Nandi J, King R L, Kaplan D S, Levine R A
Department of Medicine, State University of New York Health Science Center, Syracuse.
J Pharmacol Exp Ther. 1990 Mar;252(3):1102-7.
The inhibitory effects of Ca channel antagonists on gastric acid secretion [[14C]-aminopyrine (AP) uptake ratio] have been analyzed in isolated rabbit parletal cells (PC). Secretagogue-stimulated AP uptake was inhibited by verapamil and diltiazem in a dose-dependent manner with IC50 values of 15 and 100 microM, respectively, both in the presence and absence of extracellular Ca. In contrast, nifedipine had no effect on AP accumulation. Verapamil decreased histamine-stimulated respiration with the same IC50 as observed for AP uptake. Imidazole, a weak base, by buffering the acid spaces in PC, reversed the inhibitory effect of verapamil on respiration. In the bullfrog gastric mucosa, forskolin-stimulated proton transport was inhibited by verapamil (10(-4) M) from the luminal but not the serosal side. This inhibitory effect was reversed by either elevating KCl concentration in, or removing the drug from, the secretory solution. Verapamil inhibited gastric microsomal H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) and PC K(+)-stimulated p-nitrophenyl phosphatase activities with a higher potency than diltiazem. Inhibition of these enzymes by verapamil and diltiazem was pH dependent. The drugs competed with K+ in both H+,K(+)-ATPase and K(+)-stimulated p-nitrophenyl phosphatase reactions. Our data suggest that inhibition of the gastric proton pump by verapamil or diltiazem is not due to their Ca channel antagonism but to their interaction with the luminal high affinity K(+)-site of the H+,K(+)-ATPase under acidic conditions.
在分离的兔壁细胞（PC）中分析了钙通道拮抗剂对胃酸分泌[[14C]-氨基比林（AP）摄取率]的抑制作用。在有和没有细胞外钙的情况下，维拉帕米和地尔硫卓均以剂量依赖性方式抑制促分泌剂刺激的AP摄取，IC50值分别为15和100μM。相比之下，硝苯地平对AP积累没有影响。维拉帕米降低组胺刺激的呼吸作用，其IC50与AP摄取观察到的相同。咪唑作为一种弱碱，通过缓冲PC中的酸性空间，逆转了维拉帕米对呼吸作用的抑制作用。在牛蛙胃黏膜中，福斯可林刺激的质子转运从腔面被维拉帕米（10^(-4)M）抑制，但从浆膜面未被抑制。通过提高分泌溶液中的KCl浓度或从分泌溶液中去除药物，这种抑制作用均可逆转。维拉帕米比地尔硫卓更有效地抑制胃微粒体H⁺，K⁺-腺苷三磷酸酶（H⁺，K⁺-ATPase）和PC中K⁺刺激的对硝基苯磷酸酶活性。维拉帕米和地尔硫卓对这些酶的抑制作用是pH依赖性的。在H⁺，K⁺-ATPase和K⁺刺激的对硝基苯磷酸酶反应中，这些药物与K⁺竞争。我们的数据表明，维拉帕米或地尔硫卓对胃质子泵的抑制作用不是由于它们的钙通道拮抗作用，而是由于它们在酸性条件下与H⁺，K⁺-ATPase的腔面高亲和力K⁺位点相互作用。
