Picoprazole

Inhibition of gastric (H+ + K+)-ATPase by the substituted benzimidazole, picoprazole

The substituted benzimidazole, picoprazole, inhibited the gastric (H+ + K+)-ATPase in a concentration-and time-dependent manner. Half-maximal inhibition of the (H+ + K+)-ATPase activity was obtained at about 2 . 10(-6)M under standard conditions. In addition to the inhibition of ATPase activity, parallel inhibition of phosphoenzyme formation and the proton transport activity were achieved. Radiolabelled picoprazole was found to bind to 100 kDa peptide; this peptide was shown by phosphorylation experiments to contain the catalytic centre of the (H+ + K+)-ATPase. Studies on the (Na+ + K+)-ATPase indicated that this enzyme was unaffected by picoprazole. From the data presented and from other pharmacological studies, it is proposed that this compound inhibits acid secretion at the level of the parietal cell by its ability to inhibit the gastric proton pump, the (H+ + K+)-ATPase.

Effects of KCl and insulin on benzimidazole-inhibited canine gastric secretion

The final step in acid secretion is believed to result from the H+-K+-ATPase-mediated exchange of H+ in the parietal cell, with K+ in the lumen. To study the K+ secretion we used Picoprazole and insulin separately and together to inhibit gastric secretion stimulated in gastric fistula dogs with histamine (100 micrograms X kg-1 X h-1). Picoprazole, a substituted benzimidazole (750 mg/kg), reduced gastric H+ concentration and volume with a rise in K+ concentration [( K+]) to 20-25 meq/l. Insulin alone inhibited acid output to the same extent as Picoprazole but with a marked fall in [K+]. Insulin (0.6 U/kg) given with Picoprazole did not alter inhibition of H+ but prevented the large decrease in gastric juice [K+]. An injection of KCl (1 meq/kg) 1 h after Picoprazole did not alter the effects of the inhibitor. Pepsin secretion after insulin was delayed by Picoprazole, whereas during bethanechol chloride infusion (80 micrograms X kg-1 X h-1) pepsin output was reduced for a shorter period and to a lesser extent than acid. We concluded that insulin affects gastric H+ and K+ secretion by a mechanism not related to H+-K+-ATPase and that Picoprazole affects pepsin secretion probably indirectly via its effect on the parietal cell, where its action is quite consistent with an effect limited to inhibition of the H+-K+-ATPase of the parietal cell.

Ultrastructure of inhibited parietal cells in the rat

In acutely vagotomized rats, gastric acid secretion was stimulated with a combination of carbachol and pentagastrin, and/or inhibited with picoprazole, cimetidine, or l-hyoscyamine. The animals were killed 1 or 3 h later. Using stereologic electron microscopic methods, the relative area of the secretory surface in the parietal cells and the mean size of these cells were estimated. The parietal cells in the superficial quarter of the oxyntic mucosa were larger than those at deeper levels of the mucosa. Moreover, the secretory surface was proportionally larger in the superficial cells than in the deep cells. Stimulation by carbachol and pentagastrin produced an increase in the secretory surface area. Inhibition of stimulated acid secretion by l-hyoscyamine reduced the secretory surface to the level of the unstimulated controls. Cimetidine, given at doses that inhibited stimulated acid secretion, did not alter the mean size of the secretory membrane. After inhibition by picoprazole, stimulated acid secretion was abolished, but the secretory membrane became significantly larger than after cimetidine inhibition. These divergent patterns of morphologic reactions probably reflect the different mechanisms of inhibition at the cellular level.

Disulfide cross-linking of H,K-ATPase opens Cl- conductance, triggering proton uptake in gastric vesicles. Studies with specific inhibitors

An S-S cross-linking reagent, Cu2+-o-phenanthroline, increased the 36Cl-/Cl- exchange rate across the hog gastric vesicle membrane, which contains H,K-ATPase, but did not affect the 86Rb+/Rb+ exchange rate. The results show that closed Cl- conductance can be opened by S-S cross-linking. Gastric vesicles with opened Cl- conductance could take up H+ upon addition of MgATP without prolonged preincubation in a solution containing K+. Preincubation of gastric vesicles with picoprazole, which is a specific inhibitor of H,K-ATPase and binds to 100-kDa polypeptides of the enzyme, dose dependently inhibited opening of the Cl- conductance by Cu2+-o-phenanthroline, indicating that the Cl- conductance is part of the function of the H,K-ATPase. The effect of picoprazole was greater at alkaline pH than at acidic pH. Another H,K-ATPase inhibitor, 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl] (5-methoxycarbonyl-6-methyl)-benzimidazole (H compound), had a similar but stronger effect on the Cl- conductance than that of picoprazole. A pungent ingredient of curry, allylisothiocyanate, caused similar pH-dependent inhibition to that of picoprazole. However, another substituted benzimidazole, omeprazole, did not inhibit Cl- conductance. Substituted benzimidazoles, such as picoprazole, H compound, and omeprazole, inhibited the H,K-ATPase activity progressively with a decrease in pH of the medium. This pH dependence was the reverse of that in inhibition of Cl- conductance, suggesting that the inhibitory site of Cl- conductance is different from that of the H,K-ATPase activity and that the conformational states of the two sites change in different ways with change in pH of the medium.

Inhibition of gastric acid secretion by omeprazole in the dog and rat

The gastric antisecretory properties of omeprazole, a new potent substituted benzimidazole, have been evaluated in dogs and rats. Omeprazole was compared with another benzimidazole, picoprazole (H 149/94), and with the histamine H2-receptor antagonist cimetidine. The intravenous or intraduodenal administration of omeprazole in the gastric fistula dog inhibited histamine- and pentagastrin-stimulated acid secretion. The intravenous and intraduodenal, ED50 values for inhibition of histamine-stimulated secretion were 0.35 and 0.26 mumol/kg, respectively. Omeprazole was found to be approximately 5-10 times more potent than both picoprazole and cimetidine. After oral omeprazole administration in the Heidenhain pouch dog, the ED50 on histamine-stimulated acid secretion was found to be 1.2 mumol/kg, which corresponded to a potency 2 and 3.5 times greater than that of cimetidine and picoprazole, respectively. Measurement of the plasma concentration of unchanged omeprazole revealed an intraduodenal bioavailability of approximately 70% whereas the oral bioavailability was only approximately 15%. This variation is probably a result of partial degradation of omeprazole in the acid gastric juice. Single intraduodenal doses of omeprazole had a long-lasting inhibitory effect on histamine-stimulated acid secretion in the dog. After a dose of omeprazole, which produced total inhibition initially, the antisecretory effect was detectable for 3-4 days. Omeprazole inhibited basal and stimulated acid secretion in the rat. The intravenous ED50 was calculated to be 1.5 mumol/kg, whereas the oral potency was about 10 times lower. The effect in the rat was also of long duration. After a dose giving maximal inhibition, control acid secretion was restored after approximately 13 h.