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Alkaline secretion by frog gastric glands measured with pH microelectrodes in the gland lumen

Lucantonio Debellis, Rosa Caroppo, Eberhard Frömter * and Silvana Curci

Received 5 March 1998; accepted after revision 5 August 1998.

	ABSTRACT

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1. In the present work we have measured the pH of the secreted fluid within the gland lumen of isolated but intact gastric mucosa of Rana esculenta. Tissues were mounted in a double chamber allowing continuous perfusion of the mucosal and serosal compartment, and the measurements were made with double-barrelled pH glass microelectrodes inserted into the glands from the serosal surface under microscopic inspection.

2. During inhibition of H⁺ secretion by cimetidine (100 µM) the luminal gland pH (pH_gl) averaged 7·60 ± 0·05 pH units (mean ± s.e.m.; n = 35), a value significantly higher than bath solution pH (7·45 ± 0·02; P < 0·001) and also higher than intracellular pH of oxyntopeptic cells (pH_i), which averaged 7·53 ± 0·06 (n = 18).

3. Stimulation of acid secretion with histamine (500 µM) reversibly decreased pH_gl to values which could be as low as 2·5. Together with electrophysiological criteria this response was routinely used to verify the proper location of the microelectrode tip within the gland lumen.

4. Stimulation with carbachol (100 µM) or pentagastrin (50 µM) in the presence of cimetidine rapidly and reversibly increased pH_gl by 0·10 ± 0·01 pH units (n = 24; P < 0·001) and 0·09 ± 0·02 pH units (n = 6; P < 0·05), respectively.

5. The observation that gastric gland fluid is more alkaline than the bath solutions and that carbachol or pentagastrin further alkalinize it strongly suggests that oxyntopeptic cells participate in gastric alkaline secretion at least under cholinergic stimulation.

	INTRODUCTION

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Although it has long been known that gastric fundus mucosa is able to secrete alkali, the mechanism of alkali secretion is still controversial and it is still unclear which of the various cell types that form the epithelium are involved in this process. Most studies propose that the surface epithelial cells (SECs) generate the alkaline fluid (Garner & Flemström, 1978; Flemström & Garner, 1980; Takeuchi et al. 1982) and favour an apical (Flemström & Garner, 1980) or a basolateral (Takeuchi et al. 1982) Cl^--HCO₃^- exchanger as the essential transport step. In a recent study on Rana esculenta stomach, however, we have not been able to confirm the presence of an anion exchanger pathway in the apical cell membrane of frog SECs (Caroppo et al. 1997). On the other hand we have obtained some evidence that in the same frog species during inhibition of H⁺ secretion by cimetidine the oxyntopeptic cells (OCs) may secrete alkali (i.e. HCO₃^-) at least under cholinergic stimulation, and we have found that a basolateral Na⁺-(HCO₃^-)_n cotransporter may be involved in this process.

To clarify further the contribution of the OCs to gastric alkaline secretion we have developed a new approach that allows the pH of the gastric gland fluid of intact frog gastric mucosa to be measured with double-barrelled microelectrodes. With this technique we were able to investigate the secretory processes of gastric glands more directly in the resting state as well as under the influence of secretagogues. The results obtained confirm our view that the OCs are able to secrete HCO₃^- under carbachol stimulation, and suggest that these cells may also contribute to the basal alkaline secretion observed in the resting state.

	METHODS

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The experiments were performed on gastric fundus mucosa of Rana esculenta in accordance with the Italian guidelines for animal experiments. The frogs were kept in an aquarium at room temperature and fed with earthworms until 3-7 days prior to the experiment. After the animals had been killed by decapitation, followed by destruction of the spinal cord and brain, the stomach was isolated and the fundus mucosa was separated from the muscle layer by blunt dissection. The mucosa was then mounted horizontally as a flat sheet between two halves of a top-open Lucite chamber (aperture 0·2 cm²) with the serosal side facing up. The connective tissue layer was further removed with sharpened watch-maker forceps under direct microscopic observation in order to expose some glands for impalement with microelectrodes.

