多不饱和脂肪酸衍生的 I 型通道激活剂可缩短离体和体内的 QT 间期。
Polyunsaturated fatty acid-derived I channel activators shorten the QT interval ex-vivo and in-vivo.
机构信息
Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Department of Physiology and Biophysics, University of Miami, Miami, FL, USA.
出版信息
Acta Physiol (Oxf). 2020 Aug;229(4):e13471. doi: 10.1111/apha.13471. Epub 2020 Apr 11.
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 on I was studied using Xenopus laevis oocytes 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 pronounced I channel activating effect to better restore QT interval suggests that modifying PUFAs to target the I channel is a means to improve the QT-shortening effect.
目的
评估天然和改性多不饱和脂肪酸（PUFA）在离体和在体豚鼠心脏缩短 QT 间期的能力。
方法
在 E4031 诱导的离体豚鼠心脏长 QT2 模型中，研究了一种天然（二十二碳六烯酸[DHA]）和三种改性（亚油酸甘氨酸[Lin-GLY]、二十二碳六烯酰甘氨酸[DHA-GLY]、N-花生四烯酰牛磺酸[N-AT]）PUFA 对心室动作电位时程（APD）和 QT 间期的影响。还研究了静脉给予 DHA-GLY 对在体豚鼠心脏 QT 间期的影响。使用表达人 KCNQ1 和 KCNE1 的非洲爪蟾卵母细胞研究了改性 PUFAs 对 I 的影响。
结果
所有测试的 PUFAs 均缩短了离体豚鼠心脏的 APD 和 QT 间期，但特定改性 PUFAs 恢复基线 APD/QT 间期的能力不同，其中特定改性 PUFAs 最为有效。尽管 Lin-GLY 激活人 KCNQ1/KCNE1 通道的能力相当，但在离体心脏中，Lin-GLY 缩短 APD/QT 间期的效果不如 DHA-GLY 有效。通过构建豚鼠样 KCNE1，我们发现与 DHA-GLY 相比，Lin-GLY 对与人 KCNQ1 共表达的豚鼠样 KCNE1 诱导的激活作用较小。进一步研究了 DHA-GLY，发现它能缩短在体豚鼠心脏的 QT 间期。
结论
我们的结果表明，特定的 PUFAs 缩短了豚鼠心脏的 QT 间期。具有明显 I 通道激活作用的改性 PUFAs 更好地恢复 QT 间期的趋势表明，修饰 PUFAs 以靶向 I 通道是改善 QT 缩短作用的一种手段。
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