S. OKABE, K. SHIMOSAKO, K. AMAGASE
PHARMACOLOGICAL REGULATION OF GASTRIC ACID
SECRETION IN THE APICAL MEMBRANE OF PARIETAL CELLS;
A NEW TARGET FOR ANTISECRETORY DRUGS
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
We examined the local effect of several drugs against secretagogue-stimulated acid
secretion in dogs. Test drugs were applied to denervated gastric pouches in conscious
dogs either for 5 to 30 min beginning 1 hr after or for 30 min before intravenous
infusion of gastric secretagogues (histamine, pentagastrin, or carbachol). The antisecretory
effect of test drugs delivered by an intravenous or oral route was also examined. Local
application of acid pump inhibitors (omeprazole, leminoprazole) for 30 min beginning
l hr after histamine infusion significantly inhibited gastric acid secretion. The effect of
leminoprazole persisted for more than 8 hr after a 30 min application. A mast cell
stabilizer (FPL 52694) applied to pouches for 15 to 30 min also potently inhibited
histamine-stimulated gastric acid secretion in a time-dependent manner. The duration
of the antisecretory effect of such drugs after a 30 min application was greater than 4
hr. Locally applied leminoprazole and FPL 52694 for 30 min also significantly
inhibited pentagastrin- and carbachol-stimulated gastric acid secretion. Although
intravenous omeprazole and leminoprazole exerted a potent antisecretory effect on
histamine-induced acid secretion FPL 52694 had little or no antisecretory effect
following intravenous or oral administration. 16, 16-dimethyl prostagladin E2 also
locally inhibited histamine-stimulated acid secretion. Acid stable local anesthetics
(tetracaine, ethyl-4-aminobenzoate), histamine H2-receptor blockers (cimetidine,
ranitidine, and famotidine), and a muscarinic M1-receptor antagonist (pirenzepine) did
not exhibit local antisecretory effects. Such results strongly suggest that the apical
membrane of parietal cells possesses a pharmacologically sensitive portion similar to
the basolateral membrane, which usually mediates gastric acid secretion. The apical
membrane represents an intriguing target for new antisecretory drugs, as well as a
new medium for further elucidating the functional features of parietal cells.
K e y w o r d s: gastricacidsecretion,Heidenhainpouchdogs,omeprazole,leminoprazole,
More than 100 years has passed since Prout (1823) discovered the presence
of hydrochloric acid in the human stomach and Golgi (1893) identified parietal
cells as the acid secretory cell in oxyntic glands. During this past century, a
number of papers have been published concerning the significance of the
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2001, 52, 4, 639—656
presence of strong acid in the stomach (1, 2). In addition, the mechanism by
which parietal cells secrete gastric acid through a combination of various
receptors on the basolateral membrane and an enzyme in the apical secretory
canaliculi has been elucidated (3—5). The development of several selective
drugs, including histamine H2-receptor blockers (H2R-blockers) and proton
pump inhibitors (PPI), has greatly contributed to the understanding of the
mechanism underlying acid secretion (6—9). Utilizing such drugs, it is now
understood that gastric acid secretion is mainly regulated by stimulation of
corresponding receptors on the cell membrane via acetylcholine released from
the vagus nerve, gastrin released from antral G cells, and histamine released
from ECL cells. Gastrin-stimulated acid secretion is controlled by the release
of inhibitory mediators, such as somatostatin released from D cells. Needless to
say, H2R-blockers, such as cimetidine, ranitidine, and famotidine, and PPI,
such as omeprazole and lansoprazole, have been successful in the treatment of
acid-related diseases. Accordingly, it appears that further development of
antisecretory drugs for ulcer therapy is no longer necessitated.
Several substances or drugs have been reported to have an antisecretory
effect when locally applied to the stomach (10—17). Nonetheless, attention has
not been directed towards such drugs as either clinically useful antisecretory
drugs or investigational tools useful for the elucidation of parietal cell function.
We examined whether or not certain drugs could inhibit histamine-stimulated
gastric acid secretion when applied into denervated (Heidenhain) gastric
pouches in dogs. It was found that omeprazole, leminoprazole (acid pump
Fig. 1. Chemical structures of the main compounds that were used in this study.
inhibitors) (18, 19), FPL 52694 (a mast cell stabilizer), ME 3407 (a myosin
light chain kinase inhibitor and a functional analogue of wortmannin) (Fig. 1)
and 16, 16-dimethyl prostagladin E2 significantly inhibited histamine-stimulated
acid secretion. This report describes both the effect of locally active antisecretory
drugs and the underlying mechanisms, emphasizing the important role of the
parietal cell apical membrane for acid secretion.
