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Am J Physiol Gastrointest Liver Physiol 291: G838-G843, 2006. First published June 22, 2006; doi:10.1152/ajpgi.00120.2006
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HORMONES AND SIGNALING

Characteristics of the K+-competitive H+,K+-ATPase inhibitor AZD0865 in isolated rat gastric glands

P. Kirchhoff,1 K. Andersson,3 T. Socrates,1 S. Sidani,1 O. Kosiek,1 and J. P. Geibel1,2

1Department of Surgery and 2Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Conneticut; and 3AstraZeneca, Mölndal, Sweden

Submitted 16 March 2006 ; accepted in final form 31 May 2006


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
The gastric H+,K+-ATPase of the parietal cell is responsible for acid secretion in the stomach and is the main target in the pharmacological treatment of acid-related diseases. Omeprazole and other benzimidazole drugs, although having delayed efficacy if taken orally, have high success rates in the treatment of peptic ulcer disease. Potassium competitive acid blockers (P-CAB) compete with K+ for binding to the H+,K+-ATPase and thereby they inhibit acid secretion. In this study, the in vitro properties of AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion, are described. We used a digital-imaging system and the pH sensitive dye BCECF to observe proton efflux from hand-dissected rat gastric glands. Glands were stimulated with histamine (100 µM) and exposed to a bicarbonate- and Na+-free perfusate to induce an acid load. H+,K+-ATPase inhibition was determined by calculating pHi recovery (dpH/dT) in the presence of omeprazole (10–200 µM) or AZD0865 (0.01–100 µM). The efficacies of both drugs were compared. Our data show that acid secretion is inhibited by both the proton pump inhibitor omeprazole and the P-CAB AZD0865. Complete inhibition of acid secretion by AZD0865 had a rapid onset of activation, was reversible, and occurred at a 100-fold lower dose than omeprazole (1 µM AZD0865 vs. 100 µM omeprazole). This study demonstrates that AZD0865 is a potent, fast-acting inhibitor of gastric acid secretion, effective at lower concentrations than drugs of the benzimidazole class. Therefore, these data strongly suggest that AZD0865 has great potential as a fast-acting, low-dose inhibitor of acid secretion.

potassium competitive acid blockers; gastric acid secretion; pH measurements; gastroesophageal reflux disease

SINCE THEIR INTRODUCTION into the market, proton pump inhibitors (PPIs) have emerged as the treatment of choice for acid-related diseases such as peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD) (17, 18). The responsible ion pump for acid secretion is the H+,K+-ATPase located at the apical membrane of the parietal cell and transports H+ into the parietal cell canaliculus in exchange for K+. PPIs such as omeprazole, rabeprazole, and lansoprazole are irreversible inhibitors, which are activated in the acidic secretion that is partly due to de novo synthesis of the enzyme (9). A further limitation of this class is the degree of interpatient variability observed in their effects on acid secretion, which is due to different polymorphisms in the hepatic cytochrome P450 responsible for the metabolism of the drug (2).

In the resting cell, the pumps are internalized in a system of tubular vesicles, therefore the PPIs can only inhibit the H+,K+-ATPases that have already been activated and transferred to the apical surface of the parietal cell (8). Despite their high degree of efficacy and their worldwide clinical use, failure in the treatment of acid-related diseases has been reported, and the degree and speed of onset of symptom relief are important to patients (15). It has been estimated that ~30% of GERD patients remain symptomatic on a standard dose of PPI (5). Furthermore, PPIs have a short plasma half life, which often leads to a nocturnal acid breakthrough (12). Therapeutic oral doses of PPIs reach steady state and thus achieve their maximal effective levels after 4–5 days with typical dosing regimens (21). This slow and cumulative onset of effect of PPIs relates partly to their ability to inhibit only those pumps that are active when the PPI drug is available. After PPI administration, there is a return of acid secretion that is partly due to de novo synthesis of the enzyme (9). A further limitation of this class is the degree of interpatient variability observed in their effects on acid secretion, which is due to different polymorphisms in the hepatic cytochrome P450 responsible for the metabolism of the drug (2).

