pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts. / Skarsfeldt, Mark A; Jepps, Thomas A; Bomholtz, Sofia H; Abildgaard, Lea; Sørensen, Ulrik S; Gregers, Emilie; Svendsen, Jesper H; Diness, Jonas G; Grunnet, Morten; Schmitt, Nicole; Olesen, Søren-Peter; Bentzen, Bo H.

In: Pfluegers Archiv, Vol. 468, No. 4, 04.2016, p. 643-654.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Skarsfeldt, MA, Jepps, TA, Bomholtz, SH, Abildgaard, L, Sørensen, US, Gregers, E, Svendsen, JH, Diness, JG, Grunnet, M, Schmitt, N, Olesen, S-P & Bentzen, BH 2016, 'pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts', Pfluegers Archiv, vol. 468, no. 4, pp. 643-654. https://doi.org/10.1007/s00424-015-1779-0

APA

Skarsfeldt, M. A., Jepps, T. A., Bomholtz, S. H., Abildgaard, L., Sørensen, U. S., Gregers, E., ... Bentzen, B. H. (2016). pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts. Pfluegers Archiv, 468(4), 643-654. https://doi.org/10.1007/s00424-015-1779-0

Vancouver

Skarsfeldt MA, Jepps TA, Bomholtz SH, Abildgaard L, Sørensen US, Gregers E et al. pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts. Pfluegers Archiv. 2016 Apr;468(4):643-654. https://doi.org/10.1007/s00424-015-1779-0

Author

Skarsfeldt, Mark A ; Jepps, Thomas A ; Bomholtz, Sofia H ; Abildgaard, Lea ; Sørensen, Ulrik S ; Gregers, Emilie ; Svendsen, Jesper H ; Diness, Jonas G ; Grunnet, Morten ; Schmitt, Nicole ; Olesen, Søren-Peter ; Bentzen, Bo H. / pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts. In: Pfluegers Archiv. 2016 ; Vol. 468, No. 4. pp. 643-654.

Bibtex

@article{beb6030331804b12aed2f3c691ef2469,
title = "pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts",
abstract = "In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 {\%}, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.",
author = "Skarsfeldt, {Mark A} and Jepps, {Thomas A} and Bomholtz, {Sofia H} and Lea Abildgaard and S{\o}rensen, {Ulrik S} and Emilie Gregers and Svendsen, {Jesper H} and Diness, {Jonas G} and Morten Grunnet and Nicole Schmitt and S{\o}ren-Peter Olesen and Bentzen, {Bo H}",
year = "2016",
month = "4",
doi = "10.1007/s00424-015-1779-0",
language = "English",
volume = "468",
pages = "643--654",
journal = "Pfl{\"u}gers Archiv - European Journal of Physiology",
issn = "0031-6768",
publisher = "Springer",
number = "4",

}

RIS

TY - JOUR

T1 - pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts

AU - Skarsfeldt, Mark A

AU - Jepps, Thomas A

AU - Bomholtz, Sofia H

AU - Abildgaard, Lea

AU - Sørensen, Ulrik S

AU - Gregers, Emilie

AU - Svendsen, Jesper H

AU - Diness, Jonas G

AU - Grunnet, Morten

AU - Schmitt, Nicole

AU - Olesen, Søren-Peter

AU - Bentzen, Bo H

PY - 2016/4

Y1 - 2016/4

N2 - In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 %, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.

AB - In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 %, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.

U2 - 10.1007/s00424-015-1779-0

DO - 10.1007/s00424-015-1779-0

M3 - Journal article

C2 - 26729267

VL - 468

SP - 643

EP - 654

JO - Pflügers Archiv - European Journal of Physiology

JF - Pflügers Archiv - European Journal of Physiology

SN - 0031-6768

IS - 4

ER -

ID: 160457410