针对β1 - 肾上腺素能受体第二个细胞外环的自身免疫在兔体内诱导早期后去极化并降低钾通道密度。

Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits.

作者信息

Fukuda Yukiko, Miyoshi Shunichiro, Tanimoto Kojiro, Oota Kenichi, Fujikura Kana, Iwata Michikado, Baba Akiyasu, Hagiwara Yoko, Yoshikawa Tsutomu, Mitamura Hideo, Ogawa Satoshi

机构信息

Cardiopulmonary Division of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.

出版信息

J Am Coll Cardiol. 2004 Mar 17;43(6):1090-100. doi: 10.1016/j.jacc.2003.09.057.

DOI:10.1016/j.jacc.2003.09.057

PMID:15028372

Abstract

OBJECTIVES

We sought to define the electrophysiologic property of the rabbit heart associated with autoimmunity against the second extracellular loop of the beta(1)-adrenergic receptor.

BACKGROUND

Sudden death of patients with cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted by the presence of autoantibodies against the second extracellular loop of the beta(1)-adrenergic receptor.

METHODS

Rabbits were immunized by repetitive subcutaneous administration of a synthetic peptide corresponding to the second extracellular loop of beta(1)-adrenergic receptors (beta group; n = 30) for a mean of 4.2 months. Control rabbits received only vehicle (control group; n = 30).

RESULTS

One of the rabbits in the beta group died suddenly during the observation period, but none of the control animals died. The prevalence of sustained ventricular tachycardia was significantly higher in the beta group (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment revealed prolongation of the action potential duration (APD) in the right ventricular papillary muscle (beta: 156 +/- 5 ms vs. control: 131 +/- 4 ms; p < 0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta group (1 of 26), but not in any animals in the control group (0 of 17). A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp experiment on left ventricular M cells showed significant decreases in transient outward current (I(to1)) (-43%) and slowly activated delayed rectifier current (I(Ks)) densities (-33%), whereas the inward-rectifying K current (I(K1)) and rapidly activated delayed rectifier current (I(Kr)) densities remained unchanged.

CONCLUSIONS

Long-term immunization against the second extracellular loop of the beta(1)-adrenergic receptor caused EAD and APD prolongation and decreased the K-channel density, suggesting that an arrhythmic substrate via autoimmune mechanisms is present in cardiomyopathic patients who have autoantibodies directed against the receptors.

摘要

目的

我们试图确定与针对β1 - 肾上腺素能受体第二细胞外环的自身免疫相关的兔心脏电生理特性。

背景

心肌病患者的猝死，可能是由于致命性室性心律失常，可通过存在针对β1 - 肾上腺素能受体第二细胞外环的自身抗体来预测。

方法

通过重复皮下注射对应于β1 - 肾上腺素能受体第二细胞外环的合成肽对兔子进行免疫（β组；n = 30），平均免疫4.2个月。对照兔子仅接受赋形剂（对照组；n = 30）。

结果

β组中有一只兔子在观察期内突然死亡，但对照组动物均未死亡。β组持续性室性心动过速的发生率显著更高（β组：27只中有4只，而对照组：30只中有0只），并且标准微电极实验显示右心室乳头肌动作电位持续时间（APD）延长（β组：156±5毫秒，对照组：131±4毫秒；p < 0.05）。在β组的一只兔子中观察到早期后去极化（EAD）（26只中有1只），但对照组的任何动物中均未观察到（17只中有0只）。100 nmol/l的E - 4031剂量在β组中诱导EAD（10只中有10只），但对照组中除一只兔子外（10只中有1只）未诱导出。对左心室M细胞进行的全细胞膜片钳实验显示，瞬时外向电流（I(to1)）密度显著降低（-43%），缓慢激活延迟整流电流（I(Ks)）密度降低（-33%），而内向整流钾电流（I(K1)）和快速激活延迟整流电流（I(Kr)）密度保持不变。