Although optimizing pharmacological profiles within the PPI class may provide some clinical benefit, other areas of research may prove to be more fruitful. An alternative strategy for effective inhibition of gastric acid secretion is the use of the potassium-competitive acid blockers (P-CAB). This concept has evolved through recent decades of research into the requirement of K+ for the activation of the H+,K+-ATPase. P-CABs are lipophilic, weak bases that have high pKa values and are stable at a low pH. These properties allow them to concentrate to a high degree in parietal cell acid space, thus resulting in a fast onset of action and a direct dose-response relationship. When the P-CAB binds to the H+,K+-ATPase, it stabilizes the enzyme in the E2 conformation and, thereby, prevents the movement of H+ ions into the parietal cell canaliculus (4). These agents inhibit H+,K+-ATPase by ionically binding at or near the potassium binding site in a K+-competitive manner, thereby blocking gastric acid secretion by a direct and reversible mechanism (11, 22). This results in a very rapid onset of effect, with initial research showing that almost complete acid blockade can be achieved within 30 min of administration (22). In contrast to the PPIs, the reversible inhibitors are active in the absence of stimulated acid secretion and should therefore produce a less variable onset of the effect, and furthermore, the inhibition will follow the plasma concentration of the drug closely (22, 23).

Several P-CABs are currently undergoing clinical development, including CS-526 (R-105266), soraprazan (BY-359), and AZD0865. In our protocol, we used AZD0865 for detailed characterization and evaluation as a competitive inhibitor of gastric H+,K+-ATPase in isolated gastric glands. AZD0865 is a substitute imidazopyridine and inhibits H+,K+-ATPase activity in a K+-competitive manner. It concentrates in the acidic compartment of the parietal cell and has a luminal site of action. Available data suggest that the full effect is achieved on the first day of dosing, and similar effects are achieved with repeated dosing (1). These properties would offer improvement for patients with GERD and other acid-related diseases; however, the efficacy and tolerability of these drugs has to be investigated in large clinical studies.

The aim of the present study is to characterize the K+ competitive H+,K+-ATPase inhibitor AZD0865 in isolated rat gastric glands. Therefore, we investigated the dose-dependent inhibition of acid secretion for AZD0865 compared with omeprazole and, furthermore, the onset of inhibition of acid secretion by AZD0865.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
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Animals. Sprague-Dawley rats (150–250 g, Charles River Laboratory) were housed in climate- and humidity-controlled, light-cycled rooms, fed standard chow with free access to water, and handled according to the humane practices of animal care established by the Yale Animal Care. Prior to experiments, animals were fasted for 12 h with free access to water.

Isolation of gastric glands. Following removal of the stomach, the stomach was opened longitudinally, and the corpus and antrum were isolated and sliced into 0.5-cm square sections and washed with cold Ringer's solution to remove residual food particles. The tissues were transferred to the stage of a dissecting microscope. Individual glands were isolated using a hand-dissection technique as described previously (14). Following isolation, individual isolated glands were allowed to adhere to coverslips that had been precoated with Cell-Tak (Collaborative Research, Bedford, MA) and were transferred to the stage of an inverted microscope.

Digital imaging for intracellular pH measurements. Isolated gastric glands were incubated in a HEPES-buffered Ringer's solution containing 10 µM of the pH-sensitive dye BCECF-AM (2',7')-bis-(2-carboxyethyl)-5-(and-6)-carboxy-fluorescin, aceto-methyl ester (Molecular Probes, Eugene, OR) for 10 min as described previously (10, 16) (7). Following dye loading, the chamber was flushed with a HEPES solution to remove all nondeesterfied dye. The perfusion chamber was mounted on the stage of an inverted microscope (Olympus IX50), which was used in the epifluorescence mode with a x40 objective. BCECF was successively excited at 440 ± 10 nm and 490 ± 10 nm for BCECF, and the resultant fluorescent signal was monitored at 530 ± 10 nm using an intensified charge-coupled device camera. Individual regions of interest were outlined and simultaneously monitored during the course of the study. A minimum of 7 cells or regions was selected per gland.

Proton extrusion by individual parietal cells was monitored by observing recovery of pHi after acid loading the cells with Na+-free HEPES solution containing 20 mM NH4Cl. Parietal cells were subsequently superfused with Na+-free HEPES, which abolished all Na+/H+ exchanger (NHE) activity, trapping H+ within the cytosol and initiating an immediate drop in pHi. Under these conditions, the only potential H+ extrusion pathway is via the H+,K+-ATPase activation. Intracellular pH recovery rates were measured in Na+-free HEPES solutions containing 100 µM histamine + different concentrations of omeprazole or AZD0865, 100 µmol pentagastrin + 200 µM omeprazole or 10 µM AZD0865, and 100 µmol carbachol + 200 µM omeprazole or 10 µM AZD0865.

The intensity ratio data (490/440) were converted to pH values using the high K+/nigericin calibration technique (20). Intracellular pH recovery rates were calculated from the same initial starting pH to eliminate the potential variation in the individual intracellular buffering power of the cells under the different experimental conditions. All data, including the individual images for all wavelengths were recorded to the hard disk, which allowed us to return to the individual images after the experiment for further analysis. The recovery rates are expressed as the {Delta}pH/min and were calculated over the pH range of 6.5–6.8.

