| 653 | a ca2+-activated k+ channels | |
| 653 | a potassium sk channels | |
| 653 | a sodium current | |
| 653 | a ranolazine | |
| 653 | a inhibition | |
| 653 | a repolarization | |
| 653 | a management | |
| 653 | a variants | |
| 653 | a safety | |
| 653 | a common | |
| 653 | a Pharmacology & Pharmacy | |
| 700 | 1 | a Bomholtz, S. H.4 aut |
| 700 | 1 | a Simo-Vicens, R.4 aut |
| 700 | 1 | a Folkersen, L.4 aut |
| 700 | 1 | a Abildgaard, L.4 aut |
| 700 | 1 | a Speerschneider, T.4 aut |
| 700 | 1 | a Muthukumarasamy, K. M.4 aut |
| 700 | 1 | a Edvardsson, Nils,d 1942u Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine4 aut0 (Swepub:gu)xedvni |
| 700 | 1 | a Sorensen, U. S.4 aut |
| 700 | 1 | a Grunnet, M.4 aut |
| 700 | 1 | a Diness, J. G.4 aut |
| 710 | 2 | a Göteborgs universitetb Institutionen för medicin, avdelningen för molekylär och klinisk medicin4 org |
| 773 | 0 | t Frontiers in Pharmacologyd : Frontiers Media SAg 11q 11x 1663-9812 |
| 856 | 4 | u https://www.frontiersin.org/articles/10.3389/fphar.2020.00610/pdf |
| 856 | 4 8 | u https://gup.ub.gu.se/publication/293971 |
| 856 | 4 8 | u https://doi.org/10.3389/fphar.2020.00610 |
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