MATERIALS AND METHODS
Ten male and female beagles (10—13 kg), each with a cannulated, denervated
(Heidenhain) pouch, were used in the study no earlier than 2 months after their
operation. The interval between the experiments was no less than 7 days. Food
was withheld for 18 hr before each experiment, but water was freely provided.
The pouch of each animal was washed with 15 ml of warm saline several times
until the washings became clear. Gastric juice samples were collected throughout
the experiments every 15 min by gravity drainage (Fig. 2). Following collection
of the basal secretion for the initial 30 min, acid secretion was stimulated by
continuous intravenous infusion of histamine 2HCl (Nacalai Tesque, Kyoto,
Japan, 160 ?g/kg/hr), pentagastrin (Sigma Chemical Co., St. Louis, 8 ?g/kg/hr)
and carbachol (Sigma Chemical, 8 ?g/kg/hr) at a rate of 10 mL/hr via a catheter
inserted into a leg vein. Test drugs were generally applied to the pouches 1 hr
Fig. 2. General design for the experimental procedure in Heidenhain pouch dogs. Test drugs were applied to
the pouch for 5 to 30 min and then withdrawn. Gastric acid stimulated by intravenous infusion of histamine,
pentagstrin, or carbachol was collected every 15 min before and after drug application.
after commencement of histamine infusion, yet in certain cases drugs were
either intravenously or orally administered. During the application of the drugs,
histamine infusion was maintained at the same rate. After local application, test
drugs were removed from the pouches and each pouch was washed out with
saline three times. Thereafter, gastric juice samples were continuously collected
every 15 min for 1.5 to 5 hr for analysis of volume and acidity. Total acidity
was determined by titration of the gastric juice against 0.1N NaOH to pH 7.0,
using an automatic titrator (Radiometer; Copenhagen, Denmark); acid output
was expressed as mEq/15 min. The protocol of this study was approved by
Ethic Committee for Animal Research of Kyoto Pharmaceutical University.
Omeprazole (Astra-Japan, Osaka, Japan), leminoprazole (Nippon Chemiphar,
Tokyo, Japan), FPL-52694 and sodium chromoglycate (Fison Pharmaceutial Co.,
Osaka, Japan) were suspended in 0.5% carboxymethylcellulose (CMC, Nacalai
Tesque, Osaka, Japan). Histamine H2R-blockers, such as cimetidine (Sigma
Chemical Co., St. Louis, U.S.A.), ranitidine (Sigma), and famotidine
(Yamanouchi Pharmaceutical Co., Tokyo, Japan), were also suspended in 0.5%
CMC. Local anesthetics, such as tetracaine (Kyorin Pharmaceutical Co., Tokyo,
Japan) and ethyl-5-aminobenzoate (Wako, Osaka, Japan), were also suspended
in 0.5% CMC. 16, 16-dimethylprostaglandin E2 (Ono, Osaka, Japan) was
dissolved in a trace of ethanol and then diluted with physiological saline. All
drugs were prepared prior to administration.
Data are presented as means ? S.E.M. Statistical differences were evaluated
using the Student’s t-test or the Dunnett’s multiple comparison test, with a P
value of < 0.05 regarded as significant.
Stimulation of gastric acid secretion in dogs
Continuous infusion of histamine 2HCl (160 ?g/kg/hr) inevitably induced
maximal stimulation of gastric acid secretion l hr later; the plateau level was
maintained for more than 3 hr. During histamine infusion, the local application
of 0.5% CMC alone for 30 min essentially exerted no effect on gastric acid
secretion. Acid output was transiently reduced for 15 min after removal of the
solution, but returned to the stimulated level thereafter. Nearly the similar
results were observed with pentagastrin and carbachol infusion.
