Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202
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ABSTRACT |
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Our previous report showed gastric mucosal surface pH was determined by alkali secretion at intragastric luminal pH 3 but by acid secretion at intragastric pH 5. Here, we question whether regulation of mucosal surface pH is due to the effect of luminal pH on net acid/base secretions of the whole stomach. Anesthetized rats with a gastric cannula were used, the stomach lumen was perfused with weakly buffered saline, and gastric secretion was detected in the gastric effluent with 1) a flow-through pH electrode and 2) a fluorescent pH-sensitive dye (Cl-NERF). During pH 5 luminal perfusion, both pH sensors reported the gastric effluent was acidic (pH 4.79). After perfusion was stopped transiently (stop-flow), net acid accumulation was observed in the effluent when perfusion was restarted (peak change to pH 4.1-4.3). During pH 3 luminal perfusion, both pH sensors reported gastric effluent was close to perfusate pH (3.0-3.1), but net alkali accumulation was detected at both pH sensors after stop-flow (peak pH 3.3). Buffering capacity of gastric effluents was used to calculate net acid/alkaline secretions. Omeprazole blocked acid secretion during pH 5 perfusion and amplified net alkali secretion during pH 3 perfusion. Pentagastrin elicited net acid secretion under both luminal pH conditions, an effect antagonized by somatostatin. We conclude that in the basal condition, the rat stomach was acid secretory at luminal pH 5 but alkaline secretory at luminal pH 3.
fluorescence; Cl-NERF; in vivo; pH electrode; bicarbonate secretion; fasting stomach; fed stomach
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INTRODUCTION |
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THE STOMACH IS WIDELY KNOWN for its role in acid secretion (18) and the responsiveness of the regulatory cascades to intraluminal pH. Changes in intragastric pH are an important signal regulating acid secretion during a meal (5, 7, 8, 14, 21, 35, 36). Gastrin secretion is activated by the presence of food buffers and high luminal pH in the stomach (4, 9, 21, 35-37). Conversely, plasma gastrin concentrations decrease during fasting because of low pH values in the stomach lumen (9, 22, 38). In addition, somatostatin secretion is stimulated by a decrease in gastric luminal pH (4, 17, 22, 27-29, 37, 38). The reciprocal relationship between gastrin and somatostatin secretion, as seen in the fasted and fed states, is one of the major endocrine cycles regulating acid secretion (4, 37, 38).
Much less is known about the regulation of alkaline secretion by the stomach. Since the beginning of the last century, as originally shown by the Danish physiologist Schierbeck (1), it has been recognized tht the stomach secretes alkali. Although Teorell (34) proposed that loss of acidity from the lumen was due to back-diffusion of hydrochloric acid into the tissue, Hollander (20) first differentiated the gastric secretions as parietal and nonparietal secretions. Later, this nonparietal secretion was identified as bicarbonate secretion (1, 23, 24). Investigators have indirectly or directly measured alkali secretion by the stomach, and different methods have been developed for this purpose (1, 6, 10, 13, 16, 20, 26). One report (25) suggests that alkali secretion is greater when intragastric pH is more acidic. This and numerous in vitro (11, 13, 32) and in vivo (10, 15, 16, 19, 24, 26, 30, 31) investigations helped to develop the concept that gastric alkali secretion protects the gastric mucosal surface from high proton concentration.
Gastric alkali secretion has been studied much less than acid secretion. The major issue is that secreted alkali can be neutralized by acid in the lumen (1), making the alkali secretion difficult to detect and quantify. In most reports, acid and alkali secretion could not be studied in parallel because acid secretion had to be pharmacologically suppressed with H2 receptor antagonists (11, 12, 16, 26, 31, 32) or proton pump inhibitors (33) to "unmask" any alkali secretion.
In previous studies, we used confocal microscopy to record the influence of gastric secretions on pH directly at the gastric mucosal surface. We demonstrated that changing gastric luminal pH from 3 to 5 caused a switch between net alkali and net acid secretion dominating control of surface pH, respectively (6). The results raised the controversial suggestion that at the fasted intragastric pH (pH 3), net alkali secretion occurred in the rat stomach, even in the absence of pharmacological inhibition of acid secretion. However, this conclusion was based on studies directly at the gastric surface and could only tentatively be extrapolated to secretions by the whole stomach.
