Mechanism of gastric antisecretory effect of thiocyanate: further evidence for the thiocyanate-induced impediment in gastric H+,K+-ATPase function |
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| Authors: | J Nandi T K Ray |
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| Affiliation: | 1. Computation and Simulation Unit (Analytical Discipline and Centralized Instrument Facility), CSIR, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364002, Gujarat, India;2. Academy of Scientific and Innovative Research, CSIR, CSMCRI, Bhavnagar 364002, Gujarat, India;3. Theoretical Chemistry Section, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India;1. Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;2. Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan;3. Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt;4. Graduate School of Science and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan |
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| 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-. |
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