Background

Slow delayed rectifier potassium current (I_Ks) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of I_Ks and its involvement in age-dependent arrhythmogenesis.

Objective

The purpose of this study was to investigate age-related alteration of the I_Ks response to β-adrenergic receptor (βAR) activation.

Methods

Dunkin–Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K⁺ currents. Optical mapping of membrane potential was performed in ex vivo heart.

Results

There was no difference in I_Ks density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I_Ks potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on I_Ks in a concentration-dependent manner in old guinea pig hearts. The β₂AR antagonist, but not β₁AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned I_Ks channel and β₂AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, Gβγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I_Ks by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias.

Conclusion

βAR activation acutely induces an inhibitory I_Ks response in aging guinea pig hearts through β₂AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.

中文翻译：

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抑制性 G 蛋白介导的慢延迟整流钾通道调节有助于增加衰老心脏心律失常的易感性

背景

慢延迟整流钾电流（I _Ks）是交感神经兴奋过程中复极储备的重要组成部分。_{然而，关于 I Ks}与年龄相关的功能变化及其在年龄依赖性心律失常发生中的作用知之甚少。

客观的

本研究的目的是研究 I _Ks对 β-肾上腺素能受体 (βAR) 激活的反应与年龄相关的变化。

方法

使用了 Dunkin-Hartley 豚鼠。全细胞膜片钳记录用于记录 K ⁺电流。在离体心脏中进行膜电位的光学映射。

结果

年轻和老年豚鼠心室心肌细胞的 I _Ks密度没有差异。然而，与年轻心脏中的 I _Ks增强相反，异丙肾上腺素 (ISO)在老年豚鼠心脏中以浓度依赖性方式引起对 I _Ks的急性抑制。β ₂ AR 拮抗剂，但不是 β ₁ AR 拮抗剂，逆转了抑制反应。用抑制性 G 蛋白 (Gi) 抑制剂百日咳毒素 (PTX) 预孵育心肌细胞也逆转了抑制反应。在用克隆的 I _Ks通道和 β _{2共转染的 HEK293 细胞中}当细胞与 Gi2 共转染时，AR、ISO 增强了电流，但降低了电流，PTX 恢复了 ISO 诱导的兴奋性反应。此外，在衰老的心肌细胞中，Gβγ 抑制剂没食子蛋白、PLC 抑制剂 U73122 或蛋白激酶 C 抑制剂 Bis-1通过 ISO阻止了 I _{Ks的降低。}此外，年轻豚鼠的心脏特异性 Gi2 过度表达使心脏易发生室性快速性心律失常。PTX 预处理保护心脏免受室性心律失常。

结论

_{βAR 激活通过 β 2} AR-Gi 信号传导在衰老豚鼠心脏中急性诱导抑制性 I _Ks反应，这有助于增加衰老心脏对心律失常发生的易感性。