Both the serosal and mucosal surfaces of the tissue were continuously superfused with oxygenated Ringer solution at room temperature, flowing from reservoirs placed approximately 60 cm above the chamber. The reservoirs were weight balanced by means of steel springs in order to attain constant pressure independent of filling state. Serosal and mucosal perfusion rates were 20 and 15 ml min^-1, respectively. They were adjusted by means of a needle valve. Fast fluid exchange in the chamber was achieved within seconds from a shock-free, electronically controlled eight-way manifold.

The transepithelial potential difference (V_t) and the potential response (V_t) to application of transepithelial constant current pulses for determination of transepithelial resistance (R_t) were measured with a high-impedance differential electrometer using two flowing-boundary calomel half-cells filled with 2·7 M KCl solution, which were connected to each bath solution downstream of the tissue. The serosal bath was connected to ground.

OCs at the bottom of gastric glands were impaled by perpendicularly lowering a double-barrelled microelectrode which was mounted on a Leitz micromanipulator onto the surface of an exposed gland under oblique (45 deg) observation through a stereo microscope at × 50 magnification (Wild, Heerbrugg, Switzerland).

After the basolateral cell membrane potential (V_s) and intracellular pH (pH_i) had been recorded the electrode was further advanced until it suddenly entered the gland lumen and recorded the potential difference between gland lumen and serosal bath (V_gl) as well as the pH of the gland fluid (pH_gl). All measurements were performed with a model FD 223 dual-channel electrometer (World Precision Instruments, New Haven, CT, USA) and recorded on a strip-chart recorder (Kipp & Zonen, Delft, The Netherlands).

The control Ringer solution had the following composition (mM): 102·4 Na⁺, 4·0 K⁺, 1·8 Ca²⁺, 0·8 Mg²⁺, 91·4 Cl^-, 17·8 HCO₃^-, 0·8 SO₄^2-, 0·8 H₂PO₄^- and 11 glucose. It was gassed with 5 % CO₂ in O₂ and had a pH of 7·4.

Tissues were kept in the resting state by adding 100 µM cimetidine (SmithKline Beecham, Baranzate, Italy) to the serosal solution, or stimulated with 500 µM histamine, 100 µM carbachol or 50 µM pentagastrin (Sigma Chemical Co.) in the serosal solution.

Microelectrodes

Double-barrelled pH microelectrodes were constructed as described by Kondo et al. (1993). Briefly, two pieces of filament-containing aluminium silicate glass tubing of different diameter (1·5 mm outer diameter (o.d.) and 1·0 mm inner diameter (i.d.) and 1·1 mm o.d. and 0·75 mm i.d.) obtained from Hilgenberg (Malsfeld, Germany) were fixed in parallel and melted together by first twisting and then untwisting them at melting point before they were pulled (tip length, 20 mm) in a PE2 vertical puller (Narishige, Tokyo, Japan). Then, the back of the thin channel was closed and the thick channel was silanized for 180 s in dimethyldichlorosilane vapour (Serva, Heidelberg, Germany). After baking for 3 h at 140°C, the shank of the thick channel was backfilled with a small amount of the H⁺ ligand cocktail containing tridodecylamine (Hydrogen Ionophore II, Cocktail A; Fluka, Buchs, Switzerland) and its shaft was later filled with a buffer solution of pH 7·0 containing (mM): 500 KCl, 64·7 NaH₂PO₄, 85·3 Na₂HPO₄. The reference channel contained 500 mM KCl, and an Ag-AgCl wire was inserted and sealed with wax to prevent leak currents. Average slope and resistance of the electrodes were 55·6 ± 0·4 mV (pH unit)^-1 (n = 43), 292 ± 29 G (selective channel) and 187 ± 19 M (reference channel). All microelectrodes were calibrated in the upper half-chamber before each puncture and if the impalement was successful also after the puncture by flushing the chamber with NaCl solutions containing a mixture of KH₂PO₄ and Na₂HPO₄ to yield pH values between 6·8 and 7·8 (osmolarity, 230 mosmol l^-1).