In this study, we directly address this controversy by reporting on the dynamic balance between acid and alkali secretion in the whole stomach. With in vivo perfusion of intact rat stomach, we use two independent measures of pH (via a fluorescent indicator and pH electrode) to compare gastric acid/base secretions in response to the values of luminal pH seen in the fasted and fed stomach.
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METHODS |
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Animals. All experimental procedures were approved by the Animal Care and Use Committee of Indiana University. Male Sprague-Dawley rats (Harlan Sprague Dawley) were used for the experiments. Animals were housed individually in cages with raised mesh floors to prevent coprophagia. Animals were deprived of food for 18-20 h before experimental use but had free access to water at all times.
Surgery. For experiments, rats (250-300 g) were anesthetized with Inactin (100 mg/kg ip). A tracheal tube was inserted to facilitate breathing. The right jugular vein was cannulated with one or two catheters, and heparinized saline (150 mM NaCl and 3 IU/ml heparin) was continuously infused throughout the experiment at a total rate of 1 ml/h with a syringe pump (KDS 200, KD Scientific, New Hope, PA). The infusion lines were used as the route for intravenous administration of saline or drugs.
After a cauterized midline incision (model 100, Geiger Medical Technologies, Monarch Beach, CA) was made, the stomach was cannulated to permit continuous perfusion of the gastric lumen. The inlet tubing was routed through the esophagus and ligated at the cervical level. CO2-impermeable outlet tubing (OD, 3.28 mm; ID, 1.79 mm; Saran, Chicago, IL) was ligated at the terminal pylorus, routed through the duodenum, and exteriorized via a small lateral incision in the abdomen. After abdominal surgery was completed, the stomach was returned to its correct anatomical position, all surgical incisions were closed as much as possible, and the luminal perfusion was started (see Gastric perfusion). Abdominal wounds were covered with moistened surgical cotton to minimize dehydration. Body temperature of the surgically prepared animal was monitored by rectal thermometer (YSI, Yellow Springs, CO) and maintained at 36.5-37.0°C by a 50-W lamp. Surgically prepared animals were allowed to stabilize for 2-3 h before being used in experiments.Gastric perfusion. The stomach lumen was perfused at 0.7 ml/min (33) with a syringe pump (KDS 260). In all experiments, stomach distension was avoided, and results were not accepted if the stomach became distended during the experiment (e.g., due to perfusion blockage). Perfusates contained 150 mM NaCl, 4 mM HOMOPIPES, and 0.1 µM Cl-NERF (a pH-sensitive fluorescent dye; Molecular Probes, Eugene, OR). Perfusates were titrated to either pH 5 or pH 3 before use to approximate the physiological luminal pH measured in fed or fasted rat stomach, respectively (6). Gastric perfusion was run continuously except for defined periods in which perfusion was stopped transiently for 10 min. This "stop-flow" interval allowed intragastric accumulation of acid/alkaline secretions and thereby amplified observed changes in perfusate pH. These enhanced changes in perfusate pH were detected when perfusion was restarted and the gastric contents flowed past the downstream pH sensors (see Gastric acid/base secretion).
Gastric acid/base secretion.
As shown schematically in Fig. 1, gastric
perfusion effluent was sequentially routed past an inline reference and
pH electrode (Microelectrodes, Bedford, NH) and into a flow-through
cuvette placed in a fluorometer (Fluorolog-3, JY Horiba/SPEX, Edison, NJ). A pH meter (Orion 720A, Orion Research, Beverly, MA) passed the
pH-sensitive electrode signal to the host computer that controlled the
fluorometer. After the animal stabilization period, data from both
detectors were automatically and simultaneously recorded by the
fluorometer host computer every 10 s. The pH electrode was
calibrated by conventional pH standards flowed past the inline electrode at the same rates used during experimental measurements.
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Chemicals. The drugs used were thiobutabarbital sodium salt (Inactin, RBI, Natick, MA), pentagastrin and somatostatin (Sigma, St. Louis, MO), HOMOPIPES (Research Organic, Cleveland, OH), and omeprazole.
