人红细胞K⁺(Na⁺)/H⁺交换体抑制剂。
Inhibitors of the K+(Na+)/H+ exchanger of human red blood cells.
作者信息
Weiss Erwin, Lang Hans-Jochen, Bernhardt Ingolf
机构信息
Laboratory of Biophysics, Faculty of Natural and Technical Sciences III, University of the Saarland, P.O. Box 151150, 66041 Saarbrücken, Germany.
出版信息
Bioelectrochemistry. 2004 May;62(2):135-40. doi: 10.1016/j.bioelechem.2003.09.008.
The effect of substances as possible inhibitors of the K+(Na+)/H+ exchanger in the human red cell membrane has been tested on the (ouabain+bumetanide+EGTA)-resistant K+ influx in both physiological (HIS) and low ionic strength (LIS) solution with tracer kinetic methods. It is demonstrated that high concentrations of quinacrine (1 mM) and chloroquine (2 mM) inhibit the residual K+ influx in LIS solution to 60% and 85%, respectively, but activate it in HIS solution. Thus, chloroquine suppressed the 10-fold LIS-induced activation of the flux nearly completely. Amiloride derivatives were able to inhibit the K+ influx in both HIS and LIS solution. EIPA (75 microM) reduced the flux by about 20% and 55% in HIS and LIS solution, respectively. Newly developed drugs (HOE 642, 1 mM; HOE 694, 0.5 mM) designed to inhibit Na+/H+ exchanger isoforms showed an inhibition of the residual K+ influx of 40% and 33% in HIS and 65% and 44% in LIS solution, respectively, without haemolysis. The inhibitory effect of HOE 642 persisted in HIS (24%) and LIS (48%) solutions when Cl- was replaced by CH3SO4-. The K(+)-Cl- cotransport inhibitor DIOA (100 microM) stimulated the residual K+ influx in both solutions. It is, therefore, concluded that the K(+)-Cl- cotransporter does not contribute to the residual K+ influx both in HIS and LIS media. Okadaic acid decreased the residual K+ influx by 40% and 25% in HIS and LIS solution, respectively, showing that the residual K+ influx is affected by phosphatases like other ion transport pathways. The results show that the residual K+ influx can be decreased further by inhibiting the K+(Na+)/H+ exchanger. It remains still unclear to what extent the K+(Na+)/H+ exchanger is inhibited by the different substances used. However, the ground state membrane permeability for K+ is much smaller than assumed so far.
利用示踪动力学方法，在生理（HIS）和低离子强度（LIS）溶液中，测试了多种物质作为人红细胞膜中K⁺（Na⁺）/H⁺交换体可能的抑制剂，对（哇巴因+布美他尼+乙二醇双四乙酸）抗性K⁺内流的影响。结果表明，高浓度的喹吖因（1 mM）和氯喹（2 mM）分别将LIS溶液中的残余K⁺内流抑制至60%和85%，但在HIS溶液中却使其激活。因此，氯喹几乎完全抑制了LIS诱导的通量10倍激活。氨氯地平衍生物能够抑制HIS和LIS溶液中的K⁺内流。EIPA（75 microM）在HIS和LIS溶液中分别使通量降低约20%和55%。新开发的旨在抑制Na⁺/H⁺交换体亚型的药物（HOE 642，1 mM；HOE 694，0.5 mM）在HIS溶液中对残余K⁺内流的抑制率分别为40%和33%，在LIS溶液中为65%和44%，且无溶血现象。当Cl⁻被CH₃SO₄⁻取代时，HOE 642在HIS（24%）和LIS（48%）溶液中的抑制作用依然存在。K⁺-Cl⁻共转运抑制剂DIOA（100 microM）在两种溶液中均刺激了残余K⁺内流。因此，可以得出结论，在HIS和LIS介质中，K⁺-Cl⁻共转运体对残余K⁺内流均无贡献。冈田酸在HIS和LIS溶液中分别使残余K⁺内流降低40%和25%，表明残余K⁺内流与其他离子转运途径一样，受磷酸酶影响。结果表明，通过抑制K⁺（Na⁺）/H⁺交换体，残余K⁺内流可进一步降低。目前尚不清楚不同所用物质对K⁺（Na⁺）/H⁺交换体的抑制程度如何。然而，K⁺的基础态膜通透性比迄今所认为的要小得多。
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