All chemicals were of reagent grade and purchased from Farmitalia Carlo Erba (Milan, Italy), Sigma Chemical Co. and Fluka Chemie AG (Buchs, Switzerland).

Data analysis and statistics

All measurements are expressed as mean values ± S.E.M. of n individual recordings from which micropuncture data were analysed. The significance of the observations was evaluated by Student's t test for paired or unpaired data as appropriate and P < 0·05 denoted a statistical difference.

	RESULTS

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The gastric gland lumen pH in the resting state

As reported in an earlier study from our laboratory, when puncturing OCs in frog gastric mucosa we have occasionally noticed that the microelectrode entered the gland lumen and measured pH_gl (Debellis et al. 1992). In the meantime we have learned that it is possible systematically to study pH_gl by first impaling an OC and then gradually advancing the electrode until the tip breakes into the gland lumen or even by directly reaching the gland lumen in a single step. A recording of a typical puncture is shown in Fig. 1. In this experiment a cell was first impaled and the microelectrode was then advanced into the gland lumen when the potential recording suddenly changed to nearly the same values as measured transepithelially. To ascertain the proper location of the invisible microelectrode tip in the gland lumen the following three criteria were used.

(1) Near-identity of voltage recorded via the non-selective channel of the microelectrode (V_gl) with V_t. In thirty-five successful punctures obtained under control conditions in the resting state (100 µM cimetidine) V_t averaged -19·4 ± 1·3 mV, while at the same time V_gl averaged -19·2 ± 1·7 mV. In individual punctures the maximal difference between V_t and V_gl was 4 mV. Such differences may reflect small voltage gradients along the gland lumen or tip potential artefacts.

(2) Near-identity of the electrical resistance recorded between microelectrode reference channel and serosal bath macroelectrode (R_t,gl) with R_t (the resistance recorded between serosal and mucosal bath macroelectrodes). After correction for mucosal (in the case of R_t) and serosal (in the case of R_t and R_t,gl) bath solution resistances in the above-mentioned thirty-five punctures R_t and R_t,gl averaged 335 ± 37 and 355 ± 43 cm², respectively. The slightly higher value of R_t,gl may possibly result from puncture-related tissue distortion with partial obliteration of the gland lumen.

(3) Strong acidification of the gland lumen in response to stimulation with histamine. While criteria 1 and 2 would also be fulfilled if the microelectrode tip by chance had advanced all across the tissue into the mucosal perfusate, the acidification response to histamine clearly indicates that the tip was located in the gland lumen, because the mucosal bath was constantly perfused with HCO₃^--Ringer solution of pH_o 7·45. In order to avoid prolonged recovery times in most punctures, histamine was applied only for a short time until pH_gl had fallen off scale (< 6·0), which was considered conclusive enough for the purpose of localization. A more detailed analysis of the histamine effect is given below.

The average pH_gl measured in the presence of cimetidine (100 µM) was 7·60 ± 0·05 (n = 35). This value is significantly higher (P < 0·001) than the pH of both bath solutions (7·45 ± 0·02). The intracellular pH (pH_i) measured in OCs before penetration of the electrode tip into the gland lumen was 7·53 ± 0·06 (n = 18).

On average the stability of the punctures was remarkably good - stable pH_gl values could be recorded for up to 5 h - and the overall success rate (40 %) was similar to that achieved with OC impalements in previous studies.