Pentagastrin was first dissolved in absolute ethanol and then diluted with saline to a desired concentration (final ethanol concentration <0.1%). Omeprazole was suspended at 28 mM in 0.5% (wt/vol) carboxymethycellulose:water. Somatostatin (30 µM) was dissolved in 0.9% NaCl plus 1 mg/ml of BSA. Other agents were dissolved in distilled water. All agents were solubilized immediately before use. Routes of administration were intravenous infusion in a volume of 1 ml/h, intraperitoneal in a volume of 0.5 ml/100 g body wt, or intraluminal at a rate of 0.7 ml/min.Statistics. Data are presented as means ± SE from 4-8 rats/group. Statistical comparisons between two groups were made with an unpaired two-tailed Student's t-test. Statistical comparisons between groups used one-way ANOVA followed by Dunnett's multiple comparison test. P < 0.05 was considered significant.
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RESULTS |
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As shown schematically in Fig. 1, our goal was to perfuse the stomachs of anesthetized rats with solutions of either pH 5 or pH 3 (6) and monitor pH in the gastric effluent to measure net gastric acid/base secretion. Perfusion solutions were weakly buffered (4 mM HOMOPIPES, pKa = 4.32) and contained the pH-sensitive fluorescent dye Cl-NERF (0.1 µM). We used weakly buffered solutions to prevent sudden pH excursions during basal luminal perfusion. During our early trials we had observed that when the solution was not buffered, there were changes in gastric effluent pH under steady-state perfusion. We chose a concentration of buffer that did not affect the secreting capability of the stomach under basal and stimulated conditions (data not shown). We first compared the response of the electrode and optical pH sensors when measuring perfusion effluents from the gastric lumen in vivo, as described in METHODS.
Figure 3 shows recordings from a
representative experiment in which pH was recorded in parallel by the
two methods during luminal pH 5 perfusion. The two methods reported
identical pH changes when gastric acid secretion was stimulated by
pentagastrin and then blocked by somatostatin.
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Large changes in secretory status could be readily detected as pH
changes during continuous perfusion (as in Fig. 3), but it was more
difficult to be confident about baseline values of secretion before the
addition of regulatory agonists. This was because the value of gastric
effluent pH was too close to that of the original perfusate pH to
reliably detect the pH change. Therefore, we developed a scheme to
increase sensitivity for detecting lower secretory states. Our approach
was to impose a transient halt in perfusion (stop-flow period) and then
measure pH after restarting the perfusion. The stop-flow period allowed
the stomach secretions to transiently accumulate in the lumen. The
amplified pH change was subsequently detected by the pH sensors
(downstream of the stomach) after perfusion was restarted. Figure
4 shows a representative experiment as an
example of the response of the pH sensors during steady-state gastric
perfusion at luminal pH 5 before stop-flow, during stop-flow, and after
perfusion flow was restarted. Both optical and electrode techniques
reported a transient acidic peak after stop-flow, qualitatively
indicating net acid secretion under basal conditions. Because of the
physical arrangement of the two flow-through pH sensors in the
perfusion stream, there was a 1-min time delay between pH electrode and fluorescence measurements, which is evident in these fast time recordings. The ~200 µl volume of the fluorometer cuvette caused a
relatively slow renewal of the cuvette chamber and blunted the magnitude of pH transients compared with the pH electrode that was
simply inserted into the perfusion tubing inline. While perfusion flow
was halted, the pH electrode reading significantly increased from pH
4.79 ± 0.02 (steady-state pH value during continuous luminal pH 5 perfusion) to pH 4.88 ± 0.01 (P = 0.0054). In
contrast, Cl-NERF gave similar pH values during either perfusion
(4.79 ± 0.04) or stop-flow (4.76 ± 0.02; P =
0.26). The small drift in pH electrode readings appeared to be a flow
artifact that did not compromise the experimental observations but made
it necessary for all measurements to be made under similar flow
conditions. Despite these technical limitations, both the
Cl-NERF ratio and the pH electrode could be used to sensitively detect
the amplified pH changes revealed by stop-flow.
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Comparison of gastric response to luminal pH 5 vs. luminal pH 3.
During luminal pH 5 perfusion, the pH electrode reported a basal
steady-state pH in the gastric effluent of 4.79 ± 0.02 (P = 0.00014 vs. fresh solution; n = 8 animals; Fig.
5). For comparison, the pH of fresh
solution (without exposure to the stomach) was reported as 5.01 ± 0.01 when flowed past the pH electrode. The pH electrode reported a
transient acidification after stop-flow (peak pH after stop-flow
4.08 ± 0.19; P = 0.0069 vs. basal steady-state pH).
These results both suggest the presence of net acid secretion under
these conditions, as is also suggested in the representative experiment
shown in Fig. 4.