The composition of all solutions used is given in Table 1. All chemicals were obtained from Sigma; omeprazole and AZD0865 were synthesized at AstraZeneca R&D, Mölndal, Sweden. An unpaired Student's t-test was used to test for significant differences in pH recovery rates.


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  		Table 1. Compositions of solutions used for intracellular pH measurements in single rat gastric glands

 

   RESULTS
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High resolution video microscopy was employed to detect fluorochromic intensity changes within parietal cells in freshly isolated rat gastric glands. Measurements of acid secretion were conducted using the pHi-sensitive dye BCECF to allow for a continuous monitoring of pHi during acid secretion. Changes in pHi allowed us to observe activation or inhibition of the H+/K+-ATPase. Challenging the parietal cell with an acid load in the absence of Na+ and HCO3– allowed us to selectively investigate the apical H+,K+-ATPase as the sole H+ extrusion pathway.

Acid secretion under resting conditions and induced by different secretagogues. In the absence of secretagogues, only a low Na+ independent proton efflux was observed (Fig. 1A). Histamine (100 µmol) exposure induced an alkalinization rate of 0.056 ± 0.008 pH unit/min (Fig. 1B). Intracellular alkalinization stimulated by histamine (100 µmol) in the absence of extracellular Na+ is a function of H+,K+-ATPase, because it can be blocked by the specific inhibitor AZD0865 (10 µmol) (Fig. 1C). To show that this effect is due to the K+ competitive inhibition by AZD0865, we used also the well-known drug Schering 28080, which belongs to the same class of P-CABs. Figure 1D shows that Schering 28080 (100 µM) abolished the histamine-induced acid secretion to a rate of 0.008 ± 0.0009 pH unit/min. Figure 2 shows that proton efflux can also be induced by other secretagogues, either by 100 µM pentagastrin (0.059 ± 0.01 pH unit/min) or 100 µM carbachol (0.058 ± 0.006 pH unit/min). The next experiments showed that this alkalinization was inhibited by specific inhibitors of the H+/K+-ATPase, either omeprazole or AZD0865, demonstrating that the observed proton efflux was due to the H+,K+-ATPase activity.


Figure 1
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  		Fig. 1. Original tracing of acid secretion and inhibition by AZD0865, a reversible H+,K+-ATPase inhibitor of gastric acid secretion. Single rat gastric glands were isolated and loaded with the pH-sensitive dye BCECF to measure intracellular pH over single parietal cells, and the pHi recovery rate was calculated from the slope after an acid load using the NH4Cl prepulse technique as described previously. A: original tracing of an intracellular pH measurement demonstrating the resting parietal cell without alkalinization (proton efflux) after removing Na+ out of the perfusion bath. B: intracellular alkalinization stimulated by histamine (100 µM) in the absence of extracellular Na+. C: histamine-stimulated acid secretion is a function of H+,K+-ATPase, because it can be blocked by the specific inhibitor AZD0865 (10 µM). Histamine was present during the entire experiment and for a 15-min incubation time prior to the perfusion. D: histamine-stimulated acid secretion could also be inhibited by Schering 28080 (100 µM) that was applied during the entire experiment.

 

Figure 2
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  		Fig. 2. Acid secretion stimulated by different secretagogues. The control shows a low basal proton efflux without any stimulation (0.011 ± 0.002 pH unit/min) (n = 32 cells/5 glands/4 animals). Histamine (100 µM) caused a strong intracellular alkalinization (0.056 ± 0.008 pH unit/min) (n = 210 cells/37 glands/32 animals). Carbachol (100 µM) induced a rapid proton efflux (0.058 ± 0.006 pH unit/min) (n = 78 cells/8 glands/7 animals). Pentagastrin had nearly the same rate of acid secretion (0.059 ± 0.011 pH unit/min) (n = 48 cells/4 glands/4 animals).