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Figure 1. Micropuncture of an oxyntopeptic cell and of the gastric gland lumen with a double-barrelled pH microelectrode Upper trace (left scale): transepithelial potential difference (Vt) in millivolts (mucosal surface negative). Middle trace (right scale): cell membrane potential (Vs) and gland lumen potential (Vgl) in millivolts. Lower trace (left scale): cell pH (pHi) and pH of gland lumen (pHgl) in pH units. The superimposed voltage pulses indicate response to transepithelial constant current pulses (50 µA cm-2, 1 s duration) used for transepithelial resistance (Rt) measurements. Note that Vgl equals Vt after the microelectrode tip advanced from cell to gland lumen and that the gland lumen precipitously acidifies after changing serosal perfusion from cimetidine (100 µM) to histamine (500 µM) containing solution.

Effect of stimulation with histamine

All glands investigated responded with a strong acidification of the lumen fluid in response to histamine (500 µM). This clearly demonstrates that our gastric mucosa preparation was functionally intact. As shown in Fig. 2 the response usually began after a lag period of 5-10 min with a more or less precipitous fall of pH_gl from 7·6 to values below 6 which was fully reversible after serosal perfusion was switched back from histamine to cimetidine. Figure 3 summarizes the time course of pH_gl from eight experiments in which the measurements were continued until the histamine effect on pH_gl reached a steady state. This was usually achieved within 25 min, and although the final pH values varied considerably (ranging between 5·5 and 2·4) the time course was quite reproducible.

A comparison of Figs 1, 3 and 4 shows that in the lag period pH_gl either remained constant (pH_gl = 0·00 ± 0·01, n = 11), increased (pH_gl = 0·14 ± 0·03, n = 12; P < 0·001) or decreased (pH_gl = -0·10 ± 0·06, n = 3) transiently. The physiological significance of these observations is difficult to assess since no correlation of the response type with any other recorded parameter could be detected. However, technical artifacts (e.g. from insufficient CO₂ equilibration or instability of recording) can be excluded.

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Figure 2. Micropuncture of gastric gland lumen The reversible effect of stimulation with histamine (500 µM) was followed until pHgl reached a stable value below pH 5. Details as in Fig. 1.

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Figure 3. Time course of the gland fluid pH change in response to stimulation with histamine (500 µM) Data are expressed as means ± S.E.M. of 8 individual recordings in 8 mucosae.

Effect of cholinergic stimulation

The experiment reported in Fig. 4 shows that stimulation with 100 µM carbachol in the presence of cimetidine rapidly and significantly alkalinized the gland lumen while, after removal of carbachol and cimetidine, histamine acidified as usual. In twenty-four glands the alkalinization in response to cholinergic stimulation averaged 0·10 ± 0·01 pH units (P < 0·001). The response to carbachol was always transient. After a maximum had been reached within 5 min pH_gl gradually reclined towards its control value; however, it never reached acidic values even if the exposure to carbachol was prolonged to more than 30 min.

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Figure 4. Effect of stimulation with carbachol (100 µM in the presence of 100 µM cimetidine) followed by the effect of stimulation with histamine (500 µM) on pHgl in the same gland Note that carbachol promptly and reversibly alkalinized while histamine acidified the gland lumen. Details as in Fig. 1.

Effect of stimulation with pentagastrin

A similar response to that with carbachol was observed after stimulation with 50 µM pentagastrin in the presence of cimetidine (Fig. 5). In six glands an initial transient alkalinization of 0·09 ± 0·02 pH units (P < 0·05) was obtained which was followed by a slow decline towards control. Again, as in the case of carbachol, even prolonged exposure to pentagastrin (up to 35 min) did not cause any significant acidification of the gland lumen.

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Figure 5. Effect of stimulation with pentagastrin (50 µM) Note the initial gland fluid alkalinization followed by a slow decline towards control values. Details as in Fig. 1.

