Effect of chloride channel blockers on the cardiac CFTR chloride and L-type calcium currents

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• 作者：Walsh ; Kenneth B. ; Chongmin ; Wang
• 关键词：Chloride channel ; CFTR ; Calcium channel ; L-type ; Chloride channel blockers ; PKA ; Forskolin ; Mouse ; atrial myocytes ; Guinea pig ; ventricular myocytes
• 刊名：Cardiovascular Research
• 出版年：1996
• 期刊代码：48_00086363
• 类别：med
• 出版时间：August, 1996
• 卷：32
• 期：2
• 页码：391-399
• 文件大小：800 K

摘要

Objectives: The aim of this study was to determine the effects of Cl⁻ channel blockers on the cardiac cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ current (I_Cl) and the protein kinase A-regulated L-type calcium current (PKA-I_Ca). Methods: Whole-cell I_Cl and I_Ca were recorded from isolated guinea pig ventricular myocytes using the patch clamp technique during stimulation of PKA by forskolin (1 or 2 μM). Results: The inhibitory effects of clofibric acid, p-chlorophenoxy propionic acid, gemfibrozil, diphenylamine-2-carboxylate (DPC), anthracene-9-carboxylate, 4,4′ dinitrostilbene-2,2′-disulfonic acid and indanyloxyacetic acid 94 were examined on the two currents. Clofibric acid (1 mM), p-chlorophenoxy propionic acid (1 mM) and gemfibrozil (250 μM) produced an approximate 50%decrease in I_Cl, but had no effect on the PKA-I_Ca. Surprisingly, application of DPC (500 μM and 1 mM) and anthracene-9-carboxylate (500 μM) strongly reduced both currents. However, inhibition of the Ca²⁺ and Cl⁻ channels by DPC could be differentiated in two important ways. First, increasing the pH of the external solution from 7.4 to 10.0 prevented the block ofI_Cl by DPC, but did not attenuate the reduction in the PKA-I_Ca. Second, DPC inhibited the PKA-I_Ca in mouse atrial myocytes which lacked I_Cl. Neither 4,4′ dinitrostilbene-2,2′-disulfonic acid (100 μM) nor indanyloxyacetic acid 94 (50 μM) caused any change in either of the guinea pig ventricular currents. Conclusions: Drugs such as DPC and anthracene-9-carboxylate which block the cardiac CFTR Cl⁻ channel also inhibit the regulation of the L-type I_Ca. During β-adrenergic stimulation, changes produced by these drugs on the cardiac action potential duration will be attributable to inhibition of both the Cl⁻ and Ca²⁺ currents. Analogues of clofibric acid may serve as selective blockers of the CFTR Cl⁻ channel that can be used to determine the physiological function of I_Cl in cardiac excitation.