Evidence that 2-aminoethoxydiphenyl borate provokes fibrillation in perfused rat hearts via voltage-independent calcium channels

详细信息	查看全文 | 推荐本文 |

• 作者：Peipei Wang^a ; ¹ ; Patrick K. Umeda^a ; ¹ ; Oleg F. Sharifov^a ; ¹ ; Brian A. Halloran^b ; Edlue Tabengwa^a ; Hernan E. Grenett^a ; Ferdinand Urthaler^a ; Paul E. Wolkowicz^a ; ¹ ; ^wolk@uab.edu
• 关键词：2-Aminoethoxydiphenyl borate ; Orai ; SKF-96365 ; Ventricular fibrillation ; Focal arrhythmia
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 April, 2012
• 卷：681
• 期：1-3
• 页码：60-67
• 文件大小：1733 K

摘要

We tested whether 2-aminoethoxydiphenyl borate (2-APB) induces arrhythmia in perfused rat hearts and whether this arrhythmia might result from the activation of voltage-independent calcium channels. Rat hearts were Langendorff perfused and beat under sinus rhythm. An isovolumic balloon inserted into the left ventricle was used to record mechanical function while bipolar electrograms were recorded from electrodes sutured to the base and the apex of hearts. Western and immunofluorescence analyses were performed on rat left ventricular protein extracts and left ventricular frozen sections, respectively. Rat ventricular myocytes express Orai 1 and Orai 3, and ventricle also contains the Orai regulator Stim1. Rat hearts (n = 5) perfused with Krebs-Henseleit (KH) alone maintained sinus rhythm at 4.8 卤 0.1 Hz and stable mechanical function. By contrast, perfusing hearts (n = 5) with (KH + 22 渭M 2-APB) provoked a period of tachycardic ectopy at rates of up to 10.8 卤 0.2 Hz. As perfusion with (KH + 22 渭M 2-APB) continued, the rate of spontaneous ventricular depolarization increased to 21.8 卤 1.2 Hz and became disorganized. Heart mechanical function collapsed as developed pressure decreased from 87 卤 8.8 to 3.5 卤 1.9 mm Hg. Flow rate did not change between normal (16.6 卤 0.9 ml/min) and fibrillating (17.4 卤 0.8 ml/min) hearts. The addition of 20 渭M 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) to (KH + 22 渭M 2-APB) perfusates (n = 4) restored sinus rhythm and heart mechanical output. These data indicate that activating myocardial voltage-independent calcium channels, possibly the Orais, may be a novel cause of ventricular arrhythmia.