	DISCUSSION

Top Abstract Introduction Methods Results Discussion References

In the present publication we report the first successful experiments in which microelectrodes were inserted into the lumen of gastric glands to measure the pH of the gland fluid (pH_gl). In conjunction with cell pH measurements on oxyntic cells this approach allows the direction and time course of pH changes in both locations to be compared so that the secretory function of the OCs can be analysed more directly than was possible in the past. An alternative approach to study glandular acid/base secretion would have been to use the isolated gland perfusion technique. This, however, is exceedingly difficult to apply and thus far only one laboratory has been able to claim success with it (Waisbren et al. 1994). The present approach, on the other hand, has the advantage that the experiments are performed on intact gastric mucosa. As a result the functional relationship between the different cell types that are involved in gastric stimulation is preserved, and the events in individual glands can be correlated with overall transepithelial fluxes measured in the same preparation. Since the present technique also allows the glandular fluid composition to be altered, i.e. by diffusional exchange with the perfusate in the mucosal surface compartment - albeit with a delay of 3 to 5 min (Debellis et al. 1997) - we feel that it offers interesting new perspectives for further investigation of gastric epithelial function.

Glandular bicarbonate secretion

A surprising new finding of the present experiments is that pH_gl during inhibition of acid secretion with cimetidine was significantly more alkaline than mucosal and serosal bath solutions. This can either mean that the glandular secretion contained more bicarbonate than the bath solutions (on average 25·1 mM rather than 17·8 mM), or that CO₂ partial pressure (P_CO2) was lower in the gland lumen than in the surrounding tissue, or a combination of both. The second possibility is intriguing in view of the recent report that gastric mucosal cell membranes are practically impermeable to CO₂ (Waisbren et al. 1994 ; Boron et al. 1994). However, we favour the first possibility, because we have observed that the apical cell membrane of frog gastric mucosa cells is indeed permeable to CO₂ (Caroppo et al. 1997; Curci et al. 1997). We conclude therefore that gland lumen P_CO2 is similar to bath solution P_CO2, and that frog gastric glands, in the presence of cimetidine, secrete some HCO₃^--rich fluid. This fluid should drain into the stomach lumen and may thus contribute to resting state alkaline secretion which we have measured in the same preparation under the same experimental conditions previously (Curci et al. 1994).

Which cells do secrete bicarbonate?

Frog gastric glands consist essentially of two cell types: mucous neck cells (MNCs) which form the upper part, and OCs which form the bottom part of the gland. Since MNCs resemble the surface epithelial cells, which are generally thought to secrete both mucus and bicarbonate, one may speculate that MNCs secrete HCO₃^- which then diffuses into the bottom part of the glands where our measurements have been made. On the other hand HCO₃^- might also be secreted by OCs. Our experiments, in fact, point to OCs as the site of HCO₃^- secretion. This follows from the observation that pH_gl alkalinized transiently after application of carbachol (in the presence of cimetidine), while under the same experimental conditions the OC acidified with exactly the same (but mirror image-like) time course (see Fig. 2 of Debellis et al. 1994). This most probably indicates efflux of base from OCs into the gland lumen and hence secretion of HCO₃^-. Whether the MNCs contribute to HCO₃^- secretion in response to carbachol cannot be decided.

Mechanism of HCO₃^- secretion from OCs

Previously when studying transepithelial HCO₃^- secretion in cimetidine-treated frog gastric mucosa in response to carbachol, we have noticed a transient increase in alkaline secretion rate which lasted for up to 10 min and thus coincided exactly with the glandular alkalinization observed in the present experiments. Unless the time course of HCO₃^- secretion from OCs and SECs was by chance identical, this observation would indicate that at least some of the secreted HCO₃^- must have flowed into the stomach lumen, and this could explain why the acidification of the OCs which we have observed previously (Debellis et al. 1994) was rather large, i.e. virtually as large as the currently observed alkalinization of the gland fluid.

