TY - JOUR

T1 - Polyunsaturated fatty acid-derivedI(Ks)channel activators shorten the QT interval ex-vivo and in-vivo

AU - Skarsfeldt, Mark A.

AU - Liin, Sara I.

AU - Larsson, Hans P.

AU - Bentzen, Bo H.

PY - 2020

Y1 - 2020

N2 - Aim We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex-vivo and in-vivo guinea pig hearts. Methods The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin-GLY], docosahexaenoyl glycine [DHA-GLY], N-arachidonoyl taurine [N-AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug-induced long QT2 model of ex-vivo guinea pig hearts. The effect of DHA-GLY on QT interval was also studied in in-vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs onI(Ks)was studied usingXenopus laevisoocytes expressing human KCNQ1 and KCNE1. Results All tested PUFAs shortened ADP and QT interval in ex-vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin-GLY was not as effective in shortening APD/QT interval as DHA-GLY in ex-vivo hearts. By constructing a guinea pig-like KCNE1, we found Lin-GLY to induce less activating effect compared with DHA-GLY on human KCNQ1 co-expressed with guinea pig-like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in-vivo guinea pig hearts. Conclusion Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronouncedI(Ks)channel activating effect to better restore QT interval suggests that modifying PUFAs to target theI(Ks)channel is a means to improve the QT-shortening effect.

AB - Aim We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex-vivo and in-vivo guinea pig hearts. Methods The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin-GLY], docosahexaenoyl glycine [DHA-GLY], N-arachidonoyl taurine [N-AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug-induced long QT2 model of ex-vivo guinea pig hearts. The effect of DHA-GLY on QT interval was also studied in in-vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs onI(Ks)was studied usingXenopus laevisoocytes expressing human KCNQ1 and KCNE1. Results All tested PUFAs shortened ADP and QT interval in ex-vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin-GLY was not as effective in shortening APD/QT interval as DHA-GLY in ex-vivo hearts. By constructing a guinea pig-like KCNE1, we found Lin-GLY to induce less activating effect compared with DHA-GLY on human KCNQ1 co-expressed with guinea pig-like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in-vivo guinea pig hearts. Conclusion Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronouncedI(Ks)channel activating effect to better restore QT interval suggests that modifying PUFAs to target theI(Ks)channel is a means to improve the QT-shortening effect.

KW - guinea pig heart

KW - I(Ks)channel

KW - KCNQ1

KW - Kv7

KW - 1

KW - long QT syndrome

KW - PUFA

KW - IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR

KW - HIGH-RISK PATIENTS

KW - GUINEA-PIG

KW - VENTRICULAR MYOCYTES

KW - NA+ CHANNELS

KW - ACID ANALOGS

KW - OMEGA-3-FATTY-ACIDS

KW - KS

KW - HEART

KW - RECOMMENDATIONS

U2 - 10.1111/apha.13471

DO - 10.1111/apha.13471

M3 - Journal article

C2 - 32223014

VL - 229

JO - Acta Physiologica

JF - Acta Physiologica

SN - 1748-1708

IS - 4

M1 - 13471

ER -