Effects of omeprazole and leminoprazole on gastric acid secretion
Omeprazole, administered at a dose of 240 mg/pouch for 30 min, significantly
inhibited gastric acid secretion for approximately 1.5 hr (Fig. 3). As expected,
intravenous administration of omeprazole at a dose of 0.3 mg/kg markedly
inhibited gastric acid secretion. Local administration of leminoprazole at a dose
of 240 mg/pouch for 30 min resulted in significant inhibition of gastric acid
output stimulated by histamine, pentagastrin, and carbachol (Figs 4, 5). The
antisecretory effect for histamine-stimulated secretion persisted for more than 8
hr following local application (Fig. 6). Local application of the drug 30 min
before histamine infusion also resulted in significant inhibition of acid output,
although the degree of inhibition was slightly less than the inhibition observed
1 hr after histamine infusion. Intravenous administration of leminoprazole at
dosages of 3, 6, and 10 mg/kg significantly inhibited gastric acid secretion in a
Fig. 3. Effects of omeprazole on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. The
drug was administered either directly into the pouch for 30 min or intravenously 1 hr after intravenous
histamine infusion. Gastric acid secretion was inhibited following both local and intravenous administration.
Data is expressed as means ? S.E. for 2—6 dogs. * indicates a statistically significant difference from the
corresponding control, with P < 0.05.
Fig. 4. Effects of leminoprazole on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs.
The drug was administered locally into the pouch for 30 min, intravenously 1 hr after intravenous histamine
infusion, or orally 2 hr before histamine infusion. Note that leminoprazole significantly suppressed gastric
acid secretion when either directly applied into the pouch or intravenously delivered. Data is expressed as
means ± S.E. for 4—6 dogs. * indicates a statistically significant difference from the corresponding control,
with P < 0.05.
Fig. 5. Effects of leminoprazole on pentagastrin (8 ?g/kg/hr) and carbachol (8 ?g/kg/hr)-stimulated gastric acid
secretion in Heidenhain pouch dogs. A 30 min administration of leminoprazole into the pouch was performed 1
hr after intravenous infusion of each stimulant. Note that leminoprazole significantly suppressed gastric acid
secretion when directly administered into the pouch. Data is expressed as means ± S.E. for 6 dogs.
* indicates a statistically significant difference from the corresponding control, with P < 0.05.
Fig. 6. Duration of antisecretory effects of leminoprazole, locally applied for 30 min, on histamine-stimulated
gastric acid secretion in Heidenhain pouch dogs. Note that significant inhibition persisted for more than 8 hr.
Data is expressed as means ± S.E. for 4 dogs. * indicates a statistically significant difference from the
corresponding control, with P < 0.05.
Fig. 7. Effects of FPL 52694 on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs.
Although locally applied FPL 52694 significantly inhibited gastric acid secretion, the drug had no effect on
acid secretion following intravenous or oral delivery. Data is expressed as means ± S.E. for 4 dogs.
* indicates a statistically significant difference from the corresponding control, with P < 0.05.
dose-related manner. Nonetheless, oral administration of the drug at a dosage
of 15 or 20 mg/kg 2 hr before histamine infusion exerted no effect on gastric
acid secretion. Such a protocol also confirmed that the leminoprazole serum
concentration following local application was negligible (data not shown). In
contrast, 15 min after intravenous injection of 1 mg/kg of leminoprazole, the
serum concentration was >500 ng/mL. In a subsequent study, at the time of
autopsy 18.6 ?g of leminoprazole/g tissue was found in the gastric mucosa
following a 30 min local application of the drug at a dose of 240 mg/pouch.
Effects of FPL 52694 on gastric acid secretion
FPL 52694 delivered at doses of 10, 20, and 30 mg/pouch also inhibited
histamine-stimulated gastric acid secretion in a dose-related manner; the
inhibition was significant at dosages of 20 and 30 mg/pouch (Fig 7). In addition,
drug application at a dosage of 30 mg/pouch clearly inhibited pentagastrin- and
carbachol-stimulated acid secretion for 30 min (Fig. 8). In contrast, intravenous
administration of the drug at a dose of 5 mg/kg exerted no effect on gastric
acid secretion. In addition, oral administration of the drug at a dose of 750
mg/dog 2 hr before histamine infusion failed to affect gastric acid secretion.
Following a 15 min application, the antisecretory effect of the drug at a dose of
30 mg/pouch approximated the effect observed following a 30 min application
(Fig. 9). Even application of the drug for only 5 min resulted in significant
inhibition of gastric acid secretion. The duration of the antisecretory effect
exerted by FPL-52694 administered at a dose of 30 mg/pouch was approximately
4 hr (Fig. 10).