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Blocking the H,K-ATPase.
Detection of gastric alkali secretion has often required
pharmacological inhibition of acid secretion (1, 33);
therefore, we asked if a H,K-ATPase inhibitor (omeprazole) would unmask
greater net alkali secretion. During perfusion with luminal pH 5 (Fig. 7), the addition of omeprazole
alkalinized the gastric effluent (pH 5.03 ± 0.03; P =
0.0025 vs. basal steady-state pH in preomeprazole state) and prevented
the acidic peak observed after stop-flow (peak pH 5.34 ± 0.16).
In the presence of omeprazole, the peak pH after stop-flow was not
statistically different from the steady-state pH during continuous
perfusion (P = 0.0983). Thus although there was a trend
towards alkalinization, stop-flow could not confirm or deny the
presence of alkali secretion in the omeprazole-treated rats at luminal
pH 5. At luminal pH 3 (Fig. 8),
omeprazole significantly alkalinized steady-state pH during perfusion
(3.08 ± 0.02; P = 0.00445 vs. basal steady-state pH in
preomeprazole state), and a significant alkalinization was observed
after stop-flow (peak pH 4.02 ± 0.27; P = 0.0229 vs. postomeprazole steady-state perfusion pH). These results are
consistent with previous observations of net alkali secretion during
suppression of acid secretion and confirm that elimination of acid
secretion leads to greater net alkali secretion.
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Somatostatin blocks pentagastrin-stimulated gastric acid secretion. During either pH 5 or pH 3 perfusion, pentagastrin stimulated gastric acid secretion, as reported by the pH values, either during perfusion or after stop-flow (Figs. 7 and 8). At pH 3 (Fig. 8), addition of pentagastrin converted the net alkali secretion observed in basal conditions to a net acidic secretion.
Somatostatin inhibited the pentagastrin-stimulated gastric acid secretion during both pH 5 and pH 3 luminal perfusion (Figs. 7 and 8). The addition of somatostatin alone decreased net acid secretion at luminal pH 5 (Fig. 7) but did not modify the observed alkali secretion at luminal pH 3 (Fig. 8).Net proton secretion or consumption.
If the buffering capacity of gastric effluent is known, changes in pH
can be converted to amounts of secreted acid/base equivalents. As shown
in Fig. 9, titration of either fresh
perfusate solution or gastric effluents produced identical buffering
capacity curves. This demonstrates that gastric secretions do not alter
the buffering capacity of the solution and permits reliable estimation
of titratable acid/base equivalents added to the effluent. The small
hump in buffering capacity values at pH 4 is a result of the presence of HOMOPIPES buffer in the solution (data not shown). Results were fit
to an eighth-order polynomial (Fig. 9), and this equation was used to
derive values of net protons produced (or consumed) in the lumen.
Proton consumption is equivalent to net alkali secretion.
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Bicarbonate secretion as basis for net alkali secretion. To determine whether the alkalinization was due to acid-back diffusion or bicarbonate secretion, total CO2 content (in mM) of the gastric effluent was measured before and after the stop-flow period. The total CO2 concentration during steady-state perfusion was 2.23 ± 0.06 mM and increased to 2.38 ± 0.09 mM (stop-flow caused the appearance of an additional 0.15 ± 0.03 mM CO2; P < 0.01). For comparison, we used the buffering capacity to calculate the change in hydrogen ion concentration under the same conditions. Stop-flow caused consumption of an additional 0.16 ± 0.03 mM protons (P < 0.01), a value indistinguishable from the amount of added CO2. Because any secreted bicarbonate would be converted to CO2 (with obligatory consumption of a proton) at the prevailing pH of these experiments, these results strongly suggest that the alkalinization observed at pH 3 is quantitatively explained by bicarbonate secretion. The increased total CO2 content is more difficult to explain if acid-back diffusion was the predominant mechanism leading to luminal alkalinization.
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DISCUSSION |
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This report introduces the feasibility and benefits of combining optical and electrode measurements for the dynamic study of gastric secretions by the whole stomach in vivo. During continuous perfusion of the stomach lumen, we used two different pH measurement techniques to validate observed pH changes. Due to technical constraints, Cl-NERF pH measurements did not give exactly the same kinetic responses as pH electrode measurements. However, both measurements qualitatively and quantitatively reported similar pH changes. The consistency of results between Cl-NERF and the pH electrode supports the validity of our previous use of Cl-NERF in studies of gastric surface pH (6). Furthermore, the buffering capacity of gastric effluent remained the same as that of fresh perfusate, allowing accurate calculation of the amount of net proton secretion into the perfusate by the tissue.