 
Effects of AZD0865 and omeprazole on gastric acid secretion. Omeprazole and AZD0865 inhibited H+,K+-ATPase activity in a dose-dependent manner (Fig. 3, A and B). In this protocol, acid secretion was stimulated by histamine and expressed as {Delta}pH/min (0.056 ± 0.008). Therefore, the gastric glands were incubated with histamine (15 min), and 100 µM histamine was added throughout the whole superfusion. To investigate the inhibitory potency of both omeprazole and AZD0865, we used different concentrations of omeprazole (10–200 µM) and AZD0865 (0.01–100 µM). Each drug was present during the entire experiment, including the histamine incubation period of 15 min. The inhibitory efficacy of AZD0865 was much stronger than the inhibition by omeprazole. Figure 3, A and B, shows that inhibition of acid secretion by omeprazole and AZD0865 is a dose-dependent effect. AZD0865 abolished the acid secretion as strongly as omeprazole at a 100-fold lower concentration (1 µM AZD0865 vs. 100 µM omeprazole). The IC50 values of AZD0865 and omeprazole were 0.3 and 80 µM, respectively (Fig. 4).


Figure 3
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  		Fig. 3. Omeprazole and AZD0865 inhibit acid secretion in a dose-dependent manner. A: omeprazole concentration dependence of H+,K+-ATPase activity (intracellular alkalinization) in the presence of histamine (n = 30–40 cells/2–4 glands/3 animals for each omeprazole concentration). B: AZD0865 concentration dependence of H+,K+-ATPase activity in the presence of histamine (n = 30–40 cells/3–4 glands/3 animals for each AZD0865 concentration).

 

Figure 4
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  		Fig. 4. Effect of AZD0865 and omeprazole on H+,K+-ATPase activity in isolated glands. Dose-dependent inhibition of proton efflux ({Delta}pH/min) by AZD0865 (bullet) and by omeprazole ({blacksquare}). Experimental details were as described in MATERIALS AND METHODS. Values are means ± SE of 30–40 cells/2–4 glands/3 animals.

 
Fast and reversible inhibition of acid secretion by AZD0865. AZD0865 is a reversible proton pump inhibitor that binds to the H+,K+-ATPase in a K+-competitive manner. We investigate these characteristics of the drug in our in vitro setting. Therefore, we stimulated acid secretion with histamine (100 µM) during the entire experiment. By adding 10 µM AZD0865 to the perfusion bath, we showed that acid secretion was abolished after less than 30 s. During the same experiment, we removed the drug from the superfusion bath, and the acid secretion was visible again after 2–3 min (Fig. 5A). With the proton pump inhibitor omeprazole (200 µM), the inhibition of acid secretion was irreversible and had no rapid onset of effect (Fig. 5B). To confirm these results, we used another member of the potassium competative inhibitors, Schering 28080. Adding 100 µM Schering 28080 during the histamine-induced recovery phase resulted in an immediate inhibition of acid secretion (Fig. 5C)


Figure 5
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  		Fig. 5. Fast onset inhibitory effect and reversibility of AZD0865. A: fast inhibitory effect of AZD0865 on histamine-induced acid secretion. Histamine (100 µM) was present through the entire experiment. When the intracellular alkalinization (proton efflux) was observed, AZD0865 (10 µM) was added to the superfusion bath. The histamine-induced acid secretion was abolished after a few seconds (dotted line). Removal of AZD0865 from the perfusion solution resulted in an increase of the intracellular pH (n = 36 cells/3 gland/3 animals). B: same protocol as in A. Instead of AZD0865, we added 100 µM omeprazole in the recovery phase. Omeprazole did not abolish the proton extrusion (dotted line), and acid secretion continued at the same rate as with histamine alone. This shows that omeprazole has no fast onset of effect (n = 28 cells/3 glands/2 animals). C: fast inhibitory effect of Schering 28080 on histamine-induced acid secretion. Histamine (100 µM) was present through the entire experiment. When the intracellular alkalinization (proton efflux) was observed, Schering 28080 (100 µM) was added to the superfusion bath. The histamine-induced acid secretion was abolished after a few seconds (dotted line) (n = 18 cells/2 glands/2 animals). HP, HEPES-buffered Ringer's solution; NH, NH4Cl solution.

 
AZD0865 inhibits acid secretion independently of the stimulatory drug. In this series of experiments, we used pentagastrin, carbachol, or histamine, each in a concentration of 100 µM during the entire experiment. After stimulation with each of these single drugs, we observed similar rates of proton efflux (Fig. 2).

Figure 6A, shows that pentagastrin-induced acid secretion (0.059 ± 0.011 pH unit/min) was reduced 76% by 200 µM omeprazole (0.014 ± 0.002 pH unit/min) and 81% by 10 µmol AZD0865 (0.011 ± 0.001 pH unit/min). Also, the carbachol-stimulated proton efflux (0.058 ± 0.006 pH unit/min) was reduced 76% by 200 µM omeprazole (0.015 ± 0.002 pH unit/min) and 79% by 10 µM AZD0865 (0.012 ± 0.001 pH unit/min); Fig. 6B. Acid secretion caused by histamine and the dose-dependent inhibition by AZD0865 and omeprazole is shown in Fig. 3, A and B.


