Im W B, Blakeman D P, Mendlein J, Sachs G
Biochim Biophys Acta. 1984 Feb 29;770(1):65-72. doi: 10.1016/0005-2736(84)90074-9.
The mechanism of gastric antisecretory action for trifluoperazine, verapamil and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) has been studied utilizing isolated hog gastric membranes enriched with (H+ + K+)-ATPase. The drugs inhibited the gastric ATPase due to their apparent competition with K+ for the luminal high-affinity K+-site of the ATPase. The dose to inhibit 50% (ID50) of the ATPase in the membranes rendered freely permeable to K+ (20 mM) was 50 microM for trifluoperazine and 1.5 mM for verapamil and TMB-8. In intact hog gastric membranes which develop a pH gradient in the presence of valinomycin, ATP and KCl, however, trifluoperazine at 4 microM, verapamil and TMB-8 at 15 microM inhibited 40 and 30% of the valinomycin-stimulated ATPase activity, respectively, and also blocked the ionophore-dependent intravesicular acidification as measured by aminopyrine accumulation. The enhanced potency of the drugs to inhibit the ATPase in the intact membrane vesicles may be attributed to the accumulation of the drugs as a weak base within the vesicles, where the luminal K+-site of the ATPase is accessible. Calmodulin and Ca2+ had no effect on the extent of H+-accumulation as measured by aminopyrine accumulation in the membrane vesicles which were prepared in the presence of 1 mM EGTA. Since the drugs showed similar potency in interfering with H+ movements either in the membrane vesicles or isolated rabbit gastric glands stimulated by dibutyryl cAMP, it is reasonable to suggest the inhibitory effect of the drugs on (H+ + K+)-ATPase as a primary cause for such interferences in both cases. A trifluoperazine analog and other lipophilic amine drugs similarly inhibited (H+ + K+)-ATPase and H+ accumulation in the membrane vesicles or in the glands. We have concluded that a tertiary amine, the only common functional group among these drugs, is primarily responsible for their ability to interact with the high-affinity K+ site of the gastric ATPase.
利用富含（H⁺ + K⁺）-ATP酶的离体猪胃膜，研究了三氟拉嗪、维拉帕米和8-（N，N-二乙氨基）辛基-3,4,5-三甲氧基苯甲酸酯（TMB-8）的胃抗分泌作用机制。这些药物抑制胃ATP酶是因为它们明显与K⁺竞争ATP酶腔面的高亲和力K⁺位点。在使K⁺（20 mM）自由通透的膜中，抑制50%（ID50）ATP酶活性的三氟拉嗪剂量为50 μM，维拉帕米和TMB-8为1.5 mM。然而，在存在缬氨霉素、ATP和KCl时能形成pH梯度的完整猪胃膜中，4 μM的三氟拉嗪、15 μM的维拉帕米和TMB-8分别抑制了40%和30%的缬氨霉素刺激的ATP酶活性，并且还阻断了通过氨基比林蓄积测定的离子载体依赖性囊泡内酸化。药物在完整膜囊泡中抑制ATP酶的效力增强可能归因于药物作为弱碱在囊泡内蓄积，在那里ATP酶的腔面K⁺位点是可及的。在1 mM乙二醇双乙醚二胺四乙酸（EGTA）存在下制备的膜囊泡中，通过氨基比林蓄积测定，钙调蛋白和Ca²⁺对H⁺蓄积程度没有影响。由于药物在膜囊泡或由二丁酰环磷腺苷（dbcAMP）刺激的离体兔胃腺中干扰H⁺运动时表现出相似的效力，因此有理由认为药物对（H⁺ + K⁺）-ATP酶的抑制作用是这两种情况下此类干扰的主要原因。一种三氟拉嗪类似物和其他亲脂性胺类药物同样抑制膜囊泡或腺体中的（H⁺ + K⁺）-ATP酶和H⁺蓄积。我们得出结论，叔胺是这些药物中唯一的共同官能团，主要负责它们与胃ATP酶高亲和力K⁺位点相互作用的能力。
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