Previously, we demonstrated (6) that either acid secretion or alkali secretion could dominate control of pH in the microscopic regions adjacent to the gastric surface. We further showed that luminal pH of the stomach regulated the conversion between these two states. In both that study and the current work, we compared results when luminal pH approximated values found in the fasting (pH 3) or fed stomach (pH 5) of rats. The current work was designed to extend the previous measurements of pH regulation in microenvironments to the regulation of acid/base secretion by the whole stomach.
Our results show that in response to changes in luminal pH, the stomach converts from net acid to net alkali secretion. To balance this unusual finding, our results confirmed that more conventional aspects of the regulation of acid secretion remained intact. During intraluminal perfusion with a pH 5 solution (to mimic the pH of the fed rat stomach), gastric acid secretion was observed. As expected from the known properties of the gastric H,K-ATPase, this acid secretion could be stimulated further with pentagastrin and inhibited by omeprazole or somatostatin. In contrast, during intraluminal perfusion with pH 3 solution (to mimic the pH of the fasted stomach), net alkaline secretion dominated over acid secretion. This was most evident when secreted alkali was allowed to accumulate in the gastric lumen during a stop-flow period, so that pH changes in the gastric effluent were more pronounced. Under both luminal pH 5 or pH 3 conditions, the accumulation of acid/base secretions in the lumen can always initiate feedback regulatory mechanisms in control of gastric secretions. These feedback mechanisms can be more noticeable, especially in pentagastrin-stimulated conditions when the luminal pH becomes very acidic. However, observing the same pH values before and shortly after the stop-flow period convinced us that the short period of stopping the perfusion may not trigger those feedback mechanisms. Nevertheless, further experiments related to these short-term regulatory mechanisms could be performed. Different experimental conditions and our preliminary observations showed us that the conversion of whole stomach from acid to alkali secretory status or vice versa did not occur in such a short period of time.
The observed gastric effluent pH changes at luminal pH 3 were not due to back-diffusion of acid. Total CO2 measurements of gastric effluent confirmed that the pH changes in the gastric effluent were likely a result of bicarbonate secretion into the lumen. Pentagastrin, when added, was able to reverse the gastric secretions to net acid secretory, and omeprazole enhanced the net alkali secretion under basal conditions (presumably by blocking low basal acid secretion in these conditions). These results show the existence of steady-state gastric alkali secretion in the presence of lower intragastric pH and show that even in the absence of pharmacological suppression of H,K-ATPase, this alkali secretion is greater than acid secretion.
When pH changes were converted to amount of secreted protons, it was possible to quantitatively compare results between pH 3 and pH 5 perfusion. Exogenous pentagastrin stimulated net proton secretion during both pH 3 or pH 5 perfusion. However, the resulting acid secretion (measured as the peak pH change after stop-flow) was fourfold higher at luminal pH 5 compared with luminal secretion at pH 3. Even taking into account the amount of basal acid/base secretion under these two conditions or the alkali secretion unmasked by omeprazole, the results suggest that the ability of pentagastrin to stimulate acid secretion is limited at the lower intragastric pH. Conversely, in the presence of omeprazole, the net alkali secretion at pH 3 was sixfold greater than that at pH 5. This is consistent with an earlier report that gastric alkali secretion may be enhanced at lower intragastric pH (25). Somatostatin infusion antagonized the effect of pentagastrin on acid secretion, but somatostatin did not elicit significant net alkali secretion when added in either the presence or absence of pentagastrin. Most notably, at luminal pH 3, somatostatin alone had no effect on net alkali secretion. Because omeprazole unmasked greater alkali secretion under this same condition, the results suggest that somatostatin has an inhibitory effect on alkali secretion and/or (like pentagastrin) has limited ability to act at luminal pH 3. Further studies are needed to resolve these questions.
