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钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂达格列净对人心脏钾通道的电生理作用。

Electrophysiological Effects of the Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitor Dapagliflozin on Human Cardiac Potassium Channels.

机构信息

Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

出版信息

Int J Mol Sci. 2024 May 23;25(11):5701. doi: 10.3390/ijms25115701.

DOI:10.3390/ijms25115701
PMID:38891889
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11172209/
Abstract

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K11.1, K1.5, K4.3, K2.1, K2.1, K3.1, and K17.1, contributing to , , , , and K currents. Human channels coded by , , , , , , and were heterologously expressed in oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K11.1 and K1.5 currents, whereas K2.1, K2.1, and K17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K4.3 or K3.1 K channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current-voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K channels underlying , , , and currents. Substantial activation of K2.1 and K17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo.

摘要

钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂达格列净在糖尿病和心力衰竭的治疗中应用日益增多。临床试验表明达格列净可降低心房颤动（AF）的发生率。我们推测达格列净的抗心律失常作用可能部分归因于其对心房复极化钾（K）通道尚未被认识的作用。本研究旨在评估达格列净对克隆离子通道 K11.1、K1.5、K4.3、K2.1、K2.1、K3.1 和 K17.1 的直接药理作用，这些通道分别构成 、 、 、 、 、 和 电流。编码人类通道的 、 、 、 、 、 和 被异源表达在卵母细胞中，并使用电压钳技术记录电流。达格列净（100μM）可降低 K11.1 和 K1.5 电流，而 K2.1、K2.1 和 K17.1 电流增强。该药物对 K4.3 或 K3.1 K 通道的峰值电流幅度无显著影响。生物物理特性分析未显示达格列净对研究通道电流-电压关系有显著影响。总之，达格列净与人的心房 K 通道有直接的功能相互作用，后者是 、 、 和 电流的基础。K2.1 和 K17.1 电流的大量激活可能有助于药物的有益抗心律失常作用。间接或慢性作用仍需在体内进行研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c8/11172209/6dd011fb2a8e/ijms-25-05701-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/66c8/11172209/984e49529df1/ijms-25-05701-g002.jpg
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