Effects of miscellaneous drugs on gastric acid secretion
Both tetracaine (160, 320 and 400 mg/pouch) and ethyl-4-aminobenzoate
(300 mg/pouch) had little or no effect on gastric acid secretion (Fig. 11). In
addition, topical application for 30 min of other local anesthetic drugs, such as
sulcain (200 mg/pouch) and oxethazaine (15 mg/pouch), exerted no effect on
histamine-stimulated gastric acid secretion. The dosages of the drugs were
based on the oral antisecretory dose used for patients suffering from gastritis
and ulcers. Both sodium chromoglycate (a mast cell stabilizer), delivered at a
dose of 40 mg/pouch, and ketochifen (histamine H1-receptor antagonist),
delivered at a dose of 1 mg/pouch, resulted in no effect on acid secretion (data
histamine-stimulated gastric acid secretion when intravenously administered at
a dose of 1.0 ?g/kg. In addition, the drug also resulted in significant inhibition
for 30 min after local application to the pouch at a dose of 30 ?g/kg. Local
Fig. 8. Effects of FPL 52694 on pentagastrin (8 ?g/kg/hr )- and carbchol (8 ?g/kg/hr)- stimulated gastric acid
secretion in Heidenhain pouch dogs. Note that locally applied FPL 52694 for 30 min significantly inhibited
acid secretion stimulated by each stimulant. Data is expressed as means ± S.E. for 2—5 dogs. * indicates a
statistically significant difference from the corresponding control, with P < 0.05.
Fig. 9. Effects of locally applied FPL 52694 on histamine-stimulated gastric acid secretion in Heidenhain
pouch dogs for 5, 15, or 30 min. Note that the significant antisecretory effect was observed even after the 5
min application. Data is expressed as means ± S.E. for 4 dogs. * indicates a statistically significant difference
from the corresponding control, with P < 0.05.
Fig. 10. Duration of the antisecretory effect of FPL 52694, locally applied for 30 min, on
histamine-stimulated gastric acid secretion in Heidenhain pouch dogs. Note that significant inhibition
persisted for more than 4 hr. Data is expressed as means ± S.E. for 4 dogs. * indicates a statistically significant
difference from the corresponding control, with P < 0.05.
Fig. 11. Effects of 30 min local application of local anesthetics in Heidenhain pouch dogs. Note that the drugs
had little or no antisecretory effect. Data is expressed as means ± S.E. for 6 dogs.
application of histamine H2-receptor antagonists, such as cimetidine, (200
mg/pouch), ranitidine (150 mg/pouch), and famotidine (40 mg/pouch), for 30
min had no effect on histamine-stimulated gastric acid secretion (Fig. 12). Similar
results were obtained with local application of pirenzepine (25 mg/pouch) for 30
min. The dosage of the drugs utilized was based on the oral antisecretory dose
determined for patients suffering from ulcers.
The above results undisputedly confirmed the notion that drugs that are able
to directly inhibit gastric acid secretion from the luminal side exist (Fig. 13).
First, Konturek et al. (16) reported that although continuous infusion of
omeprazole into denervated gastric pouches of dogs significantly inhibited
pentagastrin- and histamine-stimulated acid secretion, it did not affect acid
secretion from the gastric fistula in response to such stimulants. Since serum
omeprazole level was only slightly increased at a dose that significantly inhibited
gastric acid secretion from the denervated pouch, the authors suggested that
Fig. 12. Effects of H2R-blockers, locally applied for 30 min, on histamine-stimulated gastric acid secretion
in Heidenhain pouch dogs. Note that the drugs had no antisecretory effect. Data is expressed as means ± S.E
for 6 dogs.
omeprazole exerted a local antisecretory effect in addition to a systemic effect.
In our previous report (17), we demonstrated that locally administered
omeprazole (160 mg/pouch) with NaHCO3into denervated pouches resulted in
no antisecretory effect. Nonetheless, we recently found that an increased dose
of 240 mg/pouch of omeprazole, even without NaHCO3, significantly inhibited
histamine-stimulated acid secretion. Although we did not determine the
omeprazole blood concentration following local application, it appears that
omeprazole also inhibits parietal cells from the mucosal surface, as previously
described by Kontureck et al. (16).
Similar to omeprazole, locally applied leminoprazole also suppressed acid
secretion for more than 9 hr by inhibiting parietal cells from the mucosal side.
Such a duration of the local antisecretory effect was clearly longer than that
observed following a single intravenous injection of ranitidine and famotidine.
The effect, however, was found to be reversible, as it was found to have
disappeared after 20 hr. Indeed, as we have previously reported (17),
leminoprazole, delivered at a dose of 160 mg/pouch, was not detected in the
blood of dogs after local application at a dose that inhibited acid secretion.
