I类抗心律失常药物对2,4-二硝基苯酚诱导的豚鼠心室肌细胞ATP敏感性钾电流的阻断作用。

Blockade of 2,4-dinitrophenol induced ATP sensitive potassium current in guinea pig ventricular myocytes by class I antiarrhythmic drugs.

作者信息

Wu B, Sato T, Kiyosue T, Arita M

机构信息

Department of Physiology, Oita Medical University, Japan.

出版信息

Cardiovasc Res. 1992 Nov;26(11):1095-101. doi: 10.1093/cvr/26.11.1095.

DOI:10.1093/cvr/26.11.1095

PMID:1291087

Abstract

OBJECTIVE

The aim was to assess the effects of various antiarrhythmic drugs on 2,4-dinitrophenol (DNP) induced outward current (IDNP), presumably the ATP sensitive K+ current (IK,ATP) of isolated cardiac cells and to discuss mechanisms involved in the hypoglycaemia which occurs in patients on these drugs.

METHODS

The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells was measured using whole cell voltage clamp techniques with a ramp pulse programme. The effects of seven different antiarrhythmic drugs on IDNP were examined. Action potentials were elicited at a rate of 0.2 Hz by an intracellular current injection.

RESULTS

DNP (50 mumol.litre-1) increased the quasi-steady state outward current at potentials positive to about -60 mV. This current (IDNP) was completely inhibited by the subsequent application of glibenclamide (1 mumol.litre-1), thereby suggesting that the IDNP is probably IK,ATP. Cibenzoline (10 mumol.litre-1, class Ia), disopyramide (30 mumol.litre-1, class Ia), and procainamide (100 mumol.litre-1, class Ia) significantly inhibited the IDNP by 95.5(SD 11.3)%, 77.8(21.2)%, and 76.4(23.9)% respectively. Flecainide (class 1c) inhibited the IDNP by 66.9(23.9)% at 10 mumol.litre-1 but not at 2 mumol.litre-1. Mexiletine (30 mumol.litre-1, class Ib), pilsicainide (50 mumol.litre-1, class Ic), and E4031 (10 mumol.litre-1, class III) at concentrations as high as approximately fivefold the clinically effective blood levels, did not suppress IDNP. Except for 10 mumol.litre-1 flecainide, all the concentrations listed above which blocked IDNP were within twofold of the clinical blood concentrations documented to be effective for suppression of arrhythmias. Cibenzoline, disopyramide, and procainamide, but not flecainide, belong to class Ia antiarrhythmic drugs. All these class Ia antiarrhythmic drugs "shortened" the action potential duration of guinea pig ventricular cells, an opposite change to that noted for multicellular preparations, eg, guinea pig papillary muscles.

CONCLUSIONS

Class Ia antiarrhythmic drugs (cibenzoline, disopyramide, and procainamide) inhibit IDNP (presumably IK,ATP) in guinea pig ventricular cells within a range of therapeutic concentrations. This inhibitory effect of IK,ATP can probably explain the hypoglycaemia which occurs in some patients receiving these drugs, and the prolongation of the action potential duration alleged to occur in "superfused" papillary muscles.

摘要

目的

评估各种抗心律失常药物对2,4 - 二硝基苯酚（DNP）诱导的外向电流（IDNP）的影响，该电流可能是分离心肌细胞的ATP敏感性钾电流（IK,ATP），并探讨使用这些药物的患者发生低血糖的相关机制。

方法

采用带有斜坡脉冲程序的全细胞电压钳技术，测量分离的豚鼠心室细胞的准稳态电流 - 电压关系。检测了七种不同抗心律失常药物对IDNP的影响。通过细胞内电流注入以0.2 Hz的频率诱发动作电位。

结果

DNP（50 μmol·L⁻¹）使电位正向至约 - 60 mV时的准稳态外向电流增加。随后应用格列本脲（1 μmol·L⁻¹）可完全抑制该电流（IDNP），这表明IDNP可能是IK,ATP。西苯唑啉（10 μmol·L⁻¹，Ⅰa类）、丙吡胺（30 μmol·L⁻¹，Ⅰa类）和普鲁卡因胺（100 μmol·L⁻¹，Ⅰa类）分别显著抑制IDNP达95.5（标准差11.3）%、77.8（21.2）%和76.4（23.9）%。氟卡尼（Ⅰc类）在10 μmol·L⁻¹时抑制IDNP达66.9（23.9）%，但在2 μmol·L⁻¹时无此作用。美西律（30 μmol·L⁻¹，Ⅰb类）、吡西卡尼（50 μmol·L⁻¹，Ⅰc类）和E4031（10 μmol·L⁻¹，Ⅲ类）在浓度高达临床有效血药浓度约五倍时，并未抑制IDNP。除10 μmol·L⁻¹氟卡尼外，上述所有阻断IDNP的浓度均在已记录的对抑制心律失常有效的临床血药浓度的两倍以内。西苯唑啉、丙吡胺和普鲁卡因胺属于Ⅰa类抗心律失常药物，但氟卡尼不属于。所有这些Ⅰa类抗心律失常药物均“缩短”了豚鼠心室细胞的动作电位时程，这与多细胞标本（如豚鼠乳头肌）中观察到的变化相反。