利多卡因和美西律对大鼠主动脉中ATP敏感性钾通道开放剂介导的舒张作用的差异

Differential effects of lidocaine and mexiletine on relaxations to ATP-sensitive K+ channel openers in rat aortas.

作者信息

Kinoshita H, Ishikawa T, Hatano Y

机构信息

Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, Wakayama.

出版信息

Anesthesiology. 1999 Apr;90(4):1165-70. doi: 10.1097/00000542-199904000-00032.

DOI:10.1097/00000542-199904000-00032

PMID:10201690

Abstract

BACKGROUND

In cardiac myocytes, lidocaine reduces but mexiletine increases adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that these class Ib antiarrhythmic drugs may differentially modify the activity of ATP-sensitive K+ channels. The effects of lidocaine and mexiletine on arterial relaxations induced by K+ channel openers have not been studied. Therefore, the current study was designed to evaluate whether lidocaine and mexiletine may produce changes in relaxations to the ATP-sensitive K+ channel openers cromakalim and pinacidil in isolated rat thoracic aortas.

METHODS

Rings of rat thoracic aortas without endothelia were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contractions to phenylephrine (3 x 10(-7) M), relaxations to cromakalim (10(-7) to 3 x 10(-5) M), pinacidil (10(-7) to 3 x 10(-5) M), or diltiazem (10(-7) to 3 x 10(-4) M) were obtained. Lidocaine (10(-5) to 3 x 10(-4) M), mexiletine (10(-5) to 10(-4) M) or glibenclamide (5 x 10(-6) M) was applied 15 min before addition of phenylephrine.

RESULTS

During contractions to phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxations. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10(-6) M), abolished these relaxations, whereas it did not alter relaxations to a voltage-dependent Ca2+ channel inhibitor, diltiazem (10(-7) to 3 x 10(-4) M). Lidocaine (more than 10(-5) M) significantly reduced relaxations to cromakalim or pinacidil in a concentration-dependent fashion, whereas lidocaine (3 x 10(-4) M) did not affect relaxations to diltiazem. In contrast, mexiletine (more than 10(-5) M) significantly augmented relaxations to cromakalim or pinacidil. Glibenclamide (5 x 10(-6) M) abolished relaxations to cromakalim or pinacidil in arteries treated with mexiletine (10(-4) M).

CONCLUSIONS

These results suggest that lidocaine impairs but mexiletine augments vasodilation mediated by ATP-sensitive K+ channels in smooth muscle cells.

摘要

背景

在心肌细胞中，利多卡因可降低而美西律可增加三磷酸腺苷（ATP）敏感性钾电流，这表明这些Ib类抗心律失常药物可能对ATP敏感性钾通道的活性有不同的调节作用。利多卡因和美西律对钾通道开放剂诱导的动脉舒张的影响尚未得到研究。因此，本研究旨在评估利多卡因和美西律是否会使离体大鼠胸主动脉对ATP敏感性钾通道开放剂克罗卡林和吡那地尔的舒张反应发生变化。

方法

将无内皮的大鼠胸主动脉环悬挂起来进行等长张力记录。以累积方式获得浓度-反应曲线。在对去氧肾上腺素（3×10⁻⁷ M）进行次最大收缩期间，记录对克罗卡林（10⁻⁷至3×10⁻⁵ M）、吡那地尔（10⁻⁷至3×10⁻⁵ M）或地尔硫䓬（10⁻⁷至3×10⁻⁴ M）的舒张反应。在加入去氧肾上腺素前15分钟应用利多卡因（10⁻⁵至3×10⁻⁴ M）、美西律（10⁻⁵至10⁻⁴ M）或格列本脲（5×10⁻⁶ M）。

结果

在对去氧肾上腺素的收缩过程中，克罗卡林和吡那地尔诱导出浓度依赖性舒张。一种选择性ATP敏感性钾通道拮抗剂格列本脲（5×10⁻⁶ M）可消除这些舒张反应，而它不会改变对电压依赖性钙通道抑制剂地尔硫䓬（10⁻⁷至3×10⁻⁴ M）的舒张反应。利多卡因（浓度超过10⁻⁵ M）以浓度依赖性方式显著降低对克罗卡林或吡那地尔的舒张反应，而利多卡因（3×10⁻⁴ M）不影响对地尔硫䓬的舒张反应。相反，美西律（浓度超过10⁻⁵ M）显著增强对克罗卡林或吡那地尔的舒张反应。格列本脲（5×10⁻⁶ M）可消除用美西律（10⁻⁴ M）处理的动脉对克罗卡林或吡那地尔的舒张反应。