When parietal cells are stimulated by gastric secretagogues, the activated acid
pump is expressed on the apical secretory canaliculi (20—22). It is reasonable
that both omeprazole and leminoprazole inhibited the activated acid pump
following histamine infusion. Certainly, there is a possibility that the drugs
penetrated into the oxyntic gland area and exerted an effect on the acid pumps
by entering into the parietal cells from the basolateral membrane, similar to the
effect derived from delivery by oral or intravenous routes.
Fig. 13. Schematic drawing for the site of action of the drugs that inhibit the acid secretory function of
parietal cells via basolateral membrane (receptors), the acid pump, and the apical membrane (receptors?).
It must also be noted that omeprazole has not been found to stimulate gastric
and duodenal bicarbonate secretion in rats and dogs (16, 23). We have also
demonstrated that leminoprazole and omeprazole exert no effect on bicarbonate
secretion upon local application to the gastric mucosal surface of rats (24).
Indeed, we have confirmed that upon local application of leminoprazole, the
drug failed to stimulate gastric bicarbonate secretion in dogs. Accordingly, it
becomes easy to eliminate the hypothesis that reduced gastric acid secretion
observed following local application of acid pump inhibitors is due to
neutralization of secreted acid by stimulated bicarbonate secretion. Furthermore,
Larson et al. (8) and Konturek et al. (16) have both found that omeprazole failed
to exert an effect on the circulation of the gastric mucosa of dogs.
We have also confirmed findings revealed by Nicol et al. (13) and Curwain
et al. (14, 15) that locally applied FPL 52694 significantly inhibited gastric
acid secretion stimulated by histamine, pentagastrin, and carbachol in dogs. In
contrast to the results following application of omeprazole and leminoprazole,
we found that FPL 52694 failed to exert an inhibitory effect on acid pumps
(unpublished data). Indeed, as demonstrated in the present study, FPL 52694
exerted no effect on acid secretion following either intravenous or oral
administration. Such results strongly suggest that the antisecretory effect of the
drug is solely explained by a local effect, rather than a systemic effect. In
addition, we demonstrated that the local antisecretory effect persisted for more
than 4 hr after application, yet disappeared following 9 hr. Such a result
suggests that the local effect on parietal cells is reversible.
As previously reported (25), we discovered that ME 3407 possesses a strong
inhibitory effect on acid secretion, even at doses of only 1 to 3 mg/pouch and even
after only a 15 min application to the pouches. It is even more interesting that the
antisecretory effect persisted for more than 5 hr. Nonetheless, the underlying
mechanism remains unknown. Similar to FPL 52694, ME 3407 failed to exert an
effect when orally or intravenously administered, thus suggesting that the drug
exerts its effect on parietal cells from the mucosal side of the parietal cells.
Urushidani et al. (26) reported that ME 3407 significantly enhanced the
healing of acetic acid-induced gastric ulcers in rats, by probably exacting a
potent antisecretory effect that did not inhibit the acid pump. Urushidani
further demonstrated that the inhibitory effect of ME 3407 on gastric acid
secretion was more potent when orally administered than when subcutaneously
or intraperitoneally administered. Citing our report (25), Urushidani et al. (26)
also concluded that ME 3407 directly acts on the mucosa to inhibit acid
secretion. In addition, using isolated rabbit gastric glands, Urushidani et al.
demonstrated that ME 3407 inhibited acid secretion not only by preventing
stimulation-associated redistribution of H+, K+-ATPase from microsomes into
the apical plasma membranes, but also by delocalizing ezrin from the apical
membrane. Should their findings be applicable to our study, the conclusion
could be drawn that ME 3407 exerts its local antisecretory effect through both
inhibition of redistribution of the acid pump and delocalization of ezrin
following penetration into the parietal cells from the mucosal side. Since ME
3407 resulted in no inhibitory effect after intravenous administration,
penetration of the drug into parietal cell cytoplasm to exert its effect must
occur from the apical membrane side, quite possibly from the apical secretory
canaliculi. Certainly, there also exists the possibility that ME 3407 directly acts
on apical secretory canaliculi without penetrating into parietal cell cytoplasma.