Figure 6
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  		Fig. 6. Inhibition of carbachol- and pentagastrin-induced acid secretion. Here we explored the inhibitory effect of omeprazole and AZD0865 on pentagastrin- (A) or carbachol (B)-induced acid secretion. The pentagastrin-stimulated acid secretion was significantly reduced by omeprazole (200 µM) (0.014 ± 0.002 pH unit/min) and AZD0865 (10 µM) (0.011 ± 0.001 pH unit/min). Also, carbachol-dependent proton efflux is reduced by both drugs, omeprazole (0.015 ± 0.002 pH unit/min) and AZD0856 (0.012 ± 0.001 pH unit/min) (n = 30–40 cells/3–4 glands/3 animals for each protocol).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we examined the dose-dependent inhibition of the gastric H+,K+-ATPase by the P-CAB AZD0865 and compared it with the classic proton pump inhibitor omeprazole. Furthermore, we tried to evaluate the onset of effect of AZD0865.

We employed the single gastric gland superfusion in vitro technique to investigate mechanisms of acid secretion on the cellular level. Acid secretion was induced by the classically known secretagogues histamine, carbachol, and pentagastrin, all of which led to a robust proton extrusion via the H+,K+-ATPase compared with the basal acid secretion in the resting, unstimulated gland (Fig. 2).

In subsequent studies, we examined the inhibitory effects of omeprazole and AZD0865 on the secretagogue-sensitive gastric acid secretion. Here, we confirmed the inhibitory potency of AZD0865 and omeprazole on histamine-induced acid secretion. We determined that either a concentration of 1 µM AZD0865 or 100 µM omeprazole was necessary to cause an 70–80% inhibition of secretagogue-induced proton extrusion via the H+/K+-ATPase. Furthermore, our experiments revealed that AZD0865 is able to inhibit acid secretion at a 100-fold lower concentration than omeprazole.

As mentioned in the introduction, proton pump inhibitors have a delayed onset of acute effect, and the full inhibitory effect is slow and needs several dose cycles. For example, omeprazole reaches only 30% of inhibition of acid secretion on the first day of treatment (6). Our further investigations try to examine the fast onset of AZD0865 and its reversibility, because treatments that provide faster onset of effect and increased duration of action would offer improvements for patients with GERD and other acid-related disorders. In fact, as shown in Fig. 5A, we were able to inhibit secretagogue-dependent acid secretion during maximal proton extrusion by addition of 10 µM AZD0865. On the other hand, the histamine-induced acid secretion continued after removal of AZD0865 from the superfusion bath, demonstrating the reversible nature of the binding to the H+,K+-ATPase (Fig. 5A). These results confirm the existing data of the fast onset of inhibition of acid secretion by P-CABs (13). In humans, AZD0865 was able to inhibit acid secretion, 1 h after oral dosing, to 95% (1). P-CABs are absorbed rapidly and exhibit a classically dose-effect relationship with a dose-dependent duration increasing the intragastric pH (22). In humans, more than 95% inhibition was sustained for up to 15 h for 0.8 and 1 mg/kg doses (1). Our experiments show that there is no difference in the inhibitory characteristics of AZD0865 between the classical acid-stimulating agents (histamine, carbachol, and pentagastrin). Therefore, we assume that P-CABs are not interfering with the intracellular pathway of the acid secretory process and act only on the H+,K+-ATPase as the final enzyme responsible for secreting protons, and forming HCl in the lumen of the stomach.

In summary, our findings indicate that AZD0865 offers a more rapid and elongated inhibition of gastric acid secretion at much lower concentrations than conventional proton pump inhibitors. AZD0865 is a reversible and fast-acting inhibitor of acid secretion in single gastric glands. Compared with omeprazole, AZD0865 inhibits acid secretion with a faster onset of effect and in a 100-fold lower dose. Such treatments may provide significant benefits to patients with GERD. Future studies investigating the efficacy of P-CABs in the clinical setting are awaited and will help to define their place in the treatment of acid-related diseases.


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This study was supported by the Swiss National Science Foundation Grant PBZHB–110427 (to P. Kirchhoff), National Institute of Diabetes and Digestive and Kidney Diseases Grants D-K50230 (to J. P. Geibel), DK-007259-26 (to S. Sidani), and DK-07017-29 (to T. Socrates), and a grant from AstraZeneca to J. P. Geibel.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. P. Geibel, Dept. of Surgery, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06520 (e-mail: john.geibel{at}yale.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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