Simchowitz L
Department of Medicine, John Cochran Veterans Administration Medical Center, St. Louis, Missouri.
Soc Gen Physiol Ser. 1988;43:193-208.
As part of our ongoing studies aimed at understanding the physiology of human neutrophil function, we have been investigating the nature of the principal anion-exchange mechanism in these cells. This countertransport system functions physiologically as a Cl-/HCO3- exchanger in intracellular pH regulation from alkalinization (Simchowitz and Roos, 1985). In summarizing the results of our work, it is worthwhile to keep in mind the well-defined properties of the classic inorganic anion-exchange carrier of red blood cells, as important differences between the two are evident. Inhibitor Profile In our original articles on Cl- movements (Simchowitz and De Weer, 1986; Simchowitz et al., 1986), we had identified CHC, which suppresses monocarboxylate transport in mitochondria (Halestrap and Denton, 1975), as a relatively weak inhibitor. Several structural analogues, including alpha-methylcinnamate and alpha-phenylcinnamate, exhibited enhanced activity against anion exchange. The most potent compound thus far identified was UK-5099, which was approximately 300-fold more active than CHC. The inhibitory effect of each member of this series of compounds was strictly competitive in nature: both the drug and Cl ions appeared to bind to the same external translocation site on the exchange carrier. The inhibition by several other unrelated agents (e.g., MK-473, niflumate, flufenamate, and NAP-taurine), all weak organic acids, was also of the competitive type, which suggests that these compounds bind to the carrier by virtue of their negatively charged carboxyl or sulfonic groups. In marked contrast to erythrocytes, the anion-exchange carrier of neutrophils is rather insensitive to the disulfonic stilbenes SITS and DIDS (Simchowitz and De Weer, 1986): little or no effect can be detected in 148 mM Cl-. However, under conditions of low external Cl- (5-35 mM), SITS can in fact be shown to interact weakly with the anion binding site of the exchange carrier. In a comparable vein, several other drugs, all of which have been reported to suppress Cl- fluxes in red cells (for reviews, see Sachs et al., 1975; Gunn, 1979; Knauf, 1979; Lowe and Lambert, 1983), were either completely inactive against anion exchange in neutrophils at a concentration of 1 mM or only marginally effective at doses several orders of magnitude greater than those required in red blood cells. This list included furosemide, picrylsulfonate, maleic anhydride, 5,5'-dithio-bis(2-nitrobenzoate), salicylate, 2-methoxy-5-nitrotropone, and aldrithiol.4+he external
作为我们旨在了解人类中性粒细胞功能生理学的持续研究的一部分，我们一直在研究这些细胞中主要阴离子交换机制的性质。这种反向转运系统在生理上作为一种Cl⁻/HCO₃⁻交换体，参与细胞内pH值从碱化状态的调节（Simchowitz和Roos，1985）。在总结我们的工作成果时，牢记红细胞经典无机阴离子交换载体的明确特性是很有必要的，因为两者之间的重要差异很明显。抑制剂谱 在我们最初关于Cl⁻转运的文章中（Simchowitz和De Weer，1986；Simchowitz等人，1986），我们确定了CHC，它能抑制线粒体中的单羧酸转运（Halestrap和Denton，1975），是一种相对较弱的抑制剂。几种结构类似物，包括α-甲基肉桂酸酯和α-苯基肉桂酸酯，对阴离子交换表现出增强的活性。迄今为止确定的最有效的化合物是UK-5099，其活性比CHC高约300倍。这一系列化合物中每种成员的抑制作用本质上都是严格竞争性的：药物和Cl⁻离子似乎都结合在交换载体上相同的外部转运位点。其他几种不相关的试剂（如MK-473、尼氟酸、氟灭酸和NAP-牛磺酸）的抑制作用，这些都是弱有机酸，也是竞争性的，这表明这些化合物凭借其带负电荷的羧基或磺酸基团与载体结合。与红细胞形成鲜明对比的是，中性粒细胞的阴离子交换载体对二磺酸芪类化合物SITS和DIDS相当不敏感（Simchowitz和De Weer，1986）：在148 mM Cl⁻中几乎检测不到或没有影响。然而，在低外部Cl⁻（5 - 35 mM）条件下，实际上可以证明SITS与交换载体的阴离子结合位点有弱相互作用。同样，其他几种药物，所有这些药物都已被报道能抑制红细胞中的Cl⁻通量（综述见Sachs等人，1975；Gunn，1979；Knauf，1979；Lowe和Lambert，1983），在1 mM浓度下对中性粒细胞的阴离子交换完全无活性，或者在比红细胞所需剂量大几个数量级的剂量下才略有效果。这个列表包括速尿（呋塞米）、苦味磺酸盐、马来酸酐、5,5'-二硫代双（2-硝基苯甲酸）、水杨酸盐、2-甲氧基-5-硝基托品酮和醛硫醇。4+外部