In conclusion, our results show that pH is a luminal signal regulating the dynamic physiological transition between acid and alkali secretion in the stomach. Although the intragastric proton concentration regulates this transition, other mediators such as gastrin and somatostatin likely play a role as downstream effectors. It will be important to determine the role of these and other endocrine and neurocrine regulators in the feedback mechanisms that control the transition between acid and alkali secretion. Our results are consistent with the previous observation that gastric surface pH can be regulated by either acid or alkali secretion during exposure to pH 5 or pH 3, respectively. The current report finds that net acid/base secretions measured in the microscopic space adjacent to the gastric surface mirrors net secretion observed at the level of the whole stomach. This strongly suggests that, at least under some circumstances, surface pH regulation is an extension and not an opponent of the dominant gastric secretions.
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ACKNOWLEDGEMENTS |
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We thank J. D. Kaunitz (University of California at Los Angeles/CURE, Los Angeles, CA) for the gift of omeprazole.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. H. Montrose, Indiana Univ. School of Medicine, Dept. of Cellular and Integrative Physiology, Med Sci 307, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (E-mail: mmontros{at}iupui.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.
Received 29 March 2001; accepted in final form 6 June 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Allen, A,
Flemström G,
Garner A,
and
Kivilaakso E.
Gastroduodenal mucosal protection.
Physiol Rev
73:
823-857,
1993
2.
Allen, J,
Bishop A,
Daly M,
Larsson H,
Carlsson E,
Polak J,
and
Bloom S.
Effect of inhibition of acid secretion on the regulatory peptides in the rat stomach.
Gastroenterology
90:
970-977,
1986[ISI][Medline].
3.
Aurang, K,
Wang J,
and
Lloyd K.
Somatostatin inhibition of acid and histamine release by activation of somatostatin receptor subtype 2 receptors in rats.
J Pharmacol Exp Ther
281:
245-252,
1997
4.
Brand, S,
and
Stone D.
Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria.
J Clin Invest
82:
1059-1066,
1988[ISI][Medline].
5.
Carter, D,
and
Grossman M.
Effect of luminal pH on acid secretion from Heidenhain pouches evoked by topical and parenteral stimulants.
J Physiol (Lond)
281:
227-237,
1978[ISI][Medline].
6.
Chu, S,
Tanaka S,
Kaunitz J,
and
Montrose M.
Dynamic regulation of gastric surface pH by luminal pH.
J Clin Invest
103:
605-612,
1999
7.
Cieszkowski, M,
Konturek S,
Obtulowicz W,
and
Tasler J.
Chemical stimulatory mechanism in gastric secretion.
J Physiol (Lond)
246:
143-157,
1975[Abstract].
8.
Debas, H,
and
Grossman M.
Chemicals bathing the oxyntic gland area stimulate acid secretion in dog.
Gastroenterology
69:
654-659,
1975[ISI][Medline].
9.
Dimaline, R,
Evans D,
Varro A,
and
Dockray G.
Reversal by omeprazole of the depression of gastrin cell function by fasting in the rat.
J Physiol (Lond)
433:
483-493,
1991[Abstract].
10.
Feldman, M.
Gastric bicarbonate secretion in humans: effect of pentagastrin, bethanechol, and 11,16,16-trimethyl prostaglandin E2.
J Clin Invest
72:
295-303,
1983[ISI][Medline].
11.
Flemström, G.
Active alkalinization by amphibian gastric fundic mucosa in vitro.
Am J Physiol Endocrinol Metab Gastrointest Physiol
233:
E1-E12,
1977
12.
Flemström, G,
Heylings J,
and
Garner A.
Gastric and duodenal HCO
13.
Flemström, G,
and
Sachs TG.
Ion transport by amphibian antrum in vitro. I. General characteristics.
Am J Physiol
228:
1188-1198,
1975[ISI][Medline].
14.
Fordtran, J,
and
Walsh J.
Gastric acid secretion rate and buffer content of the stomach after eating: results in normal subjects and in patients with duodenal ulcer.
J Clin Invest
52:
645-657,
1973[ISI][Medline].
15.
Forssell, H,
and
Olbe L.
Continuous computerized determination of gastric bicarbonate secretion in man.
Scand J Gastroenterol
20:
767-774,
1985[ISI][Medline].
16.
Garner, A,
and
Flemström G.
Gastric HCO
17.
Greenberg, G,
Fung L,
and
Pokol-Daniel S.
Regulation of somatostatin-14 and -28 secretion by gastric acid in dogs: differential role of cholecystokinin.
Gastroenterology
105:
1387-1395,
1993[ISI][Medline].
18.
Hersey, S,
and
Sachs G.