Agnew et al. (22), using cultured rabbit parietal cells, also provided
evidence that ME 3407 is able to prevent histamine (+isomethylxanthine)-
-stimulated acid secretion. Agnew contends that the underlying mechanism
follows from prevention of translocation of H+,K+-ATPase-rich tubulovesicles
to apical membrane vacuoles and dissociation of ezrin from the putative
cytoskeletal–membrane functional site. Similar to Urushidani et al. (26),
however, Agnew et al. did not describe whether or not ME 3407 penetrated
into the parietal cells to exert its effect or directly acted on the apical secretory
canaliculi render prevention of the secretion-activation cascade. Clarification of
the action of ME 3407 on apical secretory canaliculi represents an important
step towards elucidation of the mechanism for acid secretion from the apical
In regards to gastric integrity following local application of drugs, we have
confirmed that acid loss from the gastric lumen following local application of
leminoprazole and omeprazole does not differ from controls. Should
leminoprazole injure the gastric mucosa to result in a reduced acid output, then
the drug should also inhibit acid secretion when administered prior to histamine
infusion. Accordingly, the possibility that gastric acid secreted into the pouch
might diffuse back into the mucosa through the damaged mucosal barrier in
response to local application of the drugs is eliminated. As was previously
described, leminoprazole failed to exhibit an antisecretory effect on local
application prior to histamine infusion. Furthermore, histological studies have
demonstrated that leminoprazole does not result in injurious effects on the
gastric mucosa. In consideration of the above, it would appear that
leminoprazole locally penetrates into the oxyntic mucosa to inhibit gastric acid
secretion without entering the systemic circulation and without affecting
bicarbonate secretion, mucosal blood flow, or mucosal integrity.
We have also previously demonstrated that 2 kinds of acid-stable local
anesthetics, namely tetracaine and ethyl-4-aminobenzoate, exerted no inhibitory
activity following local applications at concentrations similar to those used in
clinical settings. Consequently, the hypothesis that FPL 52694 and ME 3407
inhibit parietal cells by a local anesthetic effect is easily eliminated.
As was expected, we confirmed in denervated dogs that three H2R-blockers,
i.e. cimetidine, ranitidine, and famotidine, either orally or intravenously
administered, markedly suppressed gastric acid secretion irrespective of the
stimulant used. Nonetheless, we were unable to confirm the local antisecretory
effect of H2-blockers, to include ranitidine, following 30 min administration
into the pouches 1 hr after starting intravenous histamine infusion. Such results
suggest that H2-blockers not only cannot reach the receptors on the basolateral
membrane of parietal cells from the mucosal surface, but also cannot be
absorbed from the gastric mucosa into the circulation.
It is of interest that Konturek et al. (12) reported that locally applied
histamine in denervated pouches of dogs resulted in a dose-dependent increase
in acid secretion, without affecting acid secretion in the main stomach. It
remains uncertain whether or not locally administered histamine stimulated the
parietal cells through the apical membrane. It remains likely that trace
histamine absorption from the gastric mucosa might have stimulated
H2-receptors on the basolateral membrane, even if the serum histamine
concentration was not elevated to detectable levels. In contrast to our results,
Konturek et al. (12) found that locally applied ranitidine significantly inhibited
gastric acid secretion stimulated by both locally and intravenously administered
histamine, without increasing the serum ranitidine level. Accordingly, Konturek
suggested that, in addition to the established systemic effect, ranitidine might
also inhibit gastric acid secretion via interaction with the mucosal membrane.
We remain unable to convincingly explain the disparity between our results
and those obtained by Konturek, despite the fact that the ranitidine dose (5 to
10 mg/ml, i.e., approximately 150 to 300 mg/pouch) was equal to or double
our dose. The difference might be due to the variation in either the histamine
dosage (80 ?g/kg/hr in Konturek’s study vs. 160 ?g/kg/hr in our study) and/or
the method of local application (infusion in Konturek’s study vs. single
application in our study).
Similar results were observed in the case of pirenzepine, an M1-receptor
antagonist; i.e. the drug exerted no effect on gastric acid secretion when
administered into the pouches for 30 min. Such a finding also suggests that
pirenzepine, localized to the mucosal surfacee, was unable to interact with
M1-receptors, which are believed to exist on ECL cells.
In summary, such findings suggest that omeprazole, leminoprazole, FPL
52694, and ME 3407 directly suppress the function of parietal cells on the
luminal surface, resulting in a reduction of acid secretion. Regardless of the
precise mechanism for a local antisecretory effect, such drugs represent a new
armamentarium that targets the apical membrane of parietal cells to control
gastric acid secretion in the treatment of acid-related diseases. Moreover, such
drugs will no doubt prove useful in the study of the function of parietal cells,
particularly in elucidating the role of the apical membrane.
In recent years, most of the genes for the expression of the above receptors
or related enzymes involved in acid secretion have been cloned, offering the