In the transepithelial flux studies we had also noticed that the carbachol-induced HCO₃^- secretion was associated with an increase in lumen-negative short circuit current, a fall in transepithelial resistance, and a fall in (apical over basal) voltage divider ratio of the OCs (Debellis et al. 1994). This pointed to an electrogenic model of HCO₃^- secretion such as that elicited by opening of an apical anion conductance. This anion conductance, which seems to transfer Cl^- as well as notable amounts of HCO₃^- (the change of alkaline secretion rate corresponded to approximately one-third of the concomitant change in short circuit current), may be activated by a rise in intracellular Ca²⁺ concentration such as observed after cholinergic stimulation in parietal cells (Chew et al. 1992 ; Delvalle et al. 1992).

Since our observations with pentagastrin resemble very closely those with cholinergic stimulation, we may conclude that pentagastrin also raised intracellular Ca²⁺ and activated the same apical anion conductance. Whether or not this Cl^- conductance is also activated in the histamine experiments in which the gland fluid transiently alkalinized is not known at present.

In conclusion we have presented evidence which indicates that during inhibition of H⁺ secretion by cimetidine the OCs in the gland of frog gastric fundus mucosa do secrete HCO₃^-. This secretory potency of the OC might be utilized in the resting stomach to clear the gland lumen from stagnant HCl, and thus protect the glandular cells from acid damage which is particularly important in view of the absence of a protective mucus layer.

	REFERENCES

Top Abstract Introduction Methods Results Discussion References

Boron, W. F., Waisbren, S. J., Modlin, I. M. & Geibel, J. P. (1994). Unique permeability barrier of the apical surface of parietal and chief cells in isolated perfused gastric glands. Journal of Experimental Biology 196, 347-360	[Abstract]
Caroppo, R., Debellis, L., Valenti, G., Alper, S., Frömter, E. & Curci, S. (1997). Is resting state HCO3- secretion in frog gastric fundus mucosa mediated by apical Cl--HCO3- exchange? The Journal of Physiology 499, 763-771	[Abstract]
Chew, C. S., Nakamura, K. & Ljungström, M. (1992). Calcium signalling mechanisms in the gastric parietal cell. Yale Journal of Biology and Medicine 65, 561-576	[Medline]
Curci, S., Caroppo, R. & Debellis, L. (1997). Microelectrode measurements of gland lumen pH and oxyntic cell pH in frog gastric mucosa demonstrate apical cell membrane permeability to CO2. XXXIII Congress of the International Union of Physiological Sciences P009.12.
Curci, S., Debellis, L., Caroppo, R. & Frömter, E. (1994). Model of bicarbonate secretion by resting frog stomach fundus mucosa. I. Transepithelial measurements. Pflügers Archiv 428, 648-654	[Medline]
Debellis, L., Caroppo, R. & Curci, S. (1997). Direct pH microelectrode measurement of acid and alkaline secretion in glands of frog gastric mucosa. FASEB Journal 11, A296 (abstract).
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Kondo, Y., Igarashi, Y., Abe, K. & Tada, K. (1993). New double-barrelled, ion-sensitive microelectrodes for measuring intracellular Cl- activities in rabbit renal collecting ducts. Tohoku Journal of Experimental Medicine 169, 51-58	[Medline]
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Acknowledgements

The authors wish to thank Dr D. Renna and Mrs L. Sgaramella for their assistance in some of the experiments and Dr M. Trotta for helpful suggestions. This work was supported by Ministero dell' Universitá e della Ricerca Scientifica e Tecnologica (MURST; 40 %) and Consiglio Nazionale delle Ricerche (CNR; grant 96.03050.04).

Corresponding author

L. Debellis: Dipartimento di Fisiologia Generale e Ambientale, Università di Bari, Via Amendola 165/A, 70126 Bari, Italy.

Email: debellis{at}biologia.uniba.it

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This Article Abstract Full Text (PDF) Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Debellis, L. Articles by Curci, S. Search for Related Content PubMed PubMed Citation Articles by Debellis, L. Articles by Curci, S.