硫氰酸盐的胃抗分泌作用机制：硫氰酸盐诱导胃H⁺，K⁺-ATP酶功能障碍的进一步证据

Mechanism of gastric antisecretory effect of thiocyanate: further evidence for the thiocyanate-induced impediment in gastric H+,K+-ATPase function.

作者信息

Nandi J, Ray T K

出版信息

Arch Biochem Biophys. 1986 Feb 1;244(2):701-12. doi: 10.1016/0003-9861(86)90639-9.

Abstract

Two hypotheses have recently been proposed for the thiocyanate inhibition of gastric acid secretion--a protonophore mechanism and an uncoupling model. The mechanistic aspects for the latter scheme have been examined on the following basis: capability of generating verifiable predictions, supporting evidence that is unambiguous, and compatibility with experimental realities. Gastric microsomes bind 5 nmol of SCN-/mg, and a "pure" and highly active fraction of H+,K+-ATPase prepared from gastric microsomes binds about 15 nmol of SCN-/mg. The affinity of SCN- binding to gastric microsomes changes from 10 to 25 mM in the presence of 20 mM K+ suggesting competition between K+ and SCN-. Potassium also displaces the bound SCN- from "pure" H+,K+-ATPase with a Ki of about 25 mM. Of the cations tested--Tl+, K+, Rb+, Cs+, NH4+, Na+, and Li+--Tl+ was the most effective in displacing bound SCN- while Na+ and Li+ were without effect. The effects of anions such as Cl-, NO3-, and gluconate were found to be nonspecific and absolutely dependent on K+ as cocation. Sulfate and OCN-, on the other hand, showed an ability to displace SCN- as both K+ and Na+ salts. For SO4(-2) the K+ form was much more effective than the Na+ salt. Besides these antagonistic effects of K+ and congeners with the H+,K+-ATPase-bound SCN-, a competition between K+ and SCN- was also observed at the level of gastric K+-stimulated pNPPase reaction. The effects of SCN- and two other unrelated anions, F- and NO2-, on artificial delta pH across the microsomal vesicles exhibited a lack of appreciable change up to 5 mM and a small (about 13%) reduction between 10 and 20 mM. However, a combination of CCCP and nigericin or valinomycin completely abolished the delta pH under identical conditions. The present data in conjunction with other reports suggest that the proton impediment model best explains the gastric antisecretory effects of SCN-.

摘要

最近有人提出了两种关于硫氰酸盐抑制胃酸分泌的假说——质子载体机制和解偶联模型。后一种假说的机制方面已基于以下几点进行了研究：产生可验证预测的能力、明确的支持证据以及与实验现实的兼容性。胃微粒体结合5 nmol SCN⁻/mg，从胃微粒体中制备的“纯”且高活性的H⁺,K⁺-ATP酶部分结合约15 nmol SCN⁻/mg。在20 mM K⁺存在下，SCN⁻与胃微粒体结合的亲和力从10 mM变为25 mM，表明K⁺与SCN⁻之间存在竞争。钾也能以约25 mM的Ki从“纯”H⁺,K⁺-ATP酶中取代结合的SCN⁻。在所测试的阳离子中——Tl⁺、K⁺、Rb⁺、Cs⁺、NH₄⁺、Na⁺和Li⁺——Tl⁺在取代结合的SCN⁻方面最有效，而Na⁺和Li⁺则没有效果。发现Cl⁻、NO₃⁻和葡萄糖酸盐等阴离子的作用是非特异性的，并且绝对依赖于K⁺作为伴随阳离子。另一方面，硫酸盐和OCN⁻作为K⁺盐和Na⁺盐都显示出取代SCN⁻的能力。对于SO₄²⁻，K⁺形式比Na⁺盐更有效。除了K⁺及其同系物与H⁺,K⁺-ATP酶结合的SCN⁻之间的这些拮抗作用外，在胃K⁺刺激的对硝基苯磷酸酶反应水平上也观察到K⁺与SCN⁻之间的竞争。SCN⁻以及另外两种无关阴离子F⁻和NO₂⁻对微粒体囊泡上人工ΔpH的影响在高达5 mM时没有明显变化，在10至20 mM之间有小幅（约13%）降低。然而，在相同条件下，CCCP与尼日利亚菌素或缬氨霉素的组合完全消除了ΔpH。目前的数据与其他报告表明，质子阻碍模型最能解释SCN⁻的胃抗分泌作用。