Gastric acid secretion.
Physiol Rev
75:
155-189,
1995
19.
Hollander, F.
Studies in gastric secretion. IV. Variations in the chlorine content of gastric juice and its significance.
J Biol Chem
97:
585-604,
1932
20.
Hollander, F.
The two-component mucous barrier.
Arch Intern Med
93:
107-120,
1954.
21.
Konturek, S,
Biernat J,
and
Oleksy J.
Serum gastrin and gastric acid responses to meals at various pH levels in man.
Gut
15:
526-530,
1974[ISI][Medline].
22.
Koop, H,
Schwab E,
Arnold R,
and
Creutzfeldt W.
Effect of food deprivation on rat gastric somatostatin and gastrin release.
Gastroenterology
82:
871-876,
1982[ISI][Medline].
23.
Lindner, A,
Cohen N,
Dreiling D,
and
Janowitz H.
Electrolyte changes in the stomach following instillation of acid solutions.
Clin Sci
25:
195-205,
1963[ISI].
24.
Makhlouf, G,
McManus J,
and
Card W.
A quantitative statement of the two-component hypothesis of gastric secretion.
Gastroenterology
51:
149-171,
1966[ISI][Medline].
25.
Matsueda, K,
Muraoka A,
Umeda N,
Misaki N,
Uchida M,
and
Kawano O.
Effect of the luminal hydrogen ion on alkali and mucus secretion in the rat stomach.
Scand J Gastroenterol Suppl
162:
35-38,
1989.
26.
Rees, W,
Botham D,
and
Turnberg L.
A demonstration of bicarbonate production by the normal human stomach in vivo.
Dig Dis Sci
27:
961-966,
1982[ISI][Medline].
27.
Sandvik, A,
Dimaline R,
Forster E,
Evans D,
and
Dockray G.
Differential control of somatostatin messenger RNA in rat gastric corpus and antrum: role of acid, food, and capsaicin-sensitive afferent neurons.
J Clin Invest
91:
244-250,
1993[ISI][Medline].
28.
Schubert, M,
Edwards N,
and
Makhlouf G.
Regulation of gastric somatostatin secretion in the mouse by luminal acidity: a local feedback mechanism.
Gastroenterology
94:
317-322,
1988[ISI][Medline].
29.
Schusdziarra, V,
Harris V,
Conlon J,
and
Arimura A.
Pancreatic and gastric somatostatin release in response to intragastric and intraduodenal nutrients and HCl in the dog.
J Clin Invest
62:
509-518,
1978[ISI][Medline].
30.
Silvis, S,
and
Doscherholmen A.
Production of bicarbonate by the human stomach.
Am J Gastroenterol
58:
138-144,
1972[ISI][Medline].
31.
Smeaton, L,
Hirst B,
Allen A,
and
Garner A.
Gastric and duodenal HCO
32.
Takeuchi, K,
Merhav A,
and
Silen W.
Mechanism of luminal alkalinization by bullfrog fundic mucosa.
Am J Physiol Gastrointest Liver Physiol
243:
G377-G388,
1982
33.
Takeuchi, K,
Ueshima K,
and
Okabe S.
Stimulation of gastric bicarbonate secretion by the analog of thyrotropin-releasing hormone, YM-14673, in the rat.
J Pharmacol Exp Ther
256:
1057-1062,
1991[Abstract].
34.
Teorell, T.
Electrolyte diffusion in relation to the acidity regulation of gastric juice.
Gastroenterology
9:
425-443,
1947[ISI].
35.
Thompson, J,
and
Swierczek J.
Acid and endocrine responses to meals varying in pH in normal and duodenal ulcer subjects.
Ann Surg
186:
541-548,
1977[ISI][Medline].
36.
Walsh, J,
Richardson C,
and
Fordtran J.
pH dependence of acid secretion and gastrin release in normal and ulcer subjects.
J Clin Invest
55:
462-468,
1975[ISI][Medline].
37.
Wu, S,
Giraud A,
Mogard M,
Sumii K,
and
Walsh J.
Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats.
Am J Physiol Gastrointest Liver Physiol
258:
G788-G793,
1990
38.
Wu, V,
Sumii K,
Tari A,
Sumii M,
and
Walsh J.
Regulation of antral gastrin and somatostatin gene expression during starvation and after refeeding.
Gastroenterology
101:
1552-1558,
1991[ISI][Medline].