轻度碱化和酸化对利多卡因或美西律通过ATP敏感性钾通道介导的血管舒张作用有不同的影响。

Mild alkalinization and acidification differentially modify the effects of lidocaine or mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels.

作者信息

Kinoshita H, Iranami H, Kimoto Y, Dojo M, Hatano Y

机构信息

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

出版信息

Anesthesiology. 2001 Jul;95(1):200-6. doi: 10.1097/00000542-200107000-00031.

DOI:10.1097/00000542-200107000-00031

PMID:11465559

Abstract

BACKGROUND

The previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel-blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate-sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta.

METHODS

Rings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 x 10(-7) M), relaxations in response to levcromakalim (10(-8) to 10(-5) M) were obtained. Lidocaine (10(-5) to 10(-4) M), mexiletine (10(-5) to 10(-4) M), or glibenclamide (10(-5) M) was applied 15 min before addition of phenylephrine.

RESULTS

Relaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate-sensitive K+ channel antagonist glibenclamide (10(-5) M), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10(-5) M) abolished these relaxations in arteries treated with mexiletine (10(-4) M) in any pH group.

CONCLUSIONS

These results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate-sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.

摘要

背景

作者之前的研究表明，I b类抗心律失常药物利多卡因会损害由三磷酸腺苷敏感钾通道介导的血管舒张，而美西律则会增强这种作用。利多卡因和美西律的药物 - 质子解离常数的负对数值不同，这表明这些药物在不同pH水平下的离子通道阻断作用可能会有所不同。然而，pH在利多卡因和美西律对钾通道介导的血管舒张作用中的作用尚未得到研究。因此，本研究旨在探讨在离体大鼠主动脉中，临床相关浓度的利多卡因或美西律对三磷酸腺苷敏感钾通道开放剂利卡林引起的血管舒张的抑制和增强作用是否会因轻度碱化或酸化而改变。

方法

将无内皮的大鼠主动脉环悬挂起来进行等长张力记录。通过改变氯化钠和碳酸氢钠的组成制备三种类型的改良Krebs-Ringer溶液（pH 7.2、7.4和7.6）。在对去氧肾上腺素（3×10⁻⁷ M）的收缩反应过程中，获得对利卡林（10⁻⁸至10⁻⁵ 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10⁻⁴ M）、美西律（10⁻⁵至10⁻⁴ M）或格列本脲（10⁻⁵ M）。

结果

在三个pH组中，对利卡林的舒张反应（被选择性三磷酸腺苷敏感钾通道拮抗剂格列本脲（10⁻⁵ M）消除）没有差异。在pH 7.4的正常Krebs-Ringer溶液中，利多卡因以浓度依赖性方式显著降低这些舒张反应。pH 7.6的碱化增强了利多卡因对这些舒张反应的抑制作用，而pH 7.2的酸化则基本消除了这种作用。相比之下，美西律在任何pH组中均能独立增强对利卡林的舒张反应。格列本脲（10⁻⁵ M）消除了用美西律（10⁻⁴ M）处理的动脉中的这些舒张反应。